Nitazoxanide for chronic hepatitis C (Review) Nikolova K, Gluud C, Grevstad B, Jakobsen JC

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 4 http://www.thecochranelibrary.com

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS

HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 1 All-cause mortality. . . . Analysis 1.2. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 2 Chronic hepatitis C-related mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 4 Adverse events. . . . . . Analysis 1.6. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 6 Failure of sustained virological response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.7. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 7 Failure of virological end-oftreatment response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.8. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 8 Participants without improvement in ALT and/or AST serum levels. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.1. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 1 All-cause mortality. Analysis 2.2. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 2 Chronic hepatitis Crelated mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.4. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 4 Adverse events. . Analysis 2.6. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 6 Failure of sustained virological response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.7. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 7 Failure of virological end-of-treatment response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.8. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 8 Participants without improvement in ALT and/or AST serum levels. . . . . . . . . . . . . . . . . . . . . . . Analysis 3.1. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 1 All-cause mortality. . . . Analysis 3.2. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 2 Chronic hepatitis C-related mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.4. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 4 Adverse events. . . . . . Analysis 3.6. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 6 Failure of sustained virological response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 3.7. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 7 Failure of virological end-oftreatment response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Analysis 3.8. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 8 Participants without improvement in ALT and/or AST serum levels. . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 4.1. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 1 All-cause mortality. . . . . . Analysis 4.2. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 2 Chronic hepatitis C-related mortality. Analysis 4.4. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 4 Adverse events. . . . . . . . Analysis 4.6. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 6 Failure of sustained virological response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 4.7. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 7 Failure of virological end-of-treatment response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 4.8. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 8 Participants without improvement in ALT and/or AST serum levels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 5.1. Comparison 5 Best-worst case scenario analysis, Outcome 1 Failure of sustained virological response. . Analysis 6.1. Comparison 6 Worst-best case scenario analysis, Outcome 1 Failure of sustained virological response. . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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[Intervention Review]

Nitazoxanide for chronic hepatitis C Kristiana Nikolova1 , Christian Gluud1 , Berit Grevstad2 , Janus C Jakobsen1 1 The Cochrane Hepato-Biliary

Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 2 Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Contact address: Kristiana Nikolova, The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, DK-2100, Denmark. [email protected]. Editorial group: Cochrane Hepato-Biliary Group. Publication status and date: Edited (no change to conclusions), published in Issue 4, 2014. Review content assessed as up-to-date: 8 March 2014. Citation: Nikolova K, Gluud C, Grevstad B, Jakobsen JC. Nitazoxanide for chronic hepatitis C. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD009182. DOI: 10.1002/14651858.CD009182.pub2. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Hepatitis C infection is a disease of the liver caused by the hepatitis C virus. The estimated number of chronically infected people with hepatitis C virus worldwide is about 150 million people. Every year, another three to four million people acquire the infection. Chronic hepatitis C is a leading cause of liver-related mortality and morbidity. It is estimated that around 5% to 20% of people with the infection will develop liver cirrhosis, which increases the risk of hepatocellular carcinoma and liver failure. Until 2011, the combination therapy of pegylated interferon-alpha (peginterferon) and ribavirin was the approved standard treatment for chronic hepatitis C. In 2011, first-generation direct-acting antivirals have been licensed, for use in combination with peginterferon and ribavirin for treating hepatitis C virus genotype 1 infection. Nitazoxanide is another antiviral drug with broad antiviral activity and may have potential as an effective alternative, or an addition to standard treatment for the treatment of the hepatitis C virus. Objectives To assess the benefits and harms of nitazoxanide in people with chronic hepatitis C virus infection. Search methods We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (last searched April 2013), The Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 3), MEDLINE (Ovid SP, 1948 to April 2013), EMBASE (Ovid SP, 1980 to April 2013), LILACS (1983 to April 2013), and Science Citation Index EXPANDED (ISI Web of Knowledge, 1900 to April 2013), using the search strategies and the expected time spans. We also scanned reference lists of identified studies. We also searched ClinicalTrials.gov and the World Health Organization’s International Clinical Trials Registry Platform search portal for registered trials, either completed or ongoing (April 2013). Selection criteria We included randomised clinical trials that examined the effects of nitazoxanide versus placebo, no intervention, or any other intervention in patients with chronic hepatitis C. We considered any co-intervention, including standard treatment, if delivered to all intervention groups of the randomised trial concerned. Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Data collection and analysis Two review authors extracted data independently. We assessed the risk of systematic errors (’bias’) by evaluation of bias risk domains. We used Review Manager 5.2 for the statistical analyses of dichotomous outcome data with risk ratio (RR) and of continuous outcome data with mean difference (MD). For meta-analyses, we used a fixed-effect model and a random-effects model, along with an assessment of heterogeneity. We assessed risk of random errors (’play of chance’) using trial sequential analysis. We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to present review results in ’Summary of findings’ tables. Main results We included seven randomised clinical trials with a total of 538 participants with chronic hepatitis C. Participants were 18 years of age or older, all diagnosed with chronic hepatitis C genotype 1 or 4. All of the trials had a high risk of bias. All of the trials compared nitazoxanide with placebo or no intervention, and six out of seven of the trials included different antiviral co-interventions administered equally to all intervention groups. Only one trial, comparing nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin, provided information that there were no deaths due to any cause or due to chronic hepatitis C (100 participants, very low quality evidence). The relative effect of nitazoxanide versus placebo or no intervention on adverse events was uncertain (37 out of 179 (21%) versus 30 out of 152 (20%); RR 1.10; 95% CI 0.71 to 1.71; I2 = 65%; four trials; very low quality evidence). Nitazoxanide decreased the risk of failure to achieve sustained virological response when compared with placebo or no intervention (159 out of 290 (55%) versus 133 out of 208 (64%); RR 0.85; 95% CI 0.75 to 0.97; I2 = 0%; seven trials; low quality evidence) and also the risk of failure to achieve virological end-of-treatment response (125 out of 290 (43%) versus 110 out of 208 (53%); RR 0.81; 95% CI 0.69 to 0.96; I2 = 46%; seven trials; low quality evidence). Trial sequential analysis supported the metaanalysis result for sustained virological response, but not the meta-analysis for virological end-of-treatment response. Meta-analysis also showed that nitazoxanide did not decrease the number of participants who showed no improvement in alanine aminotransferase and aspartate aminotransferase serum levels when compared with placebo or no intervention (52 out of 97 (54%) versus 47 out of 95 (49%); RR 1.09; 95% CI 0.84 to 1.42; I2 = 0%; three trials; very low quality evidence). None of the included trials assessed the effects of nitazoxanide on morbidity or on quality of life. Histological changes were only reported on a subset of three participants out of thirteen participants included in a long term-follow-up trial. Authors’ conclusions We found very low quality, or no, evidence on nitazoxanide for clinically- or patient-relevant outcomes, such as all-cause mortality, chronic hepatitis C-related mortality, morbidity, and adverse events in participants with chronic hepatitis C genotype 1 or 4 infection. Our results of no improvement in alanine aminotransferase and aspartate aminotransferase serum levels were also uncertain. No conclusion could be drawn about liver histology because of a lack of data. Our results indicate that nitazoxanide might have an effect on sustained virological response and virological end-of-treatment response. However, both results could be influenced by systematic errors because all the trials included in the review had a high risk of bias. Furthermore, only the beneficial effect on number of participants achieving sustained virological response was supported when we applied trial sequential analysis. The results on virological end-of-treatment response might, therefore, be caused by a random error. We totally lack information on the effects of nitazoxanide in participants with chronic hepatitis C genotypes 2 or 3 infection. More randomised clinical trials with a low risk of bias are needed to assess the effects of nitazoxanide for chronic hepatitis C.

PLAIN LANGUAGE SUMMARY Nitazoxanide for chronic hepatitis C What is chronic hepatitis C, and why is it a problem? Hepatitis C is a virus that infects people’s liver. When an infection goes on for a long time, it is said to be ‘chronic’. Hepatitis C is mainly transmitted between people through contact with infected blood (mostly through illegal drug use that involves needle-sharing, but possibly from mother to baby in the womb, or through having sex with an infected person). Usually people infected with hepatitis C have no symptoms in the early stages of the infection; however, about 60% to 70% of them go on to develop severe liver-related problems which eventually lead to death. There are about 150 million people in the world with chronic hepatitis C infection and more than 350,000 of them die from this liver infection each year. Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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What are the treatments for chronic hepatitis C infection? The current standard treatment for chronic hepatitis C is a combination of two medicines, pegylated interferon-alpha (interferon) and ribavirin. Interferon is not widely available globally and can have some adverse (harmful) effects. It works better on some types (genotypes) of the hepatitis C virus than others. Nitazoxanide belongs to a class of antiviral medicines with activity against a broad range of viruses. It is the first medicine in this class to be investigated for its effect on chronic hepatitis C infection. The purpose of this review This Cochrane review tried to identify the benefits and harms of treating chronic hepatitis C infection with nitazoxanide. Findings of this review The review authors searched the medical literature up to April 2013, and identified seven relevant medical trials, with a total of 538 participants. The trials were performed in two countries, the USA and Egypt. All the trials had low numbers of participants, and the methods used in them were not of a high quality, which makes potential overestimation of benefits and underestimation of harms more likely. All the trials only included participants with chronic hepatitis C genotype (type) 1 or 4 infection. Outcomes important to people who suffer from this infection include: death from all causes, death from chronic hepatitis C infection, how unwell you feel (morbidity), quality of life, and adverse events caused by the medicines. This review found no information, or very little low quality evidence, about the effects of nitazoxanide on any of these outcomes. Nitazoxanide might have a beneficial effect on virus activity that can be monitored by analysis of blood samples (sustained virological response (SVR) and virological end-of-treatment response (ETR), but this is not certain. Indeed, the review authors could not draw any conclusions about the benefits or harms of nitazoxanide for people with chronic hepatitis C infection. More randomised clinical trials of high methodological quality are needed to establish the effects of nitazoxanide in people with chronic hepatitis C.

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Nitazoxanide compared with placebo or no intervention for chronic hepatitis C (Overall ’Summary of findings’ table) Patient or population: people with chronic hepatitis C Settings: primary care in Egypt and USA Intervention: nitazoxanide Comparison: placebo or no intervention Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Relative effect (95% CI)

No of participants (studies)

Quality of the evidence (GRADE)

Comments

Corresponding risk

Placebo or no interven- Nitazoxanide tion No deaths

No deaths

Not estimable

100 (1)



1,2,4,5 very low

-

Chronic hepatitis C-re- No deaths lated mortality

No deaths

Not estimable

100 (1)



1,2,4,5 very low

-

Morbidity

No reports on participants developing morbidity in any trials making this comparison

No reports on partici- Not estimable pants developing morbidity in any trials making this comparison

0

-

-

Adverse events

197 per 1000

217 per 1000

RR 1.10 (0.71 to 1.71)

383 (4)



1,2,3,4 very low

-

Failure of sustained vi- 639 per 1000 rological response

544 per 1000

RR 0.85 (0.75 to 0.97)

498 (7)

⊕⊕

1,2,4 low

-

Failure of virologi- 529 per 1000 cal end-of-treatment response

428 per 1000

RR 0.81 (0.69 to 0.96)

498 (7)

⊕⊕

1,2,4 low

-

All-cause mortality

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Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Participants without im- 495 per 1000 provement in ALT and/or AST serum levels

539 per 1000

RR 1.09 (0.84 to 1.42)

271 (3)



1,2,3,4 very low

-

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; ALT: alanine aminotransferase; AST: aspartate aminotransferase GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: we are very uncertain about the estimate 1 The

trial(s) was (were) of high risk of bias number of events in the intervention and control group was less than 300 3 The confidence intervals overlapped 1, and either 0.75 or 1.25, or both 4 The assumed risk is the control group risk 5 Only one trial reported on mortality 2 The

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BACKGROUND

Description of the condition Hepatitis C is a disease of the liver caused by the hepatitis C virus. Hepatitis C virus is an enveloped RNA virus that constitutes the genus Hepacivirus within the Flaviviridae family (van Regenmortel 2000; Penin 2004). The hepatitis C virus is classified into 11 major virus genotypes, with six of the genotypes occurring more frequently (Foster 2009). The hepatitis C virus genotypes differ from each other by up to 30% in the nucleotide sequence and there is a large and growing number of subtypes (Rosenberg 2001). Furthermore, hepatitis C virus genotypes differ according to geographic region (Davis 1999). Genotype 1, followed by genotypes 2 and 3 are most common in the USA, while genotype 4 is more common in Africa and the Middle East, including Egypt. However, in Europe, as a result of an increase in the number of people who inject drugs, there has been an increase in infections of hepatitis C virus genotype 4. Genotypes 5 and 6 are common in South Africa and Southeast Africa (McKenzie 2011). Although a genotype does not predict the clinical outcome of the infection, it does predict the likelihood of viral response to treatment, and this may guide the duration of treatment (Manns 2001; Fried 2002; Hadziyannis 2004). The estimated number of people around the world who are chronically infected with hepatitis C virus is about 150 million (WHO 2011). Every year, another three to four million people acquire the infection (WHO 2010). Chronic hepatitis C virus infection is diagnosed when hepatitis C virus antibodies are present in the blood, and serum aminotransferase levels are high and remain elevated for more than six months, as spontaneous viral clearance by the body is very rare after four to six months of infection (McKenzie 2011). Polymerase chain reaction (PCR) testing for hepatitis C virus RNA is used to establish the presence of chronic hepatitis C in the blood. The PCR will detect the presence of the viral genome in serum in almost all people with chronic hepatitis C infection (Ghany 2009). Diagnosis of chronic hepatitis C may be difficult in patients who have a solidorgan transplant, are on dialysis, are taking corticosteroids, or have agammaglobulinaemia (genetic condition that affects the body’s ability to fight infection), and this is why it is recommended that RNA testing is used in these patients. RNA testing should also be used for patients with anti-hepatitis C virus who have liver disease caused injury to the liver, i.e., due to alcohol, iron overload, or autoimmunity (Ghany 2009). A study performed by Amon et al in the USA has shown that the prevalence of hepatitis C virus in injecting drug users is very high (Amon 2008). Amon et al found that one in three people who abuse drugs become infected with hepatitis C virus within five years (Amon 2008). About 85% of infected people become chronic carriers of the hepatitis C virus (Seeff 2002). These people are relatively young (McKenzie 2011). Carriers of the virus are often unaware that they

are infected, as many remain asymptomatic. In many patients, hepatitis C infection is only recognised when it reaches a chronic symptomatic phase (Hodgson 2003). The interval between infection with the virus and the symptoms of cirrhosis may exceed 30 years in people with favourable risk factors. However, 20% of the chronic hepatitis C virus carriers may develop cirrhosis within 20 years, or less, of being infected, and this happens most often to people who abuse alcohol or are co-infected with human immunodeficiency virus (HIV) type 1 or hepatitis B virus (Lauer 2001). Between 1% to 4% of patients with advanced fibrosis or cirrhosis are at risk of developing hepatocellular carcinoma each year (Lauer 2001). Chronic hepatitis C virus infection is a common indication for liver transplantation (OPTN 2005). There are some diseases that may be confused with chronic hepatitis C; these include alcoholism, hepatitis B, hepatitis D, nonalcoholic steatohepatitis, and others (Ghany 2009). Each year, around 350,000 people are likely to die from hepatitis C-related liver diseases worldwide (WHO 2011).

Description of the intervention Thiazolides are a class of antiviral drugs with activity against bacteria and a broad range of DNA and RNA viruses (Rossignol 2001). Nitazoxanide is a thiazolide with activity against anaerobic bacteria and also protozoa (Pankuch 2006). Nitazoxanide was originally developed for the treatment of infectious diarrhoea caused by Cryptosporidium parvum andGiardia lamblia (Pankuch 2006). The antiviral activity of nitazoxanide was discovered by chance in patients with acquired immunodeficiency syndrome (AIDS) who were treated for cryptosporidial diarrhoea and had co-infection with the hepatitis B or hepatitis C virus (Rossignol 2001). Nitazoxanide is the first thiazolide undergoing clinical development for treatment of chronic hepatitis C, and new generation thiazolides are proposed for treating chronic hepatitis B and C, enteric viruses, herpes viruses, and influenza (Rossignol 2009b). Currently, nitazoxanide is licensed as Alinia® (Romark Laboratories, USA) in the USA, in the form of tablets and oral suspension, and it is administered for diarrhoea and enteritis caused by Cryptosporidium parvum and Giardia lamblia to adults and children from 12 months of age. Nitazoxanide may provide an alternative, more effective treatment option than the standard treatment for chronic hepatitis C (Rossignol 2009b).

How the intervention might work When treating chronic hepatitis C virus infection, the goal is to prevent complications and death caused by the infection (Ghany 2009). Frequently, the sustained virological response is the outcome used to monitor hepatitis C virus treatment (Strader 2004). Sustained virological response is defined as the “absence of hepatitis C virus RNA from serum by a sensitive PCR-based assay 24 weeks

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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following discontinuation of therapy” (Ghany 2009). If hepatitis C virus cannot be detected at the end of a 24-week or 48-week course of therapy, it is referred to as an end-of-treatment response. Virological end-of-treatment response and sustained virological response are used as a putative surrogate outcomes for clinicallyrelevant outcome measures such as mortality, morbidity, quality of life, and adverse reactions, but they have not been validated in this role (Gluud 2007; Brok 2009; Brok 2010; Koretz 2013). Existing interventions, such as ribavirin alone or in combination with interferon, are disappointing as the proportion of patients with sustained virological response is small, and the percentage of adverse events such as influenza-like symptoms, depression, neutropenia, thrombocytopenia are high (Strader 2004; Brok 2009; Brok 2010). A combination of weekly subcutaneous injections of long-acting pegylated interferon-alpha and oral ribavirin to previously untreated patients has shown an overall sustained virological response of 56% (Strader 2004; Brok 2010). This compares with interferon monotherapy which has a sustained virological response in less than 20% of chronic hepatitis C patients (Myers 2002), and with the combination of interferon plus ribavirin, which has a sustained virological response in about 40% of chronic hepatitis C patients (Brok 2010). As more and more treatments for chronic hepatitis C become available, the possibility of moving away from the current standard treatment and its limitations becomes increasingly likely (Aman 2012). In 2011, two first-generation direct-acting antivirals (DAAs), telaprevir and boceprevir, were licensed for use in treatment of hepatitis C virus genotype 1 infection, and in 2013 two new drugs, sofosbuvir (Sovaldi®) and simeprevir (Olysio®) were approved as combination therapies with ribavirin (Kowdley 2013; Lawitz 2013). Studies have indicated that sofosbuvir and simeprevir have effects on sustained virological responses (FDA 2014). Although these DAAs might achieve high sustained virological response, all of the trials conducted had sustained virological response as their primary outcome, and very few of them assessed clinically relevant outcomes, such as mortality, morbidity, or quality of life. Nitazoxanide may have potential among the many antiviral drugs that have become available (Stockis 2002; Korba 2008a; Korba 2008b). Stockis et al studied healthy participants and found that a 500 mg tablet of nitazoxanide, administered orally with food, is partially absorbed from the gastrointestinal tract and rapidly hydrolyzed in the plasma, forming the active circulating metabolite tizoxanide (desacetyl-nitazoxanide) (Stockis 2002). Nitazoxanide is not detected in the plasma. Both nitazoxanide and tizoxanide are believed to inhibit replication of the hepatitis C virus (Korba 2008a). The maximum serum concentrations of tizoxanide recorded by Stockis et al reached approximately 10 g/mL (37 M). Tizoxanide is glucurono-conjugated in the liver and excreted in urine and bile (Stockis 2002). Korba et al suggested that the inhibitory effect of nitazoxanide on viral replication of hepatitis C may be due to cellular processes required for virus protein produc-

tion and assembly (Korba 2008a). Korba et al found that nitazoxanide induced changes in the intracellular environment that may lead to a change in the effect of subsequent treatment with other anti-hepatitis C virus drugs, particularly interferon alpha (Korba 2008b). The genotype of the hepatitis C virus is of importance as it might predict viral response to treatment. The new approved antiviral drugs all target genotype 1 which is the most prevalent genotype worldwide. So far, only sofosbuvir shows activity against genotypes 1, 2, 3, and 4 and does not work in all patients. Therefore, there is a need to identify new antivirals that are effective against other genotypes.

Why it is important to do this review Several randomised clinical trials investigating the efficacy and adverse events of nitazoxanide for the treatment of chronic hepatitis C have been finalised and published. However, a systematic review assessing the benefits and harms of nitazoxanide in the treatment of patients with chronic hepatitis C has not been conducted. We have not been able to identify any meta-analyses on the benefits and harms of nitazoxanide, administered alone or in combination with other drugs, for chronic hepatitis C virus infection. The results of our Cochrane systematic review may have an impact on treatment of people with chronic hepatitis C virus infection, healthcare costs, and may also be used to decide future research topics.

OBJECTIVES To assess the benefits and harms of nitazoxanide in people with chronic hepatitis C virus infection.

METHODS

Criteria for considering studies for this review

Types of studies We included randomised clinical trials that examined the effects of nitazoxanide versus placebo, no intervention, or any other intervention for chronic hepatitis C virus infection. Trials were included irrespective of language of publication, publication type, or publication status. We also reported the information on harms from quasi-randomised studies or observational studies retrieved by our literature search for randomised clinical trials.

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Types of participants We included trial participants diagnosed with chronic hepatitis C according to any of the following criteria: 1. anti-hepatitis C virus antibodies present in the serum and serum aminotransferase activity elevated for more than six months (Ghany 2009); 2. evidence of inflammation due to chronic hepatitis C on liver biopsy (Strader 2004; Ghany 2009); 3. suspicion of hepatitis C virus confirmed by quantitative analysis of hepatitis C virus RNA through PCR or transcriptionmediated amplification testing (Ghany 2009; NIH 2010); or 4. by any other method used for diagnosis of people with chronic hepatitis C. Participants included in the trials were classified as treatment-naive (not previously treated with antiviral drugs), relapsers (those with a transient response to previous antiviral treatment), or non-responders (those who did not respond to previous antiviral treatment). We also included trial participants with a concomitant or preceding disease, such as HIV, solid organ transplant recipients, those receiving haemodialysis, or with another form of liver disease that might be responsible for the liver problem, for example hepatitis B infection, alcoholism, or iron overload.

or any medical event that might have jeopardised the patient, or required intervention to prevent it (ICH-GCP 1997). All other adverse events (that is, any medical occurrence not necessarily having a causal relationship with the treatment but that did, however, cause a dose reduction or discontinuation of the treatment) were considered as being non-serious. Secondary outcomes

1. Quality of life (any valid continuous outcome scale used by the trialists). 2. Failure of virological response: number of participants without sustained virological response: number of participants with detectable hepatitis C virus RNA (i.e., above lower limit of detection) in the serum by a sensitive PCR-based essay or by a transcription-mediated amplification testing 24 weeks after end of treatment, or at end of treatment (lack of an early virological response can be used to predict non-responders and a lack of sustained virological response (Fried 2011)). 3. Number of participants without improvement in alanine aminotransferase and aspartate aminotransferase serum levels, (aspartate aminotransferase more than 40 IU/L) from baseline to weeks 8, 16, end of treatment, and end of maximum follow-up. 4. Number of participants without histological improvement.

Types of interventions We included all randomised clinical trials examining the effects of nitazoxanide for chronic hepatitis C comparing: 1. nitazoxanide versus placebo or no intervention; 2. nitazoxanide in combination with any other intervention for chronic hepatitis C versus placebo or no intervention; 3. nitazoxanide versus any other active intervention. All co-interventions, including any form of standard treatment, were allowed if administered equally to all intervention groups. Types of outcome measures

Primary outcomes

1. All-cause mortality. 2. Chronic hepatitis C-related mortality (as defined by the trialists). 3. Morbidity: number of participants who developed cirrhosis, ascites, variceal bleeding, hepatic encephalopathy, or hepatocellular carcinoma. 4. Adverse events: serious adverse events were defined according to the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice as any untoward medical occurrence that at any dose resulted in death, was lifethreatening, required inpatient hospitalisation or prolongation of existing hospitalisation, or resulted in persistent or significant disability or incapacity, or was a congenital anomaly/birth defect,

Search methods for identification of studies

Electronic searches We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (last searched April 2013) (Gluud 2013), The Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 3), MEDLINE (Ovid SP, 1948 to April 2013), EMBASE (Ovid SP, 1980 to April 2013) , LILACS (1983 to April 2013), and Science Citation Index EXPANDED (ISI Web of Knowledge, 1900 to April 2013) (Royle 2003), using the search strategies and time spans presented in Appendix 1. We also searched Clinical trials.gov at www.clinicaltrials.gov and the World Health Organisation’s International Clinical Trials Registry Platform Search portal (ICTRP) (WHO) at apps.who.int/ trialsearch/Default.aspx for registered trials, either completed or ongoing. Searching other resources We searched bibliographic references, conference abstracts, journals, and grey literature for further trials. We searched for publications from 1980 onward, as testing of nitazoxanide started after 1980 (Reddy 2012). Furthermore, we reviewed the reference lists and contacted the principal authors of identified trials. We also contacted pharmaceutical companies that produce nitazoxanide

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to inquire about information and request data relating to unpublished randomised clinical trials.

Data collection and analysis We performed the systematic review and meta-analyses following the recommendations of The Cochrane Collaboration (Higgins 2011), and The Cochrane Hepato-Biliary Group (Gluud 2013). In the case of cross-over trials, we had planned to include data only from the first period (Higgins 2011). The analyses were performed using Review Manager 5.2 (RevMan 2012), and TSA version 0.9 (Wetterslev 2008; CTU 2011; Thorlund 2011). We calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) using fixed-effect and random-effects models of metaanalyses based on intention-to-treat or available data analysis. We reported results from both meta-analysis models, discussing any discrepancies.

Selection of studies Two of the authors, KN and BG, independently identified the trials for inclusion in accordance with the inclusion criteria of the review protocol and listed the excluded studies with the reasons for their exclusion. KN and BG resolved disagreements through discussions. CG was the arbitrator in case of disagreements.

Data extraction and management KN and BG used a standardised data collection form to extract data regarding source, eligibility, methods, participants, genotype, disease, interventions, outcomes, and results of trials. Data were collected from either the published reports or were obtained directly from authors of the publications by email. KN and BG extracted all data independently. KN and BG resolved disagreements through discussions. CG was the arbitrator in case of disagreements.

Assessment of risk of bias in included studies Methodological quality, hence risk of bias, was defined as confidence that the design and report of the randomised clinical trials restrict bias in the comparison of the intervention (Moher 1998). We assessed the following risk of bias domains using the revised Cochrane Collaboration’s ’Risk of bias’ tool provided in theCochrane Handbook for Systematic Reviews of Interventions as well as in the Cochrane Hepato-Biliary Group Module. The domains are based on empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovi 2012a; Savovi 2012b).

Allocation sequence generation

• Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if performed by an independent person not otherwise involved in the trial. • Uncertain risk of bias: the method of sequence generation was not specified. • High risk of bias: the sequence generation method was not random. Allocation concealment

• Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (for example, if the allocation sequence was hidden in sequentiallynumbered, opaque, and sealed envelopes). • Uncertain risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment. • High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants. Blinding of participants, personnel, and outcome assessors

• Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding. • Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results. • High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes were likely to be influenced by lack of blinding. Incomplete outcome data

• Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, were employed to handle missing data. • Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias in the results. • High risk of bias: the results were likely to be biased due to missing data. Selective outcome reporting

• Low risk of bias: all outcomes were pre-defined and reported, or all clinically relevant and reasonably expected

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outcomes were reported. The trial was registered either on the www.clinicaltrials.gov web site or a similar register, or there was a published protocol. • Uncertain risk of bias: it was unclear whether all predefined and clinically relevant and reasonably expected outcomes were reported. • High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.

hepatitis C-related mortality, and morbidity (Hollis 1999; Gluud 2013): 1. ’Best-worst’ case scenario analyses: participants with missing outcome data were considered to be successes in the experimental group and failures in the control group. The denominator included all the participants in the trial. 2. ’Worst-best’ case scenario analyses: participants with missing outcome data were considered to be failures in the experimental group and successes in the control group. The denominator included all the participants in the trial.

Other bias

• Low risk of bias: the trial appeared to be free of other components that could put it at risk of bias. • Uncertain risk of bias: it was uncertain whether the trial was free of other components that could put it at risk of bias. • High risk of bias: there were other factors in the trial that could put it at risk of bias, e.g., for-profit involvement, authors have conducted trials on the same topic, etc. We assessed trials as being at low risk of bias if they were judged to have a low risk of bias in all the above domains. We assessed a trial as being at high risk of bias if it was judged to have an uncertain or high risk of bias in any of the above domains. KN and BG resolved disagreements through discussions. CG was the arbitrator in case of disagreements. Measures of treatment effect For dichotomous outcomes we calculated the risk ratio (RR), and for continuous outcomes we used the mean difference (MD), both with a 95% confidence interval (CI).

Assessment of heterogeneity We attempted to assess heterogeneity in three ways (Higgins 2002): graphically, by using forest plots; by the Chi2 test where P values of less than 0.10 determine statistical significance; and by the I2 statistic. Roughly, we read the I2 test value in the following way: from 0% to 40%, heterogeneity may not be important; from 30% to 60%, heterogeneity may be moderate; from 50% to 90%, heterogeneity may be substantial; and from 75% to 100%, heterogeneity may be considerable.

Assessment of reporting biases For any type of outcome where there were at least ten trials included in the meta-analysis, we planned to test for funnel plot asymmetry (Higgins 2011). Nevertheless, asymmetric funnel plots are not necessarily caused by publication bias, and publication bias does not necessarily lead to asymmetry in a funnel plot (Egger 1997).

Data synthesis Dealing with missing data KN contacted investigators of the trials to request missing data. We performed our analyses based on the intention-to-treat principle, using imputation of dichotomous data for the outcomes: 1. If data were missing regarding all-cause mortality and chronic hepatitis C-related mortality, we assumed that the participants lost to follow-up had survived. Therefore, the denominator included the number of randomised participants in the respective trial. 2. If data were missing regarding morbidity, adverse events, failure of sustained virological response, failure of virological end-of-treatment response, participants without improvement in alanine aminotransferase or aspartate aminotransferase serum levels, or number of participants without histological improvement, we assumed that participants lost to follow-up had such an event. Therefore, we included all the participants randomised in the trial in the denominator. We had planned to perform sensitivity analyses using two extreme scenarios for participants with incomplete or missing data for the first three primary outcomes, i.e., all-cause mortality, chronic

For the statistical analyses, we used Review Manager 5.2 (RevMan 2012). For meta-analyses with more than one trial we used both a fixed-effect model (DeMets 1987) and a random-effects model (DerSimonian 1986), along with an assessment of heterogeneity. We presented the results with both meta-analytic methods. If there were no differences in the results, we presented the results with the fixed-effect model only.

Trial sequential analysis

We applied trial sequential analysis to minimise the risks of random error (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009, Wetterslev 2009; Thorlund 2010; CTU 2011; Thorlund 2011). Cumulative meta-analyses are at risk of producing random errors due to sparse data and repetitive testing on the accumulating data (Brok 2008; Wetterslev 2008). To minimise random errors, we calculated the required information size, i.e., the number of participants needed in a meta-analysis to detect or reject a certain intervention effect (Wetterslev 2008). The information size calculation should also account for the diversity present in the meta-

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analysis (Wetterslev 2009). In our meta-analysis, the required information size was based on the assumption of a plausible RR reduction of 20% or on the RR reduction observed in the included trials with low risk of bias (Wetterslev 2008). The underlying assumption of trial sequential analysis is that testing for significance may be performed each time a new trial is added to the meta-analysis. We added the trials according to the year of publication, and if more than one trial was published in a year, trials were added alphabetically according to the last name of the first author (Wetterslev 2008). On the basis of the required information size and risk for type I (5%) and type II (20%) errors, trial sequential monitoring boundaries can be constructed (Wetterslev 2008). These boundaries determine the statistical inference one may draw regarding the cumulative meta-analysis that has not reached the required information size. If the trial sequential monitoring boundary is crossed before the required information size is reached, firm evidence may be established and further trials may turn out to be superfluous. On the other hand, if the boundary is not surpassed, it is probably necessary to perform more trials in order to detect or reject a certain intervention effect. As default, type I error of 5%, type II error of 20%, and diversity-adjusted required information size were used unless otherwise stated (Wetterslev 2008; Wetterslev 2009).

’Summary of findings’ table We assessed the quality of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to present review results in ’Summary of findings’ (SoF) tables (GRADEPro 3.6 (http://ims.cochrane.org/ revman/gradepro)). A SoF table consists of three parts: information about the review, a summary of the statistical results, and the grade of the quality of evidence. The quality assessment of the available evidence is comprised of the number of studies, the types of studies (randomised or observational), and five factors including risk of bias, inconsistency of results, indirectness of evidence, imprecision, and publication bias that affect the quality of the evidence. The five factors are used to judge whether the quality of the collected evidence should be decreased or increased.

RESULTS

Description of studies See: Characteristics of included studies; Characteristics of excluded studies.

Subgroup analysis and investigation of heterogeneity The following subgroup analyses were considered and performed whenever possible. 1. Risk of bias: trials that were judged to be at low risk of bias compared to trials judged to be at high risk of bias. 2. Participants: trials with treatment-naive patients compared to relapsers and non-responders to previous antiviral interventions. 3. Genotype: trials with participants infected with different hepatitis C virus genotypes. 4. Dose of nitazoxanide: trials with different doses of nitazoxanide. 5. Different regimens of nitazoxanide in combination with any other intervention for chronic hepatitis C. 6. Co-infections and co-morbidities: participants with HIV, solid organ transplant recipients, participants receiving haemodialysis, with hepatitis B, alcoholism, iron overload, etc. 7. Adults compared to adolescents and children. The difference between subgroups was assessed by the test of interaction (Altman 2003).

Results of the search We identified a total of 282 bibliographic references through the electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register (n = 15), The Cochrane Central Register of Controlled Trials (CENTRAL) (n = 11), MEDLINE (n = 36), EMBASE (n = 142), LILACS (n = 14), and Science Citation Index Expanded (n = 64). We identified three other references on one ongoing trial (accessed January 2014) through searching clinicaltrials.gov. Two other references were identified through other sources. We excluded 75 duplicates and screened 212 references. We excluded 164 clearly irrelevant references through reading abstracts. Thus, we assessed 48 references for eligibility. We excluded additionally 22 of these references as they did not fulfil the inclusion criteria. Out of the 26 references left, 23 were on seven trials fulfilling the inclusion criteria of our review, and three references were on one still ongoing trial. We could not identify any references on randomised clinical trials through scanning reference lists of the identified ones. The reference flow is shown in Figure 1.

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Figure 1. Study flow diagram

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Included studies Seven trials fulfilled all of the inclusion criteria. Details about the trial interventions, participants characteristics, methods, and the outcomes are shown in the ’Characteristics of included studies’ table. A summary of the included trials and a summary of the characteristics of the included trials are shown in additional tables (Table 1; Table 2). The earliest included trial was published in 2008 (Rossignol 2008a), and the latest in 2012 (Basu 2012a). Four trials had a parallel group design with two intervention groups (Rossignol 2008a; Shiffman 2009/2011; Bacon 2010; Shehab 2012), and the other three trials included three intervention groups (Keeffe 2009a; Rossignol 2009a; Basu 2012a).

Design

Four trials compared nitazoxanide monotherapy versus placebo (Rossignol 2008a; Keeffe 2009a; Shiffman 2009/2011; Bacon 2010). One of these trials compared nitazoxanide monotherapy versus placebo without additional antiviral drugs (Rossignol 2008a). The other three trials compared nitazoxanide monotherapy followed by an addition of the combination of peginterferon and ribavirin (i.e., standard treatment) versus placebo followed by an addition of standard treatment (Keeffe 2009a; Shiffman 2009/2011; Bacon 2010). Two trials compared nitazoxanide monotherapy followed by the addition of standard treatment versus no intervention plus standard treatment (Rossignol 2009a; Shehab 2012). One trial compared nitazoxanide plus telaprevir and standard treatment versus no intervention plus telaprevir and standard treatment (Basu 2012a).

Participants

Four publications reported on the sex of the participants ( Rossignol 2008a; Rossignol 2009a; Bacon 2010; Shehab 2012); 336 out of 353 were males (95.2%) based on the per protocol analyses of the trials. Participants were 18 years of age or older, all diagnosed with chronic hepatitis C genotypes 1 or 4. One participant in one of the trials was found to be co-infected with hepatitis B, and an exception was made to allow this person concerned to continue to participate in the trial (Rossignol 2008a). A total of 350 participants were treatment-naive, i.e., had not had any previous antiviral therapy (Keeffe 2009a; Rossignol 2009a; Bacon 2010; Shehab 2012). A total of 51 participants were treatment-experienced (Rossignol 2008a; Rossignol 2009a; Basu 2012a); 24 were only treatment-experienced to peginterferon (Rossignol 2009a), five were treatment-experienced to both peginterferon and ribavirin (Rossignol 2008a), and the previous treatments given to the remaining 22 participants was unclear (Basu 2012a). Only one of these trials specified how these treatmentexperienced participants responded to their previous treatment; participants in Basu 2012a were all stated to be partial-relapsers. Two trials included 84 participants who were non-responders to peginterferon and ribavirin (Shiffman 2009/2011; Basu 2012a). Only six participants out of all the participants included in this review were relapsers and it was unknown to which therapy (Basu 2012a). It was not known whether 47 participants in total had previously been treated with any antiviral-interventions (Rossignol 2008a; Basu 2012a). None of the trial participants was reported to be co-infected with any other concomitant or preceding disease except for one participant in the Rossignol 2008a trial who was co-infected with hepatitis B virus infection (HBV).

Interventions Sample sizes

The seven trials contained a total of 538 randomised participants, but only 507 of these were used in the per protocol analyses of the trials.

Setting

The seven trials originated either from the USA or Egypt. Two trials were conducted in more than one centre in the USA (Shiffman 2009/2011; Bacon 2010), four trials were conducted in one or more centres in Egypt (Rossignol 2008a; Keeffe 2009a; Rossignol 2009a; Shehab 2012), and one trial did not specify where it was conducted (Basu 2012a). All seven trials included in our review were published in English.

The trials were slightly heterogeneous in terms of dosage regimen and duration of administration of nitazoxanide (see Characteristics of included studies table). Six of the seven included trials used the same dose of nitazoxanide, i.e., the standard dose of 500 mg twice daily (Rossignol 2008a; Rossignol 2009a; Shiffman 2009/2011; Bacon 2010; Basu 2012a; Shehab 2012). However, the Basu 2012a trial also used 500 mg three times daily in one of its treatment groups. The seventh trial used higher doses of nitazoxanide, i.e., 675 mg and 1350 mg twice daily (Keeffe 2009a). Dosages were similar in all of the trials that included the standard treatment in their study. Peginterferon was administered weekly at 180 µg in four trials (Keeffe 2009a; Rossignol 2009a; Shiffman 2009/2011; Bacon 2010). In the Basu 2012a trial, 180 µg peginterferon was given every other week, and in the Shehab 2012 trial, 160 µg was administered weekly. Administration of ribavirin

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was weight-based, and varied from 1000 mg to 1200 mg daily in five trials (Keeffe 2009a; Rossignol 2009a; Shiffman 2009/2011; Bacon 2010; Shehab 2012). One trial had a fixed dose of 1200 mg ribavirin daily (Basu 2012a). The dosage of telaprevir was 750 mg three times daily (Basu 2012a). The duration of treatment in all trials varied. All trials had a monotherapy of nitazoxanide or placebo administered over between four and 24 weeks, except for the trial by Basu 2012a for which it was uncertain. Continuation of therapy in combination with other drugs proceeded for between 24 to 48 weeks. Six of the trials had a 24 week follow-up after completion of treatment (Rossignol 2008a; Rossignol 2009a; Bacon 2010; Keeffe 2009a; Shiffman 2009/2011; Shehab 2012). The follow-up was unclear in the Basu 2012a trial. The details are displayed in Table 2. None of the trials compared a long duration of nitazoxanide treatment with a short duration of nitazoxanide treatment.

Outcomes

All the included trials evaluated the effect and efficacy of nitazoxanide on sustained virological response and virological endof-treatment response, and four trials evaluated participants who showed no improvement in alanine aminotransferase levels according to the authors’ definitions (See Characteristics of included studies) (Rossignol 2008a; Rossignol 2009a; Shiffman 2009/2011; Shehab 2012). Five trials evaluated the safety of nitazoxanide for treatment of chronic hepatitis C by looking at number of participants with adverse events (Rossignol 2008a; Keeffe 2009a; Rossignol 2009a; Bacon 2010; Shehab 2012). For more details, see the Characteristics of included studies table. Only one trial reported on all-cause mortality and chronic hepatitis C-related mortality (Shehab 2012). None of the trials reported on quality of life, development of morbidity, and only one trial with a long-term follow-up reported

on the number of participants with histological changes (Rossignol 2008a). We wrote to the contact authors of four of the trials in order to obtain additional information about the trials (Rossignol 2008a; Rossignol 2009a; Basu 2012a; Shehab 2012), and received answers relating to Shehab 2012, Basu 2012a, and Keeffe 2009a. Detailed information is given in the Characteristics of included studies table.

Excluded studies We excluded 22 references to 16 studies. Four studies were not randomised (Basu 2009; Keeffe 2009; Yoffe 2009; Asrani 2010) and the remaining 12 studies were review articles of no interest to our review (Characteristics of excluded studies). Data on adverse events were reported as not serious, mild to moderate, and intermittent in nature in the study by Yoffe 2009. This study enrolled 14 treatment-naive patients with chronic hepatitis C genotype 1 to receive nitazoxanide plus peginterferon and ribavirin. Four patients developed adverse events including diarrhoea (n = 3), rash (n = 2), cellulitis (n = 3), and laryngitis (n = 1). These data are not part of the meta-analysis on adverse events.

Ongoing studies We identified one ongoing trial (Kohla ongoing); we hope that the results from this trial will be included in the next update of this review.

Risk of bias in included studies All of the included trials had high risk of bias, as they were judged to be at high risk or unclear risk in at least one domain (Risk of bias in included studies). A summary of our assessment, by domain and trial, is presented in Figure 2 and Figure 3.

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Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study

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Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies

All of the included trials stated that they allocated participants randomly to comparison groups. The generation of the allocation sequence was described in three trials (Rossignol 2008a; Rossignol 2009a; Basu 2012a) (Table 2). Both Basu 2012a and Rossignol 2008a used sealed envelopes, however, there was no information about whether the envelopes had been sequentially-numbered and were opaque. Rossignol 2009a randomised participants sequentially to one of the three treatment groups using the next available package of study medication, however, as the investigators were not blinded to intervention groups, it is possible that the allocation may have been foreseeable. Accordingly, allocation concealment was assessed as being at high risk of bias in all the trials. The method of blinding of participants and personnel was partially described in two of the trials (Rossignol 2008a; Rossignol 2009a). One of the included trials was an open-label trial and was judged as being at high risk of bias (Shehab 2012). The four remaining trials did not provide information about blinding in the trial, and, therefore, the risk of bias was judged to be high (Keeffe 2009a; Shiffman 2009/2011; Bacon 2010; Basu 2012a). Incomplete data were addressed adequately in five of the seven trials (Rossignol 2008a; Rossignol 2009a; Bacon 2010; Basu 2012a; Shehab 2012), which were judged to have a low risk of bias for this domain. The other two trials were judged to have a high risk of bias for this domain (Keeffe 2009a; Shiffman 2009/2011). Six of the seven trials were judged to have a low risk of selective re-

porting bias, as primary and secondary outcomes were adequately assessed. Only one of the trials had a high risk of bias for this domain as not all the outcomes were adequately described (Shiffman 2009/2011). Other potential sources of bias All except two of the trials had received or seem to have received funding from the medical industry (Romark Laboratories, LCTampa, FL, USA) (Basu 2012a; Shehab 2012), which put the trials at high risk of bias in terms of for-profit bias.

Effects of interventions See: Summary of findings for the main comparison Nitazoxanide for chronic hepatitis C; Summary of findings 2 Nitazoxanide for chronic hepatitis C; Summary of findings 3 Nitazoxanide for chronic hepatitis C; Summary of findings 4 Nitazoxanide for chronic hepatitis C; Summary of findings 5 Nitazoxanide for chronic hepatitis C

Nitazoxanide versus placebo or no intervention

Primary outcomes

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All-cause mortality or chronic hepatitis C-related mortality Only one trial provided information on all-cause mortality and on chronic hepatitis C-related mortality (Shehab 2012). None of the participants in the trial died during the follow-up period (Analysis 1.1; Analysis 1.2).

Morbidity None of the included trials reported on the number of participants who developed cirrhosis, ascites, variceal bleeding, hepatic encephalopathy, or hepatocellular carcinoma during the trial. Only baseline data on morbidity were assessed, and this was done in only four of the seven included trials (Rossignol 2008a; Keeffe 2009a; Rossignol 2009a; Bacon 2010). Therefore, data on this outcome could not be included in the analyses (Analysis 1.3).

Adverse events

Overall effect of nitazoxanide versus placebo or no intervention including trials with and without cointerventions Four trials reported on the number of participants who experienced serious and non-serious adverse events (Rossignol 2008a; Rossignol 2009a; Bacon 2010; Shehab 2012). Sixty-seven out of a total of 331 participants (20%) were reported as having had adverse events. The meta-analysis with both the fixed-effect model and random-effects model showed no significant difference in the effect of nitazoxanide versus placebo or versus no intervention on the number of participants who experienced adverse events (37 out of 179 (21%) versus 30 out of 152 (20%); fixed-effect model: RR 1.10; 95% CI 0.71 to 1.71; I2 = 65%, P value 0.68) (Analysis 1.4). As there were no trials with an overall low risk of bias, we performed a trial sequential analysis on all included trials that reported on adverse events (Figure 4). The trial sequential analysis showed no evidence to support or refute the theory that nitazoxanide influences the number of participants with adverse events (Figure 4).

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Figure 4. Trial sequential analysis of the fixed-effect meta-analysis of the effect of nitazoxanide versus placebo or no intervention on adverse events in chronic hepatitis C infected patients. The trial sequential analysis is performed with a type 1 error of 5% (two sided), a power of 80%, an assumed control proportion of number of patients with adverse events of 20%, and an anticipated relative risk reduction (RRR) of 40%. The diversity-adjusted required information size (DARIS) to detect or reject a RRR of 40% with a between trial heterogeneity in the meta-analysis is estimated to 1946 participants. The actually accrued number of participants is 331, which is only 17% of the required information size. The blue cumulative Z-curve does not cross the conventional statistical boundaries or the red inward sloping trial sequential monitoring boundaries for benefit or harm. Not even with a large RRR of 40% is there evidence to support that nitazoxanide has any effect on adverse events. The cumulative Z-curve does not reach the futility area, demonstrating that further trials may be needed.

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Nitazoxanide versus placebo Adverse events were reported in 11 out of 25 (44%) of the participants in the nitazoxanide group versus six out of 25 (24%) in the placebo group in the Rossignol 2008a trial; this difference was not statistically significant (P value 0.15). Two of these 17 participants had serious adverse events that required hospitalisation; one in each of the two intervention groups. None of the participants with adverse events discontinued the intervention (Analysis 1.4). The Rossignol 2008a trial provided no information on dose-reductions in participants that had adverse events.

Nitazoxanide plus standard treatment versus placebo plus standard treatment Bacon 2010 reported adverse events in 11 out of 75 (15%) participants in the nitazoxanide plus standard treatment group versus seven out of 37 (19%) participants in the placebo plus standard treatment group; there was no significant difference between the groups (P value 0.56). Of the participants who experienced adverse effects, seven from the nitazoxanide group and four from the placebo group discontinued treatment due to the adverse events (Analysis 1.4). The Bacon 2010 trial provided no information on dose-reductions due to adverse events.

five in the no intervention plus standard treatment group. The intervention dose reductions were not specified in the Rossignol 2009a trial. The Shehab 2012 trial reported dose reductions of peginterferon in four participants in the nitazoxanide plus standard treatment group versus seven participants in the no intervention plus standard treatment group. The dose of ribavirin was also reduced in three participants in the standard treatment group.

Subgroup differences Tests for subgroup differences showed no significant difference in effect between trials assessing: 1. the effects of nitazoxanide versus placebo; 2. nitazoxanide plus standard treatment versus placebo plus standard treatment; and 3. nitazoxanide plus standard treatment versus no intervention plus standard treatment (P value 0.34).

Secondary outcomes

Quality of life None of the included trials reported on quality of life. Failure to achieve sustained virological response

Nitazoxanide plus standard treatment versus no intervention plus standard treatment Adverse events were reported in 15 out of 79 (19%) participants in the nitazoxanide plus standard treatment group versus 17 out of 90 (19%) participants in the no intervention plus standard treatment group in the two trials with this comparison (Rossignol 2009a; Shehab 2012). In the Shehab 2012 trial, none of the participants had serious adverse events that required hospitalisation. Three participants discontinued treatment due to adverse events in the standard treatment group, compared with two in the nitazoxanide group. In the Rossignol 2009a trial one participant in the standard treatment group had an adverse event that required hospitalisation. Five participants in the standard treatment group discontinued medication because of adverse events. The metaanalysis showed no statistically significant difference between the effect of nitazoxanide plus standard treatment and standard treatment alone (fixed-effect model: RR 1.00; 95% CI 0.51 to 1.96; I 2 = 85%, P value 0.99) (Analysis 1.4). The Rossignol 2009a trial reported that seven participants experienced dose-reductions as a result of adverse events; two participants in the nitazoxanide plus standard treatment group versus

Overall effect of nitazoxanide versus placebo or no intervention All of the included trials reported on the proportion of participants who failed to achieve sustained virological response. In the nitazoxanide group a total of 159 out of 290 (55%) participants failed to achieve sustained virological response versus 133 out of 208 (64%) participants in the placebo or no intervention group. The meta-analysis with both the fixed-effect model and randomeffects model showed a significant difference in favour of nitazoxanide versus placebo or no intervention (fixed-effect model: RR 0.85; 95% CI 0.75 to 0.97; I2 = 0%, P value 0.02) (Analysis 1.6). As there were no trials at low risk of bias, we performed a trial sequential analysis on all included trials that reported on failure of sustained virological response. The trial sequential analysis of the data supports the statistically significant effect of nitazoxanide versus placebo or no intervention for sustained virological response (Figure 5). The result of the trial sequential analysis is shown by the cumulated Z-curve (blue curve) that crosses the trial sequential monitoring boundary for benefit (red inward sloping curve),

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which implies that there is evidence for a beneficial effect of nitazoxanide in encouraging sustained virological response; this result is free of risk of random errors. However, as stated above, we cannot exclude risks of systematic errors (bias). Figure 5. Trial sequential analysis of the fixed-effect meta-analysis of the effect of nitazoxanide versus placebo or no intervention on risk of failure of sustained virological response in patients with chronic hepatitis C virus infection. The trial sequential analysis is performed with a type 1 error of 5% (two sided), a power of 80%, an assumed control proportion of number of participants with failure of sustained virological response of 64%, and an anticipated relative risk reduction (RRR) of 20%. The diversity-adjusted required information size (DARIS) to detect or reject a RRR of 20% with a between trial heterogeneity in the meta-analysis is estimated to 419 participants. The actually accrued number of participants is 498. The blue cumulative Z-curve crosses the red inward sloping trial sequential monitoring boundaries for benefit. This implies that there is no risk of random error in the estimate of a beneficial effect of nitazoxanide versus placebo or no intervention.

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We performed sensitivity analyses using two extreme scenarios for participants with incomplete or missing data regarding sustained virological response. Firstly, we performed a best-worst case scenario analysis assuming that participants with data missing for this outcome in the nitazoxanide group did achieve sustained virological response, and that all participants in the placebo or no intervention group for whom the relevant data were missing did not achieve sustained virological response. This sensitivity analysis with the fixed-effect model revealed a statistically significant effect favouring nitazoxanide versus placebo or no intervention (best-worst case scenario: RR 0.81; 95% CI 0.70 to 0.94, I2 = 63%, P value 0.004; four trials) (Analysis 5.1). Secondly, we performed a worst-best case scenario analysis where we assumed that participants with data missing for this outcome in the nitazoxanide group did not achieve sustained virological response, and that all participants in the placebo or no intervention group for whom the relevant data were missing did achieve sustained virological response. This sensitivity analysis with the fixed-effect model did not reveal a statistically significant effect of nitazoxanide versus placebo or no intervention (worst-best case scenario: RR 0.87; 95% CI 0.76 to 1.01; I2 = 4%, P value 0.06) (Analysis 6.1). Nitazoxanide versus placebo Rossignol 2008a reported on failure of sustained virological response in 21 out of 25 (84%) participants in the nitazoxanide group versus 25 out of 25 (100%) participants in the placebo group; there was no significant difference between the groups (P value 0.07). Nitazoxanide plus standard treatment versus placebo plus standard treatment Three trials reported on failure of sustained virological response in participants treated with nitazoxanide plus standard treatment versus placebo plus standard treatment (Keeffe 2009a; Shiffman 2009/2011; Bacon 2010). Out of 150 participants given nitazoxanide plus standard treatment, 89 failed to achieve sustained virological response (59%) versus 51 out of 67 (76%) participants given placebo plus standard treatment. The meta-analysis showed no statistically significant difference between the treatment groups on sustained virological response using both the fixed-effect model and random effects-model (fixed-effect model: RR 0.85; 95% CI 0.72 to 1.00; I2 = 64%, P value 0.05) (Analysis 1.6). Nitazoxanide plus standard treatment versus no intervention plus standard treatment Two trials reported on failure of sustained virological response in participants treated with nitazoxanide plus standard treatment versus no intervention plus standard treatment (Rossignol 2009a; Shehab 2012). Forty-one out of 91 (45%) participants given nita-

zoxanide plus standard treatment failed to achieve sustained virological response versus 46 participants out of 90 (51%) in the standard treatment group. The meta-analysis showed no statistically significant difference between the treatment groups for failure of sustained virological response (fixed-effect model: RR 0.88; 95% CI 0.65 to 1.19; I2 = 0%, P value 0.05) (Analysis 1.6). Nitazoxanide plus standard treatment plus telaprevir versus no intervention plus standard treatment plus telaprevir Only one trial compared nitazoxanide plus standard treatment plus telaprevir versus no intervention plus standard treatment plus telaprevir (Basu 2012a). The trial reported failure of sustained virological response in eight out of 24 (33%) participants in the nitazoxanide plus standard treatment plus telaprevir group versus 11 out of 26 (42%) participants in the standard treatment plus telaprevir group there was no significant difference between the groups (P value 0.52). Subgroup differences Tests for subgroup differences showed no significant difference in effect between the trials assessing: 1. the effects of nitazoxanide versus placebo; 2. nitazoxanide plus standard treatment versus placebo plus standard treatment; and 3. nitazoxanide plus standard treatment versus no intervention plus standard treatment (P value 0.99). Failure of virological end-of-treatment response

Overall effect of nitazoxanide versus placebo or no intervention All of the included trials reported on risk of failure of virological end-of-treatment response. Failure of virological end-of-treatment response was reported in 235 out of 498 (47%) participants of the included trials. In the nitazoxanide groups, a total of 125 out of 290 (43%) participants failed to achieve virological end-oftreatment response versus 110 out of 208 (53%) participants in the placebo or no intervention group. Meta-analysis with both the fixed-effect model and the random-effects model showed a significant beneficial effect for nitazoxanide versus placebo or no intervention (fixed-effect model: RR 0.81; 95% CI 0.69 to 0.96; I2 = 46%, P value 0.01) (Analysis 1.7). As there were no trials with a low risk of bias, we performed a trial sequential analysis on all included trials that reported on failure to achieve virological end-of-treatment response (Figure 6). The trial sequential analysis does not support the statistically significant findings of the meta-analysis for a beneficial effect of nitazoxanide in preventing failure to achieve virological end-of-treatment response.

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Figure 6. Trial sequential analysis of the fixed-effect meta-analysis of the effect of nitazoxanide versus placebo or no intervention on risk of failure of virological end-of-treatment response in patients with chronic hepatitis C virus infection. The trial sequential analysis is performed with a type 1 error of 5% (two sided), a power of 80%, an assumed control proportion of number of patients who failed to achieve a virological end-oftreatment response of 53%, and an anticipated relative risk reduction (RRR) of 20%. The diversity-adjusted required information size (DARIS) to detect or reject a RRR of 20% with a between trial heterogeneity in the meta-analysis is estimated to 2263 participants. The actually accrued number of participants is 498, which is 22% of the required information size. The blue cumulative Z-curve does not cross the red inward sloping trial sequential monitoring boundaries for benefit or harm. Therefore, there is no evidence to support that nitazoxanide influences number of patients who failed (which is not even drawn by the programme) to achieve virological end-of-treatment response. The cumulative Z-curve does not reach the futility area, demonstrating that further trials may be needed.

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Nitazoxanide versus placebo Rossignol 2008a reported failure of virological end-of-treatment response in 18 out of 25 (72%) participants in the nitazoxanide group versus 25 out of 25 (100%) participants in the placebo group; the difference between the groups was statistically significant (P value 0.01).

Only one trial investigated nitazoxanide plus standard treatment plus telaprevir versus no intervention plus standard treatment plus telaprevir (Basu 2012a). The trial reported failure of virological end-of-treatment response in five out of 24 (21%) participants receiving nitazoxanide in combination with telaprevir and standard treatment versus 10 out of 26 (38%) participants in the telaprevir plus standard treatment group (Basu 2012a). The difference between the treatment groups was not statistically significant (P value 0.19) (Analysis 1.7).

Nitazoxanide plus standard treatment versus placebo plus standard treatment Three trials reported on risk of failure of virological end-of-treatment response in participants treated with nitazoxanide plus standard treatment versus placebo plus standard treatment (Keeffe 2009a; Shiffman 2009/2011; Bacon 2010). Sixty-eight out of 150 (45%) participants given nitazoxanide plus standard treatment failed to achieve virological end-of-treatment response versus 46 participants out of 67 (69%) in the placebo plus standard treatment group. Meta-analysis using the fixed-effect model showed a statistically significant beneficial effect for nitazoxanide plus standard treatment on failure of virological end-of-treatment response (RR 0.73; 95% CI 0.60 to 0.89; I2 = 80%, P value 0.002), but this significant difference was not maintained when we used the random-effects model (RR 0.64; 95% CI 0.36 to 1.15; I2 = 80%, P value 0.14) (Analysis 1.7).

Subgroup differences Tests for subgroup differences showed no significant difference in effect between the trials assessing: 1. the effects of nitazoxanide versus placebo; 2. nitazoxanide plus standard treatment versus placebo plus standard treatment; and 3. nitazoxanide plus standard treatment versus no intervention plus standard treatment (P value 0.16). Participants without improvement in alanine aminotransferase or aspartate aminotransferase serum levels

Overall effect of nitazoxanide versus placebo or no intervention Nitazoxanide plus standard treatment versus no intervention plus standard treatment Two trials reported on risk of failure of virological end-of-treatment response in participants treated with nitazoxanide plus standard treatment versus no intervention plus standard treatment (Rossignol 2009a; Shehab 2012). Thirty-four out of 91 (37%) participants given nitazoxanide plus standard treatment failed to achieve virological end-of-treatment response versus 29 out of 90 (32%) participants in the standard treatment group. Meta-analysis showed no statistically significant difference in effect of nitazoxanide added to standard treatment versus no intervention plus standard treatment on failure of virological end-of-treatment response (fixed-effect model: RR 1.16; 95% CI 0.78 to 1.73; I2 = 0%, P value 0.46) (Analysis 1.7).

Nitazoxanide plus standard treatment plus telaprevir versus no intervention plus standard treatment plus telaprevir

Three trials reported on participants who did not show improvement in alanine aminotransferase or aspartate aminotransferase serum levels (Rossignol 2008a; Rossignol 2009a; Shehab 2012). Ninety-nine participants out of a total of 192 (52%) participants in the included trials, were reported as not showing improvement in alanine aminotransferase or aspartate aminotransferase serum levels. Meta-analysis with both the fixed-effect model and the random-effects model showed no significant effect of nitazoxanide (52 out of 97 (54%) participants) versus placebo or other intervention (47 out of 95 (49%) participants) (fixed-effect model: RR 1.09; 95% CI 0.84 to 1.42; I2 = 0%, P value 0.50) (Analysis 1.8). As there were no trials with a low risk of bias, we performed a trial sequential analysis on all included trials that reported on the number of participants who did not show improvement in alanine aminotransferase or aspartate aminotransferase levels (Figure 7). The trial sequential analysis showed that there is no evidence to support or refute an effect of nitazoxanide on participants who do not show improvement in alanine aminotransferase or aspartate aminotransferase levels.

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Figure 7. Trial sequential analysis of the fixed-effect meta-analysis of the effect of nitazoxanide versus placebo or no intervention on number of participants with chronic hepatitis C virus infection without improvement in alanine aminotransferase or aspartate aminotransferase serum levels. The trial sequential analysis is performed with a type 1 error of 5% (two sided), a power of 80%, an assumed control proportion of number of patients with morbidity of 49%, and an anticipated relative risk reduction (RRR) of 20%. The diversity-adjusted required information size (DARIS) to detect or reject a RRR of 20% with a between trial heterogeneity in the meta-analysis is estimated to 806 participants. The actually accrued number of participants is 192, which is 24% of the required information size. The blue cumulative Z-curve does not cross the red inward sloping trial sequential monitoring boundaries for benefit or harm. Therefore, there is no evidence to support that nitazoxanide has any effect on number of participants without change in alanine aminotransferase or aspartate aminotransferase serum levels. The cumulative Z-curve does not reach the futility area (which is not even drawn by the programme), demonstrating that further trials may be needed.

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Nitazoxanide versus placebo The Rossignol 2008a trial compared nitazoxanide versus placebo, and reported only on the number of participants who showed no improvement in alanine aminotransferase levels. This trial reported on these participants from baseline to end-of-treatment only as per protocol (23 participants in the active group and 24 in the placebo group), and did not provide information on alanine aminotransferase levels for the remaining participants. The participants were assigned as either ’normalised’, ’remained normal’, ’remained elevated’, or ’normal to elevated’. Data in the Data and analyses section are based on the intention-to-treat principle. Out of a total of 25 participants, 18 participants (72%) in the nitazoxanide group versus 20 out of 25 (80%) participants in the placebo group showed no improvement in alanine aminotransferase levels; the difference between the groups was not significant (P value 0.51) (Analysis 1.8).

Nitazoxanide plus standard treatment versus no intervention plus standard treatment The two trials that compared nitazoxanide plus standard treatment versus no intervention plus standard treatment, also reported on the number of participants who showed no improvement in alanine aminotransferase levels (Rossignol 2009a; Shehab 2012). The Rossignol 2009a trial only reported on unimproved alanine aminotransferase levels in participants who achieved sustained virological response. The Shehab 2012 trial included all participants in the report on the number of participants who showed no improvement in alanine aminotransferase levels. Meta-analysis showed no statistical significant difference between groups for nitazoxanide in combination with standard treatment versus no intervention plus standard treatment on the number of participants who showed no improvement in alanine aminotransferase or aspartate aminotransferase serum levels (34 out of 72 (47%) versus 27 out of 70 (39%), respectively) (fixed-effect model: RR 1.24; 95% CI 0.85 to 1.80; I2 = 0%, P value 0.27) (Analysis 1.8).

Subgroup differences Tests for subgroup differences showed no significant difference in effect between the trials assessing: 1. the effects of nitazoxanide versus placebo; 2. nitazoxanide plus standard treatment versus placebo plus standard treatment; and 3. nitazoxanide plus standard treatment versus no intervention plus standard treatment (P value 0.20).

Number of participants without histological improvement None of the trials reported on participants who showed no histological improvement (Analysis 1.9). Long-term follow-up Only one of the included trials assessed outcomes at a long-term follow-up (Rossignol 2008a). Thirteen out of the 50 participants included in the multicentre Rossignol 2008a trial were assessed in a long-term follow-up trial by Kabil 2011. Of the 13 participants, nine were from the original nitazoxanide group that had included 25 participants, and four were from the original placebo group that had included 25 participants. How the 13 participants were selected for the long-term follow-up was not specified (Kabil 2011). During the follow-up period the participants did not receive any antiviral treatment. Although no serious adverse events were reported in either of the treatment groups, and none of the total of 13 participants developed cirrhosis, two of the nine participants given nitazoxanide experienced adverse events. None of the participants required dose reduction or discontinued treatment due to adverse events. Six out of the nine participants given nitazoxanide failed to achieve sustained virological response and virological end-of-treatment response versus all of the participants in the placebo group who failed to achieve these virological responses. No significant improvement was identified between treatment groups for mean alanine aminotransferase levels before and after treatment. Three participants achieved sustained virological response; two were associated with normalisation of alanine aminotransferase levels, while the third fluctuated. Participants who were non-responders showed no improvement in alanine aminotransferase levels. The Rossignol 2008a trial only reported data on histological improvement for the long-term follow-up study (Kabil 2011). Paired liver biopsies before and after treatment were performed in three participants. In a post treatment liver biopsy one of the participants that had achieved sustained virological response, showed no worsening of fibrosis and minimal improvement in his necroinflammatory score. This participant was from the nitazoxanide group. The other two participants who had liver biopsy after treatment were non-responders from the placebo group. In one of them fibrosis had worsened and there was a minimal increase in the necroinflammatory score. The other participant showed regression of both fibrosis- and necroinflammatory stage. Only one participant had a liver biopsy at the long-term follow-up; this participant was a non-responder and showed no worsening of fibrosis. Subgroup analyses

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We conducted subgroup analyses stratifying the trials according to hepatitis C virus genotype and dose of nitazoxanide. We also performed a subgroup analysis comparing treatment-naive participants to relapsers and non-responders to previous antiviral interventions. In the Rossignol 2008a trial, five out of the 50 participants were treatment-experienced with peginterferon and ribavirin; three were in the nitazoxanide group (n = 25), and two were in the placebo group.

Treatment-naive compared to relapsers and non-responders Trials reporting on the number of treatment-naive participants with adverse events showed no statistically significant difference between nitazoxanide (17%) versus placebo or no intervention (19%) using both the fixed-effect model and the random-effects model (fixed-effect model: RR 0.92; 95% CI 0.54 to 1.56; I2 = 71%, P value 0.75). None of the trials that included relapsers and non-responders participants reported on adverse events (Analysis 2.4). The subgroup analyses stratifying the trials according to previous antiviral therapy showed a statistically significant difference for failure of sustained virological response between the nitazoxanide group (52%) versus the placebo or no intervention group (60%) (fixed-effect model: RR 0.82; 95% CI 0.69 to 0.96; I2 = 55%, P value 0.02) (Analysis 2.6). Meta-analysis of trials with treatmentnaive participants showed a statistically significant effect on achieving sustained virological response, favouring nitazoxanide; eightytwo out of 187 participants (44%) failed to achieve sustained virological response versus 75 out of 135 participants (56%) in the placebo or no intervention group using both the fixed-effect model and the random-effects model (fixed-effect model: RR 0.78; 95% CI 0.62 to 0.97; I2 = 37%, P value 0.03). Meta-analysis of trials that included relapsers and non-responders did not show any significant difference between the nitazoxanide group (80%) versus the placebo or no intervention group (78%) (fixed-effect model: RR 0.91; 95% CI 0.77 to 1.09; I2 = 0%, P value 0.31) for failure of sustained virological response. The test for subgroup difference showed no significant difference (P value 0.26) (Analysis 2.6). Meta-analysis of subgroups stratifying the trials according to previous antiviral therapy on failure of virological end-of-treatment response showed no statistically significant difference between the nitazoxanide group (41%) versus the placebo or no intervention group (48%) (fixed-effect model: RR 0.82; 95% CI 0.67 to 1.00; I2 = 49%, P value 0.05) (Analysis 2.7). Meta-analysis of trials with treatment-naive participants showed no statistically significant difference on failure of virological end-of-treatment response between the nitazoxanide group (32%) versus the placebo or no intervention group (39%) when both the fixed-effect model and the random-effects model were used (fixed-effect model: RR 0.80; 95% CI 0.60 to 1.06; I2 = 58%, P value 0.12) (Analysis 2.7). The trials that included relapsers and non-responders also did not show

any significant difference between the nitazoxanide group (86%) versus the placebo or no intervention group (100%) (fixed-effect model: RR 0.87; 95% CI 0.75 to 1.00, P value 0.05) for failure of virological end-of-treatment response (Analysis 2.7). Testing for subgroup differences showed no significant difference (P value 0.60). Those trials that included treatment-naive participants that reported on the number of participants who showed no improvement in alanine aminotransferase or aspartate aminotransferase serum levels showed no statistically significant difference between groups for nitazoxanide (47%) versus placebo or no intervention (39%) using both the fixed-effect model and the random-effects model (fixed-effect model: RR 1.24; 95% CI 0.85 to 1.80; I2 = 0%, P value 0.27). None of the trials that included relapsers and non-responders reported on the number of participants who did not show improvement in alanine aminotransferase or aspartate aminotransferase serum levels (Analysis 2.8).

Genotype 1- compared to genotype 4-infected participants A subgroup meta-analysis of the number of genotype 4 participants with adverse events showed no significant difference between nitazoxanide (25%) versus placebo or no intervention (20%) using both a fixed-effect model and a random-effects model (fixed effects-model: RR 1.24; 95% CI 0.74 to 2.08; I2 = 72%, P value 0.42) (Analysis 3.4). Only one trial with genotype 1 participants reported on the number with adverse events; there was no significant difference between the nitazoxanide group (15%) versus placebo or no intervention group (18%) (fixed-effect model: RR 0.78; 95% CI 0.33 to 1.84, P value 0.56) for adverse events. Testing for subgroup differences showed no significant difference (P value 0.36) (Analysis 3.4). Meta-analysis using both the fixed-effect model and the randomeffects model showed no significant difference between nitazoxanide versus placebo or no intervention for failure of sustained virological response in either genotype 1 participants (64% in the nitazoxanide group versus 68% in the placebo or no intervention group) (fixed-effect model: RR 0.88; 95% CI 0.74 to 1.04; I2 = 0%, P value 0.13), or in genotype 4 participants (46% in the nitazoxanide group versus 61% in the placebo or no intervention group) (fixed-effect model: RR 0.83; 95% CI 0.68 to 1.02; I2 = 0%, P value 0.07). Testing for subgroup differences showed no significant difference (P value 0.70) (Analysis 3.6). The three trials that included genotype 1 participants showed a statistically significant difference between the nitazoxanide group (50%) versus placebo or no intervention group (61%), favouring nitazoxanide, on failure of virological end-of-treatment response using the fixed-effect model and the random-effects model (fixedeffect model: RR 0.76; 95% CI 0.61 to 0.93; I2 = 52%, P value 0.010) (Bacon 2010; Shiffman 2009/2011; Basu 2012a). The trials including genotype 4 participants showed no statistically significant difference between the nitazoxanide group (37%) versus

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placebo or the no intervention group (47%) for failure of virological end-of-treatment response (fixed-effect model: RR 0.88; 95% CI 0.69 to 1.12; I2 = 70%, P value 0.29). Testing for subgroup difference showed no significant difference (P value 0.38) (Analysis 3.7). Subgroup meta-analysis on the number of participants with no improvement in alanine aminotransferase serum levels in trials including genotype 4 participants showed no significant difference between the nitazoxanide group (54%) versus placebo or no intervention group (49%) using both the fixed-effect model and random-effects model (fixed-effect model: RR 1.09; 95% CI 0.84 to 1.42; I2 = 0%, P value 0.50). No trials with genotype 1 participants reported on the number of participants without improvement in alanine aminotransferase or aspartate aminotransferase serum levels (Analysis 3.8).

anide, between the nitazoxanide group (13%) versus the placebo or no intervention group (43%) on the risk in failure of virological end-of-treatment response using the fixed-effect model and the random-effects model (fixed-effect model: RR 0.36; 95% CI 0.17 to 0.76; I2 = 0%, P value 0.008). Testing for subgroup differences did show a statistical significant difference (P value 0.03) (Analysis 4.7). We planed to perform subgroup analyses on the number of participants who showed no improvement in alanine aminotransferase or aspartate aminotransferase serum levels, stratifying the trials according to the dose of nitazoxanide administered, but we could not do this because all the trials that provided information on this outcome had used the standard dose of nitazoxanide. However, subgroup analysis did not show any significant difference between the nitazoxanide group (54%) and the placebo or no intervention group (49%) (fixed-effect model: RR 1.09; 95% CI 0.84 to 1.42; I2 = 0%, P = 0.50) (Analysis 4.8).

Nitazoxanide dose comparison Six out of the seven trials included administered the standard dose of nitazoxanide (500 mg twice daily) to participants (Rossignol 2008a; Rossignol 2009a; Shiffman 2009/2011; Bacon 2010; Basu 2012a; Shehab 2012). Two trials used higher daily doses of nitazoxanide (Basu 2012a; Keeffe 2009a). We planed to perform a subgroup meta-analyses for adverse events, stratifying trials according to standard dose versus experimentaldose of nitazoxanide, but we could not do so because all trials that provided information about adverse events had used the standard dose of nitazoxanide, which for this subgroup did not show any significant difference between the nitazoxanide group (21%) versus placebo or no intervention group (20%) (fixed-effect model: RR 1.10; 95% CI 0.71 to 1.71; I2 = 65%, P value 0.68) (Analysis 4.4). Subgroup analyses of trials that administered the standard dose of nitazoxanide revealed no statistically significant difference in the effect of nitazoxanide (60%) versus placebo or no intervention (65%) for failure of sustained virological response using both the fixed-effect model and random-effects models (fixed-effect model: RR 0.87; 95% CI 0.76 to 1.00; I2 = 0%, P value 0.05). Metaanalysis of trials that administered experimental doses of nitazoxanide also failed to show any significant difference between nitazoxanide (24%) versus placebo or no intervention (45%) (fixedeffect model: RR 0.57; 95% CI 0.31 to 1.04; I2 = 0%, P value 0.07%). Testing for subgroup difference revealed no statistical significant difference (P value 0.17) (Analysis 4.6). Subgroup analyses of trials that administered the standard dose of nitazoxanide revealed no statistically significant difference in effect of nitazoxanide (49%) versus placebo or no intervention (53%) on failure of virological end-of-treatment response using both the fixed-effect model and random-effects model (fixed-effect model: RR 0.85; 95% CI 0.72 to 1.00; I2 = 0%, P value 0.06). However, the meta-analysis of trials that administered the experimental-dose of nitazoxanide did show a significant effect, favouring nitazox-

Abandoned subgroup analyses We could not perform subgroup analyses in which the included trials were to be stratified according to risk of bias, different regimens of nitazoxanide in combination with any other intervention for chronic hepatitis C, co-infections and co-morbidities, or adults compared to adolescents and children since none of the above were included in the trials. Summary of findings tables We prepared five ’Summary of findings’ (SoF) tables, summarising the results of all the reported outcomes (Summary of findings for the main comparison; Summary of findings 2; Summary of findings 3; Summary of findings 4; Summary of findings 5). Nitazoxanide plus peginterferon versus no intervention plus standard treatment (peginterferon and ribavirin) Rossignol 2009a also compared nitazoxanide plus peginterferon versus no intervention plus standard treatment (i.e., peginterferon and ribavirin). This comparison could not be included in the data and analyses section and is therefore only described in the text below. One (2.5%) participant died from a motor vehicle accident in the standard treatment group (n = 40 participants), and one (4%) non serious adverse event was reported among the 28 participants in the nitazoxanide plus peginterferon group. In addition, in the nitazoxanide plus peginterferon group three participants discontinued medication due to adverse events, and four participants experienced dose-reductions as a result of adverse events . Twenty-two (55%) participants failed to achieve sustained virological response and 14 (35%) participants failed to achieve virological end-of-treatment response in the nitazoxanide plus peginterferon group.

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The number of participants who showed no improvement in alanine aminotransferase were only reported for the subset of participants who achieved sustained virological response at week 24 after end-of-treatment as per protocol (16 participants in the nitazoxanide plus peginterferon group). The participants were assigned as either ’normalised’, ’remained normal’, ’remained elevated’, or ’normal to elevated’. Five (31%) out of 16 participants in the nitazoxanide plus peginterferon group showed no improvement in alanine aminotransferase levels. Rossignol 2009a did not report on the number of participants who showed no histological improvement or on quality of life in the nitazoxanide plus peginterferon group.

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Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Nitazoxanide compared with placebo for chronic hepatitis C Patient or population: people with chronic hepatitis C Settings: primary care in Egypt and USA Intervention: nitazoxanide Comparison: placebo Outcomes

Illustrative comparative risks* (95% CI)

Relative effect (95% CI)

No of participants (studies)

Quality of the evidence (GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Nitazoxanide

No deaths

No deaths

Not estimable

0

-

-

Chronic hepatitis C-re- No deaths lated mortality

No deaths

Not estimable

0

-

-

Morbidity

No reports on participants developing morbidity in any trials making this comparison

No reports on partici- Not estimable pants developing morbidity in any trials making this comparison

0

-

-

Adverse events

240 per 1000

440 per 1000

RR 1.83 (0.80 to 4.19)

50 (1)



1,2,3,4 very low

The assumed risk was the control group risk

Failure of sustained vi- 1000 per 1000 rological response

840 per 1000

RR 0.84 (0.70 to 1.01)

50 (1)

⊕⊕

1,2,4 low

The assumed risk was the control group risk

Failure of virologi- 1000 per 1000 cal end-of-treatment response

730 per 1000

RR 0.73 (0.56 to 0.93)

50 (1)

⊕⊕

1,2,4 low

The assumed risk was the control group risk

All-cause mortality

29

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Participants without im- 800 per 1000 provement in ALT and/or AST serum levels

720 per 1000

RR 0.90 (0.66 to 1.23)

50 (1)

⊕⊕

1,2,4 low

The assumed risk was the control group risk

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; ALT: alanine aminotransferase; AST: aspartate aminotransferase GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: we are very uncertain about the estimate 1 The

trial(s) was (were) of high risk of bias number of events in the intervention and control group was less than 300 3 The confidence intervals overlapped 1 and either 0.75 or 1.25 or both 4 The assumed risk is the control group risk 2 The

30

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Nitazoxanide plus peginterferon and ribavirin compared with placebo plus peginterferon and ribavirin for chronic hepatitis C Patient or population: people with chronic hepatitis C Settings: primary care in Egypt and USA Intervention: nitazoxanide plus peginterferon and ribavirin Comparison: placebo plus peginterferon and ribavirin Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Relative effect (95% CI)

No of participants (studies)

Quality of the evidence (GRADE)

Comments

Corresponding risk

Placebo plus peginter- Nitazoxanide plus peginferon and ribavirin terferon and ribavirin All-cause mortality

No deaths

No deaths

Not estimable

0

-

-

Chronic hepatitis C-re- No deaths lated mortality

No deaths

Not estimable

0

-

-

Morbidity

No reports on participants developing morbidity in any trials making this comparison

No reports on partici- Not estimable pants developing morbidity in any trials making this comparison

0

-

-

Adverse events

189 per 1000

147 per 1000

RR 0.78 (0.33 to 1.84)

112 (1)



1,2,3,4 very low

The assumed risk was the control group risk

Failure of sustained vi- 761 per 1000 rological response

647 per 1000

RR 0.85 (0.72 to 1.00)

217 (3)

⊕⊕

1,2,4 low

The assumed risk was the control group risk

Failure of virologi- 687 per 1000 cal end-of-treatment response

501 per 1000

RR 0.73 (0.60 to 0.89)

217 (3)

⊕⊕

1,2,4 low

The assumed risk was the control group risk

31

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Participants without im- No reports on ALT and/or No reports on ALT and/or Not estimable provement in ALT and/or AST serum levels AST serum levels AST serum levels

0

-

-

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; ALT: alanine aminotransferase; AST: aspartate aminotransferase GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: we are very uncertain about the estimate 1 The

trial(s) was (were) of high risk of bias number of events in the intervention and control group was less than 300 3 The confidence intervals overlapped 1 and either 0.75 or 1.25 or both 4 The assumed risk is the control group risk 2 The

32

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Nitazoxanide plus peginterferon and ribavirin compared with no intervention plus peginterferon and ribavirin for chronic hepatitis C Patient or population: people with chronic hepatitis C Settings: primary care in Egypt and USA Intervention: nitazoxanide plus peginterferon and ribavirin Comparison: peginterferon and ribavirin Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Relative effect (95% CI)

No of participants (studies)

Quality of the evidence (GRADE)

Comments

Corresponding risk

Peginterferon and rib- Nitazoxanide plus peginavirin terferon and ribavirin No deaths

No deaths

Not estimable

100 (1)



1,2,4 very low

-

Chronic hepatitis C-re- No deaths lated mortality

No deaths

Not estimable

100 (1)



1,2,4 very low

-

Morbidity

No reports on participants developing morbidity in any trials making this comparison

No reports on partici- Not estimable pants developing morbidity in any trials making this comparison

0

-

-

Adverse events

189 per 1000

189 per 1000

RR 1.00 (0.51 to 1.96)

181 (2)



1,2,3,4 very low

The assumed risk was the control group risk

Failure of sustained vi- 511 per 1000 rological response

450 per 1000

RR 0.88 (0.65 to 1.19)

181 (2)

⊕⊕

1,2,4 low

The assumed risk was the control group risk

Failure of virologi- 322 per 1000 cal end-of-treatment response

374 per 1000

RR 1.16 (0.78 to 1.73)

181 (2)



1,2,3,4 very low

The assumed risk was the control group risk

All-cause mortality

33

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Participants without im- 386 per 1000 provement in ALT and/or AST serum levels

478 per 1000

RR 1.24 (0.85 to 1.80)

181 (2)



1,2,3,4 very low

The assumed risk was the control group risk

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; ALT: alanine aminotransferase; AST: aspartate aminotransferase GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: we are very uncertain about the estimate 1 The

trial(s) was (were) of high risk of bias number of events in the intervention and control group was less than 300 3 The confidence intervals overlapped 1 and either 0.75 or 1.25 or both 4 The assumed risk is the control group risk 2 The

34

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Nitazoxanide plus telaprevir plus peginterferon and ribavirin compared with no intervention plus telaprevir plus peginterferon and ribavirin for chronic hepatitis C Patient or population: people with chronic hepatitis C Settings: primary care in Egypt and USA Intervention: nitazoxanide plus telaprevir plus peginterferon and ribavirin Comparison: telaprevir plus peginterferon and ribavirin Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Relative effect (95% CI)

No of participants (studies)

Quality of the evidence (GRADE)

Comments

Corresponding risk

Telaprevir plus peginter- Nitazoxanide plus feron and ribavirin telaprevir plus peginterferon and ribavirin All-cause mortality

No deaths

No deaths

Not estimable

0

-

-

Chronic hepatitis C-re- No deaths lated mortality

No deaths

Not estimable

0

-

-

Morbidity

No reports on participants developing morbidity in any trials making this comparison

No reports on partici- Not estimable pants developing morbidity in any trials making this comparison

0

-

-

Adverse events

See comment

See comment

Not estimable

0

-

-

Failure of sustained vi- 423 per 1000 rological response

334 per 1000

RR 0.79 (0.38 to 1.62)

50 (1)



1,2,3,4 very low

The assumed risk was the control group risk

Failure of virologi- 385 per 1000 cal end-of-treatment response

208 per 1000

RR 0.54 (0.22 to 1.36)

50 (1)



1,2,3,4 very low

The assumed risk was the control group risk

35

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Participants without im- No reports on ALT and/ provement in ALT and/or or AST serum levels in AST serum levels any of the trials with this comparison

No reports on ALT and/ Not estimable or AST serum levels in any of the trials with this comparison

0

-

-

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) CI: confidence interval; RR: risk ratio; ALT: alanine aminotransferase; AST: aspartate aminotransferase GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality: we are very uncertain about the estimate 1 The

trial(s) was (were) of high risk of bias The number of events in the intervention and control group was less than 300 3 The confidence intervals overlapped 1 and either 0.75 or 1.25 or both 4 The assumed risk is the control group risk 2

36

DISCUSSION Summary of main results We included seven trials, with a total of 538 participants, that examined the benefits and harms of nitazoxanide versus placebo or no intervention for chronic hepatitis C. The meta-analyses showed no significant difference in effect between nitazoxanide versus either placebo or no intervention for all-cause mortality, chronic hepatitis C-related mortality, adverse events, or number of participants who showed no improvement in alanine aminotransferase or aspartate aminotransferase serum levels. Trial sequential analyses showed that more trials are needed to confirm or refute the effects of nitazoxanide for chronic hepatitis C. Our meta-analysis showed that when nitazoxanide was compared with placebo or no intervention there was a significant decrease in the proportion of participants who failed to achieve sustained virological response and virological end-of-treatment response that favoured nitazoxanide. Trial sequential analysis confirmed the meta-analysis result for sustained virological response, however, it showed that more trials are needed before any conclusions about the effect of nitazoxanide on virological end-of-treatment response can be drawn. All of the included trials had a high risk of bias, so even the result for sustained virological response might be biased. None of the trials reported on quality of life, number of participants who did not show histological improvement, or number developing morbidity. Only one trial included a long-term follow-up, however, only a small fraction (13 participants) of the originally included participants were included in this follow-up.

Overall completeness and applicability of evidence This systematic review examined the evidence of seven randomised clinical trials on nitazoxanide, with or without co-interventions, for the treatment of chronic hepatitis C. Out of the seven included trials, only two were available as full-text publications. The included trials were few in number and had low numbers of participants; all trials used different comparisons and co-interventions. This clinical heterogeneity may limit the interpretation of the review results. However, if there are no interactions between the experimental intervention and the co-interventions, the effects of the co-interventions should even out and the trial results should demonstrate the effects of the experimental intervention versus no intervention. All of the participants included in the trials were diagnosed with chronic hepatitis C, and only one was reported to be co-infected with another concomitant or preceding disease. We performed a subgroup analyses on participants that were treatment-naive, relapsers, and non-responders. We observed no significant subgroup

differences. Some of the trials included other types and other classifications of participants (e.g., partial responders). This systematic review shows that nitazoxanide might have a significant effect on decreasing the risk of failure to achieve sustained virological response in treatment-naive participants, but not in treatment-experienced participants. Nevertheless, a test of interaction showed no significant difference between treatment-naive and treatment-experienced participants. Meta-analyses of the other outcomes did not show any significant difference between interventions for treatment-naive and treatment-experienced participants. Since our review results can only concern the types of participants included in the identified trials, we cannot conclude anything certain about the effects of nitazoxanide in people with comorbid chronic hepatitis C and other diseases, or in partial responders. We pooled data on serious and non-serious adverse events from four trials, randomising a total of 331 participants, in this review. None of the trials reported on quality of life or on morbidity, or on the number of participants who showed no improvement in aspartate aminotransferase serum levels. Three trials reported on the number of participants who showed no improvement in alanine aminotransferase serum levels. Only one trial had a longterm follow-up in which it provided limited information on failure to achieve histological improvement (Rossignol 2008a). Only one trial reported all-cause mortality and chronic hepatitis C-related mortality (Shehab 2012). All the included trials used sustained virological response and virological end-of-treatment response as outcome measures, however, the clinical relevance of these surrogate outcomes is questionable. If nitazoxanide should have an effect on morbidity and mortality, one prerequisite might be that it significantly affect virological load. We did observe a beneficial effect of nitazoxanide on sustained virological response and virological end-of-treatment response; however, there were no data on the development of morbidity in participants in the nitazoxanide groups versus the no intervention groups. This finding underlines the persistent difficulty of proving that sustained virological response is a valid surrogate for clinically-relevant outcomes (Gluud 2007; Brok 2009; Brok 2010; Kong 2012; Sitole 2013; Koretz 2013; Yang 2013; Gurusamy 2014; Hauser 2014a; Hauser 2014b). For our primary outcome measures, i.e., all-cause mortality and chronic hepatitis C mortality and morbidity, longer follow-up periods seem necessary, especially considering that other studies show increases in morbidity and mortality in people with chronic hepatitis C as they enter their 30s, 40s and 50s living with the disease (Smith 2012). The median length of trial duration was 12 months, with a median follow-up of six months (one trial had a follow-up of only four months). Only one trial had a three-year and a long-term follow-up (Rossignol 2008a). Long-term effects of nitazoxanide are therefore unclear. In our analysis, nitazoxanide was administered with the current standard treatment for chronic hepatitis C, i.e., peginterferon and

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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ribavirin, in six out of the seven included trials. Nitazoxanide is being investigated to see whether this new antiviral is more effective and better tolerated than the current standard treatment for chronic hepatitis C. This review has not showed a significant difference with regard to drug tolerance, i.e., adverse events. However, both interferon-alpha and ribavirin have severe adverse reactions (Chutaputti 2000; Soza 2002; Sulkowski 2004; Brok 2009; Brok 2010), which might make it hard to detect any less severe adverse events that nitazoxanide might cause. We also considered other important and pre-defined co-variates such as genotype, previous antiviral treatment, and dose of intervention. A lack of trials with a low risk of bias, or trials specifying different regimes of nitazoxanide or including different kinds of participants meant it was not possible to perform subgroup analyses of other pre-defined co-variates, including trial risk of bias, different regimens of nitazoxanide in combination with any other intervention for chronic hepatitis C, co-infections and co-morbidities, and comparison of adults to adolescents and children. We planned to do best-worst and worst-best case scenario sensitivity analyses for missing data for all-cause mortality, chronic hepatitis C-related mortality and morbidity, but we abandoned these analyses as we had no data on these outcomes. Instead, we did a sensitivity analysis on a secondary outcome, failure of sustained virological response, as we had data that included dropouts. The best-worst case sensitivity analysis revealed that our results were compatible with a beneficial effect of nitazoxanide on sustained virological response. Attrition bias does not seem to explain our results.

Trials with high risk of bias tend to overestimate beneficial effects and tend to underestimate harmful effects (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovi 2012a; Savovi 2012b). We performed trial sequential analyses to assess the risk of random error, which is higher when data come from small information sets (Wetterslev 2009b). All of the trial sequential analyses - except for that for the surrogate outcome of sustained virological response showed that more trials are needed to assess the effects of nitazoxanide reliably. As included less than ten trials, we could not assess the risk of publication bias as we could not test for funnel plot asymmetry. This is a clear limitation of our review.

Heterogeneity Heterogeneity among trials might be due, for example, to differences in duration of treatment, differences in infection genotype, and disease severity of participants at entry, all of which might affect the effects of nitazoxanide. To reflect our concern about heterogeneity, we conducted all analyses using both a fixed-effect model and a random-effects model analysis. Results from the two models differed only for the comparisons of nitazoxanide plus standard treatment versus placebo plus standard treatment for failure to achieve sustained virological response, and for end-of-treatment virological response.

High versus low dose subgroup analysis

Quality of the evidence

Risks of systematic error and random errors All of the trials were assessed as being at high risk of bias so our results may overestimate benefits and underestimate harms. The main limitations in the reporting of the trials were the lack of clarity of the random sequence generation, lack of concealment of allocation, and lack of blinding. It is surprising that after having written about poor methodological quality in hepato-biliary trials and other trials for years, we still encounter such obvious defects (Schulz 1995; Gluud 1998; Moher 1998; Gluud 1999; Kjaergard 2001; Gluud 2002; Gluud 2006; Wood 2008; Savovi 2012a; Savovi 2012b). This review included only seven trials and a total of only 538 participants. Almost all our results are imprecise because they are based on a low number of randomised participants and few events, and thus have wide confidence intervals around the estimate of effect. The low number of included trials participants results in an increased risk of providing an unrealistic estimate of the intervention effects due to ’play of chance’ (random errors). Moreover, risk of bias is known to impact the estimated intervention effect.

With regard to tolerance for nitazoxanide, we have to take into consideration the doses tested. Two trials used a higher dose of nitazoxanide than the standard dose of 500 mg twice daily (Keeffe 2009a; Basu 2012a). In one of these trials (Keeffe 2009a), nitazoxanide was well tolerated with no serious adverse events or drug discontinuation. No information on adverse events or on drug discontinuation was provided in the other trial (Basu 2012a). The Keeffe 2009a trial reported that high dose nitazoxanide in combination with peginterferon and ribavirin has the potential to increase sustained virological response rates in comparison to those achieved using the standard dose. Subgroup analysis did not show any statistically significant effect of the higher experimental dose or of the standard dose of nitazoxanide on sustained virological response. However, the higher dose had a significant effect in achieving virological end-of-treatment response, whereas the standard dose had no significant effect on this outcome. Testing for subgroup difference showed a significant difference between the standard dose of nitazoxanide and the higher experimental dose for achieving virological end-of-treatment response. Nevertheless, results from subgroup analyses should always be interpreted with caution. Therefore, more clinical trials of higher nitazoxanide doses may be needed to examine the potential on the use of high dose of nitazoxanide.

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Potential biases in the review process We conducted this review according to methods outlined in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two of the authors extracted data independently for the review, which minimizes the risk of inaccurate data extraction. We performed and published a review protocol, outlining the objective of our review and listing our outcomes, before any data searches, data extractions and analyses were made. In addition, we performed meta-analyses with both fixed-effect and the randomeffects models, and performed trial sequential analyses plus sensitivity analyses. We performed a comprehensive literature search, and where relevant information was missing, we tried to contact authors of the trials to obtain additional information and all relevant data. Three trial authors replied and provided relevant data for our predefined outcome measures. However, it was not possible to obtain results for the majority of the outcomes. This is a major limitation of our review, primarily because of the risk of selective outcome reporting bias. We contacted relevant authors of trials and also pharmaceutical companies to inquire about information and data held on potentially unpublished trial results. As far as we know, we have obtained all of the available data there are to find to date that investigate the efficacy of nitazoxanide for chronic hepatitis C. It was only possible to complete three of the seven subgroup analyses we originally considered and planned. The low number of participants limited the power of subgroup analyses significantly for observing any statistical difference in effect estimates on the different outcomes.

Agreements and disagreements with other studies or reviews Nitazoxanide did not show any significant effect on serious as well as non-serious adverse events. This result is in accordance with a randomised clinical trial of nitazoxanide compared with metronidazole in the treatment of symptomatic giardiasis in 110 children (Ortiz 2001). This is also comparable to the results from two other randomised clinical trials. The first addressed treatment of diarrhoea caused by Cryptosporidium parvum (Rossignol 2001) and showed that nitazoxanide was well tolerated by participants, and no significant adverse events were observed. The second trial reported on treatment of cryptosporidial diarrhoea in participants with AIDS in Mexico (Rossignol 1998); here adverse events reported by participants receiving nitazoxanide were identical to those reported by participants receiving placebo. Although these clinical trials showed that nitazoxanide was well tolerated, the trials only included 100 and 66 participants, respectively. In 2011 the United Sates Food and Drug Administration (FDA) approved two direct-antiviral agents, boceprevir and telaprevir, for chronic hepatitis C virus therapy. Telaprevir is like nitazoxanide;

it is a new direct-acting drug that has an antiviral effect on the hepatitis C virus. However, telaprevir (and boceprevir) is indicated only for use against chronic hepatitis C genotype 1 infections. One of the trials included in the review investigated use of nitazoxanide with telaprevir and standard treatment; this combination did not show any significant effect on sustained virological response. However, clinical data findings from three phase III randomised clinical trials showed that a combination of telaprevir with peginterferon and ribavirin resulted in a higher sustained virological response within a shorter time period than standard treatment alone (Jacobson 2011; Sherman 2011; Zeuzem 2011). Two phase III clinical trials have been conducted to evaluate the efficacy of boceprevir (Bacon 2011; Poordad 2011), which showed high sustained virological response rates (over 66%). Future regimens may, following FDA indications (FDA 2014), not the use of interferon injections. Sofosbuvir (Sovaldi) is the first drug that has currently demonstrated safety and efficacy to treat certain types of hepatitis C virus infection without the need for co-administration of interferon (FDA 2014). The FDA approved sofosbuvir and simeprevir (Olysio) on 6 December 2013 and 22 September 2013, respectively. These are two new direct-antiviral agents for treatment of chronic hepatitis C infection in combination with classical antiviral treatment. Triple regimens of these drugs have indicated treatment efficacy with high sustained virological response rates (Kowdley 2013; Lawitz 2013; FDA 2014). However, the two triple regimen trials for sofosbuvir are both open-label studies with a primary outcome measure of sustained virological response and, although the trials on simeprevir are randomised, double-blinded, and placebo-controlled, none of these, or the ones conducted on sofosbuvir, have tested their clinical impact on outcomes other than adverse events (Kowdley 2013; Lawitz 2013). Many other direct-antiviral agents have been identified and hold promise for treatment of chronic hepatitis C genotype 1. Treatment with daclatasvir plus asunaprevir has yielded a sustained virological response of 95% (Everson 2012), but again, all these future regimens assess sustained virological response and not clinically relevant outcomes. These findings about the effects of direct-antiviral agents may correspond to effects that nitazoxanide possibly might have on sustained virological response, that are shown in this systematic review. However, the evidence for the effects of telaprevir, boceprevir, sofosbuvir, and simeprevir, is based on larger trials with a higher number of participants than the nitazoxanide trials included in this review. Furthermore, these trials evaluated only surrogate outcomes, such as sustained virological response, and did not assess any clinically relevant outcomes. Observational evidence has indicated that a sustained virological response to interferon is associated with a reduced risk of developing hepatocellular carcinoma (Brown 2000). However, observational studies should always be interpreted with great caution as they often overestimate benefits and underestimate harms

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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(Jakobsen 2013). As only one long-term follow-up trial was included in this review, it is difficult to know whether a sustained virological response, caused by nitazoxanide might be associated with a reduced risk of developing hepatocellular carcinoma.

AUTHORS’ CONCLUSIONS Implications for practice Currently, we cannot confirm or refute the effects of nitazoxanide for people with chronic hepatitis C. Our results show that more trials with a low risk of bias are needed to assess whether nitazoxanide versus placebo or no intervention has any effect on patientrelevant outcomes. Our results indicate that nitazoxanide might increase the sustained virological response; however, this is a surrogate outcome with questionable clinical relevance. Also, subgroup analyses indicate that higher doses of nitazoxanide might have a beneficial effect on end-of-treatment virological response, however, results for sustained virological response were uncertain, and more clinical trials of higher nitazoxanide doses are needed to examine its potential. All of the included trials had a high risk of bias, so the few indications of a potentially beneficial effect for nitazoxanide might be questionable.

Implications for research More trials with a low risk of bias are needed to assess the effects of nitazoxanide for chronic hepatitis C. Clinically relevant outcomes such as mortality, morbidity, adverse events, and quality of life ought to be assessed, and trials should have a long-term follow-up. More trials are needed that assess nitazoxanide as monotherapy, and also in combination with standard treatment or other kinds of interventions for chronic hepatitis C. Control interventions should primarily be placebo, or placebo plus the other interventions (not nitazoxanide) used in the experimental group (Jakobsen 2013). Such trials need to be conducted according to the SPIRIT statement (SPIRIT 2013a; SPIRIT 2013b), and reported according to the CONSORT statement (Schulz 2012). Furthermore, trialists should upload full protocols, including plans for statistical analysis and depersonalised individual patient data to allow analyses of the value of sustained virological response for clinicallyrelevant outcomes in publicly-controlled registers.

ACKNOWLEDGEMENTS We thank Hany Shehab for sending us additional data. Peer reviewers: Goran Hauser, Serbia; Juan Cristóbal Gana, Peru. Contact editor: Rosa G Simonetti, Italy.

REFERENCES

References to studies included in this review

Bacon 2010 {published data only} ∗ Bacon B, Shiffman M, Lim J, Berman A, Rustgi V, Keeffe E. A phase II, randomized, double-blind, placebocontrolled study of nitazoxanide plus peginterferon and ribavirin in naive patients with chronic hepatitis C genotype 1 infection: final report. Gastroenterology 2010;139(1):e18. Bacon B, Shiffman M, Lim J, Berman A, Rustgi V, Keeffe E. Phase 2 randomized, double-blind, placebo-controlled study of nitazoxanide plus peginterferon and ribavirin in HCV genotype 1 naive patients: week 12 sustained virological response rate. Journal of Hepatology 2010;52 (Suppl 1):S3. Bacon B, Shiffman M, Lim J, Berman A, Rustgi V, Keeffe E. Phase 2 randomized, double-blind, placebo-controlled study of nitazoxanide plus peginterferon and ribavirin in HCV genotype 1 patients: interim analysis shows increase in EVR. Journal of Hepatology 2009;50(Suppl 1):S381. Berrie C. Combined thiazolide nitazoxanide plus PEG-IFN Alfa-2a/ribavirin improved viral response in HCV genotype 1: presented at EASL 2010. http: //www.firstwordpharma.com/node/604408?tsid=17#

axzz2y2MTgiDa (accessed 4.04.2014). NCT00637923. Study of nitazoxanide, peginterferon alfa-2a and ribavirin in treatment-naive hepatitis C patients (STEALTH-3). http://clinicaltrials.gov/show/ NCT00637923 (accessed 24 January 2014). Basu 2012a {published data only} Basu P, Nair T, Farhat S, Ang L, Jafri M, Mittimani K, et al.Pegylated interferon alfa, nitazoxanide, telapravir, ribavirin, in genotype 1 undergoing prior experienced chronic hepatitis C patients-a randomized placebo control clinical pilot trial (INTRIGUE C) interim. Hepatology International 2012; Vol. 22nd Conference of the Asian Pacific Association for the Study of the Liver, APASL 2012 Taipei Taiwan:64. [CRS–ID: 6800100000029745] Basu P, Nair T, Farhat S, Ang L, Mittimani K, Shah NJ, et al.Peg-interferon alfa, nitazoxanide, telapravir, ribaverin, in genotype 1 in treatment experienced chronic hepatitis C patients - a randomized control pilot trial. Journal of Gastroenterology and Hepatology 2012; Vol. 27, issue S5: 207. [CRS–ID: 6800100000029736] ∗ Basu P, Shah N, Farhat S, Siriki R, Rahman M, Lynn A, et al.Pegylated interferon alfa, nitazoxanide, telaprevir, ribavirin, in genotype 1 undergoing prior experienced chronic hepatitis C patients - a randomized placebo

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control clinical pilot trial (intrigue-C). American Journal of Gastroenterology 2012; Vol. 107, issue S1:S154. [CRS–ID: 6800100000029740] Basu P, Shah N, Farhat S, Siriki R, Rahman MD, Lynn A, et al.Pegylated interferon alfa, nitazoxanide, telaprevir, ribavirin, in genotype 1 undergoing prior experienced chronic hepatitis C patients - a randomized placebo control clinical pilot trial (INTRIGUE-C) Interim. American Journal of Gastroenterology 2012; Vol. 142, issue 5:S932. [CRS–ID: 6800100000029788] Keeffe 2009a {published data only} Keeffe EB, Elfert A, Abousaif S, Rossignol J. Controlled release nitazoxanide in combination with peginterferon alfa2a plus ribavirin results in high early virologic response rates for treatment of chronic hepatitis C genotype 4. Hepatology 2009; Vol. 50, issue 4 (Suppl):1038A. ∗ Keeffe EB, Elfert AA, Abousaif SA. Dose-related increase in virologic responses using controlled release nitazoxanide plus peginterferon alfa-2A and ribavirin for treatment of chronic hepatitis C genotype 4: final report. Journal of Hepatology 2011;54(Suppl 1):S479–80. Rossignol 2008a {published data only} Kabil SM, Soliman MS, Youssef SM, Mounier BI. A controlled study of nitazoxanide (NTZ) 3 years after treatment of hepatitis C genotype 4. Journal of the Egyptian Society of Parasitology 2011;41(2):251–61. ∗ Rossignol JF, Kabil SM, El-Gohary Y, Keeffe EB. Clinical trial: randomized, double-blind, placebo-controlled study of nitazoxanide monotherapy for the treatment of patients with chronic hepatitis C genotype 4. Alimentary Pharmacology & Therapeutics 2008; Vol. 28:574–80. Rossignol JF, Kabil SM, El-Gohary Y, Keeffe EB. Randomized double blind placebo-controlled trial of nitazoxanide in the treatment of patients with chronic hepatitis C genotype 4 [abstract]. Journal of Hepatology 2008;48(Suppl 2):S311-2. Rossignol 2009a {published data only} ∗ Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Improved virologic response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon, and ribavirin. Gastroenterology 2009;136(3):856–62. Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB. Randomized controlled trial of nitazoxanide-peginterferonribavirin, nitazoxanide-peginterferon and peginterferon-ribavirin in the treatment of patients with chronic hepatitis C genotype 4. Journal of Hepatology 2008;48(Suppl 2):S30. Rossignol JF, Elfert A, El-Gohary Y, Keeffe EB, Glenn J. Interim data from a randomized controlled trial of nitazoxanide-peginterferon-ribavirin, nitazoxanidepeginterferon and peginterferon-ribavirin in the treatment of patients with chronic hepatitis C genotype 4. Hepatology 2007;46(4 Suppl 1):316A–317A. Shehab 2012 {published data only} NCT01276756. Efficacy of nitazoxanide in the treatment of chronic hepatitis C virus (HCV). http:// clinicaltrials.gov/ct2/show/NCT01276756?term=Effi-

cacy+of+nitazoxanide+in+the+treatment+of+chronic+hepatitis+C+virus+%28HCV%2 rank=1 (accessed 24 January 2014). [: NCT01276756] Shehab H [pers comm]. Efficiacy of nitazoxanide in the treatment of chronic hepatitis C virus (HCV). By email 28.11.2012. ∗ Shehab H, Elbaz T, Draz D. The addition of nitazoxanide to pegylated interferon and ribavirin does not improve SVR rates in chronic HCV genotype 4. Journal of Hepatology 2013; Vol. 58, issue Suppl 1:495. Shiffman 2009/2011 {published data only} NCT00495391. Study of nitazoxanide, peginterferon alfa2a and ribavirin for the treatment of hepatitis c (STEALTH2). http://clinicaltrials.gov/ct2/show/NCT00495391? term=NCT00495391&rank=1 (accessed 24 January 2014). Shiffman M, Ahmed A, Jacobson I, Pruitt R, Keeffe E. Phase 2 randomized, double-blind, placebo-controlled study of nitazoxanide with peginterferon alfa-2A and ribavirin in nonresponders (NR) with chronic HCV genotype 1: week 28 interim analysis. Journal of Hepatology 2009; Vol. 50, issue Suppl 1:S385. ∗ Shiffman ML, Ahmed A, Jacobson IM, Pruitt RE, Keeffe EB. Phase 2 randomized, double-blind, placebo-controlled study of nitazoxanide with peginterferon alfa-2a and ribavirin in nonresponders (NR) with chronic hepatitis C genotype 1: final report. Journal of Hepatology 2010;52 (Suppl 1):S459–S71.

References to studies excluded from this review Asrani 2010 {published data only} Asrani SK, Anderson S, Wilson J, Myhre LJ, Heimbach J, Kremes WK, et al.Nitazoxanide for the prevention of recurrent hepatitis C virus infection after liver transplantation: A pilot study. Hepatology 2010;52(S1): 874A. Basu 2009 {published data only} Basu P, Rayapudi K, Shah NJ, Krishnaswamy N, Pacana T, Khemani J, et al.Effects of high dose ribavirin (RBV), alinia (nitazoxanide) and pegylated Interferon (peg) alfa-2a in attaining sustained viral response (SVR) in treatment of chronic hepatitis C (ERAIS-C Trial) - interim results in naive genotype 1 patients. Hepatology 2009; Vol. 50, issue 4:730A–1A. [CRS–ID: 6800100000029790] Basu P, Rayapudi K, Shah NJ, Pacana T, Krishnaswamy N, Brown R. Effect of high-dose ribavirin (RBV), alinia (nitazoxanide) and pegylated Interferon (pegifn) alfa-2a in attaining sustained virologic response (SVR) in treatment of chronic hepatitis C. Journal of Hepatology 2010; Vol. 52, issue S1:S102. [CRS–ID: 6800100000029779] Basu PP, Rayapudi K, Pacana T, Shah NJ, Brown R. Effects of high dose ribavirin, alinia (R) (nitazoxanide) and pegylated interferon alfa-2a in attaining sustained viral response in treatment of chronic hepatitis C (ERAISC Trial) - interim results in naive genotype 1 patients. American Journal of Gastroenterology 2009;104(Suppl 3): S125. Basu PP, Rayapudi K, Pacana T, Shah NJ, Krishnaswamy N, Brown RS. Effect of high-dose ribavirin (RBV), alinia

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(nitazoxanide) and pegylated interferon (pegIFN) alfa-2a in attaining sustained virologic response (SVR) in treatment of chronic hepatitis C (ERAIS-C Trial) in naïve genotype 1 patients. International Journal of Infectuous Diseases 2010;14 (S2):S1–S2. Basu PP, Rayapudi K, Pacana T, Shah NJ, Krishnaswamy N, Brown RS. Effects of high-dose ribavirin (RBV), alinia (nitazoxanide) and pegylated interferon (pegIFN) alfa-2a in attaining sustained virological response (SVR) in treatment of chronic hepatitis C (ERAIS-C trial) in naive genotype 1 patients. Gastroenteology 2010;138(5):S–218. Kamal 2011 {published data only} Kamal SM. Hepatitis C virus genotype 4 therapy: progress and challenges. Liver International 2011; Vol. 31, issue Suppl 1:45–52. Kanda 2010 {published data only} Kanda T, Imazeki F, Yokosuka O. New antiviral therapies for chronic hepatitis C. Hepatology International 2010; Vol. 4, issue 3:548–61. Keeffe 2007 {published data only} Keeffe EB. Future treatment of chronic hepatitis C. Antiviral Therapy 2007; Vol. 12, issue 7:1015–25. Keeffe 2009 {published data only} Keeffe EB, Rossignol JF, Elfert A, Abdelatif S, Cravens L, Phuong TLT. Controlled release tablet improves pharmacokinetics, viral kinetics and tolerability of nitazoxanide for treatment of chronic hepatitis C. 19th Conference of the Asian Pacific Association for the Study of the Liver, Hong Kong, China. Hepatology International 2009;3:34–69. Keeffe 2009b {published data only} Keeffe EB. Current research on nitazoxanide in the treatment of chronic hepatitis C. Gastroenterology and Hepatology 2009; Vol. 5, issue 9:620–2. Mederacke 2009 {published data only} Mederacke I, Wedemeyer H. Nitazoxanide for the treatment of chronic hepatitis C New opportunities but new challenges?. Annals of Hepatology 2009; Vol. 8, issue 2: 166–8. Parfieniuk 2009 {published data only} Parfieniuk A, Flisiak R. New perspectives in treatment of chronic hepatitis C [Nowe mozliwosci leczenia przewleklych zakazen HCV]. Gastroenterologia Polska 2009; Vol. 16, issue 4:329–32. Pockros 2008a {published data only} Pockros PJ. Emerging therapies for chronic hepatitis C virus. Gastroenterology and Hepatology 2008; Vol. 4, issue 10:729–34. Pockros 2008b {published data only} Pockros PJ, Balart LA. Advances in hepatology research. Reviews in Gastroenterological Disorders 2008; Vol. 8, issue 3:194–212. Pockros 2009 {published data only} Pockros PJ. Emerging therapy for chronic hepatitis C: Highlights from the 59th Annual Meeting of the American

Association for the Study of Liver Diseases, 31 October4 November 2008, San Francisco, CA. Reviews in Gastroenterological Disorders. 2009; Vol. 9, issue 1:27–34. Rossignol 2008b {published data only} Rossignol JF, Keeffe EB. Thiazolides: a new class of drugs for the treatment of chronic hepatitis B and C. Future Microbiology 2008; Vol. 3, issue 5:539–45. [CRS–ID: 6800100000028352; JC—-NLM: Journal ID:101278120] Rossignol 2008c {published data only} Rossignol JF, Elfert A, Keeffe EB. Evaluation of a 4 week lead-in phase with nitazoxanide (NTZ) prior to peginterferon (pegifn) plus NTZ for treatment of chronic hepatitis C: final report. Hepatology 2008; Vol. 48, issue 4: 1132A–1133A. [CRS–ID: 6800100000029791] Rossignol 2010 {published data only} Rossignol JF, Elfert A, Keeffe EB. Evaluation of a 4-week lead-in with nitazoxanide (NTZ) prior to peginterferon (PegIFN) plus NTZ for treatment of chronic hepatitis C. Journal of Clinical Gastroenterology 2010; Vol. 44, issue 7:504–9. [DOI: 10.1097/MCG.0b013e3181bf9b15; PUBMED: 20048684] Rossignol JF, Elfert A, Keeffe EB. Evaluation of a 4-week lead-in with nitazoxanide (NTZ) prior to peginterferon (PegIFN) plus NTZ for treatment of chronic hepatitis C: final report. Hepatology 2008; Vol. 48, issue Suppl: 1132A–3A. Yoffe 2009 {published data only} Yoffe B, Gasitashvili K, Khaoustov V. Interim results: single center pilot efficacy study of nitazoxanide plus pegylated alpha-2a interferon and ribavirin in prior genotype 1 nonresponders with HCV induced cirrhosis. Journal of Hepatology 2009;50(Suppl 1):S353. Yoffe B, Gasitashvili K, Khaoustov V. Pilot study of leadin nitazoxanide plus pegylated alpha-2a interferon and ribavirin in HCV-genotype 1 nonresponders with cirrhosis: Interim results. Hepatology 2009;50(S4):1034A.

References to ongoing studies Kohla ongoing {published data only} Kohla M, EL-Said H, El-Fert AY, Ehsan N, Ezzat S, Taha HA. Impact of nitazoxanide on early virologic response (EVR) in Egyptian patients with chronic hepatitis C genotype 4: a double blind placebo-controlled trial. Hepatology 2012; Vol. 56, issue S1:583A. [CRS–ID: 6800100000029739] Kohla M, El-Said H, El-Fert A, Ehsan N, Ezzat S, Taha H. Impact of nitazoxanide on rapid virologic response in patients with chronic hepatitis C genotype 4: a double blind placebo-controlled trial. Journal of Gastroenterology and Hepatology 2012; Vol. 27, issue S5:236. [CRS–ID: 6800100000029735] NCT01197157. Study of the impact of nitazoxanide on chronic hepatitis patients. http://clinicaltrials.gov/ct2/ show/NCT01197157?term=NCT01197157&rank=1 (accessed 24 January 2014).

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Sitole 2013 Sitole M, Silva M, Spooner L, Comee MK, Malloy M. Telaprevir versus boceprevir in chronic hepatitis C: a metaanalysis of data from phase II and III trials. Clinical Therapeutics February 2013;35(2):190–7. [DOI: 10.1016/ j.clinthera.2012.12.017] Smith 2012 Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Teo CG. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. Centers for Disease Control and Prevention 2012;61(RR04):1–18. Soza 2002 Soza A, Everhart JE, Ghany MG, Doo E, Heller T, Promrat K, et al.Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology 2002;36(5):1273–9. [PUBMED: 12395340] SPIRIT 2013a Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krle a-Jeri K, et al.SPIRIT 2013 Statement: defining standard protocol items for clinical trials. Annals of Internal Medicine 2013;158:200–7. SPIRIT 2013b Chan A-W, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin J, et al.SPIRIT 2013 Explanation and elaboration: guidance for protocols of clinical trials. BMJ 2013;346: e7586. Stockis 2002 Stockis A, Allemon AM, De Bruyn S, Gengler C. Nitazoxanide pharmacokinetics and tolerability in man using single ascending oral doses. International Journal of Clinical Pharmacology and Therapeutics 2002;40:213–20.

Thorlund 2011 Thorlund K, Engstrøm J, Wetterslev J, Brok J, Imberger G, Gluud C. User manual forTrial Sequential Analysis (TSA). ctu.dk/tsa/files/tsa˙manual.pdf 2011 (accessed 23 April 2013). van Regenmortel 2000 van Regenmortel MHV, Fauquet CM, Bishop DHL, Carstens EB, Estes MK, Lemon SM, et al.Virus Taxonomy: Seventh Report of the International Committee on Taxonomy of Viruses. San Diego: Academic Press, 2000. Wetterslev 2008 Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. Journal of Clinical Epidemiology 2008;61(1):64–75. Wetterslev 2009 Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Medical Research Methodology 2009;9:86. Wetterslev 2009b Wetterslev J, Thorlund K, Brok J, Gluud C. Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. Journal of Clinical Epidemiology 2008;61:64–75. WHO 2010 World Health Organization. Viral hepatitis. Report by the secretariat. apps.who.int/gb/ebwha/pdf˙files/WHA63/ A63˙15-en.pdf 2010 (accessed January 2011). WHO 2011 World Health Organiziation. Hepatitis C. Fact sheet No. 164. http://www.who.int/mediacentre/factsheets/fs164/en/ index.html 2011; Vol. (accessed 24 January 2014).

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Wood 2008 Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman GD, et al.Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ (Clinical Research Ed.) 2008;336:601–5. Yang 2013 Yang D, Liang HJ, Li D, Wei X, Ma L, Jia Z. The efficacy and safety of telaprevir-based regimens for treating chronic hepatitis C virus genotype 1 infection: a meta-analysis of randomized trials. Internal Medicine 2013;52(6):653–60. Zeuzem 2011 Zeuzem S, Andreone P, Pol S. Telaprevir for retreatment of HCV infection. New England Journal of Medicine 2011; 364:2417–28. [DOI: 10.1056/NEJMoa1013086] ∗ Indicates the major publication for the study

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CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Bacon 2010 Methods

A phase II randomised, double-blinded, placebo-controlled trial (STEALTH C-3 trial) conducted in 13 centres in the USA

Participants

112 treatment-naive patients with chronic hepatitis C genotype 1 who underwent 2:1 randomisation Mean age: nitazoxanide group = 50 ± 7 years; placebo group = 51 ± 8 years Inclusion criteria: liver biopsy compatible with chronic hepatitis C within 36 months of study, serum hepatitis C virus RNA measured using Cobas TaqMan hepatitis C virus test (LOQ = 50 IU/mL) and Versant hepatitis C virus RNA Qualitive Assay (LOD = 10 IU/mL) Exclusion criteria: previous treatment with any interferon or interferon-based treatment for chronic hepatitis C; sexually active females of child-bearing age who were pregnant, breast-feeding or not using birth control; males whose female partners were sexually active and pregnant or of child-bearing potential and not using birth control; other causes of liver disease including autoimmune hepatitis; transplant recipients receiving immune suppression therapy; positive screening tests for anti-HAV IgM Ab, HBsAg, anti-HBc IgM Ab or anti-HIV Ab; decompensated cirrhosis; history of variceal bleeding; ascites; hepatic encephalopathy; CTP score > 6 or MELD score > 8; alcohol consumption of > 40 g/day or an alcohol use pattern that would interfere with the study; absolute neutrophil count < 1500 cells/mm3 ; platelet count < 135,000 cells/mm3 ; haemoglobin < 12 g/dL for women and < 13 g/dL for men, or serum creatinine concentration ≥ 1.5 times ULN; hypothyroidism or hyperthyroidism not effectively treated with medication; HgbA1c > 7.5 or history of diabetes mellitus; BMI > 34; serious or severe bacterial infection(s); ulcerative or hemorrhagic/Ischaemic colitis; pancreatitis; haemoglobinopathies. History or other clinical evidence of: significant or unstable cardiac disease; chronic pulmonary disease associated with functional impairment; severe or uncontrolled psychiatric disease, including severe depression, history of suicidal ideation, suicidal attempts or psychosis requiring medication or hospitalisation, or both; uncontrolled severe seizure disorder; requiring concomitant theophylline or methadone; immunologically-mediated disease requiring more than intermittent anti-inflammatory medications for management or frequent or prolonged use of corticosteroids; severe retinopathy or clinically relevant ophthalmological disorder due to diabetes mellitus or hypertension; hypersensitivity or intolerance to nitazoxanide or any of the excipients comprising the nitazoxanide tablets, peginterferon alfa-2a injectable solution or ribavirin tablets Participants who failed to achieve ≥ 2 log decrease undetectable hepatitis C virus RNA at week 28 were discontinued as failures and were excluded from the study

Interventions

Nitazoxanide (n = 75): nitazoxanide 500 mg twice daily for a 4-week lead-in period followed by a continued 500 mg nitazoxanide twice daily plus peginterferon alfa-2a 180 µg weekly and weight-based ribavirin (1000 to 1200 mg/d) for 48 weeks Placebo (n = 37): placebo 500 mg twice daily over a 4-week lead-in period followed by a continued 500 mg placebo twice daily plus peginterferon alfa-2a 180 µg weekly and weight-based ribavirin (1000 to 1200 mg/d) for 48 weeks

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Outcomes

Primary outcomes SVR rates at 24 weeks (6 months) Secondary outcomes To evaluate if the results of this STEALTH C-3 study were consistent with previously observed results of treatment with nitazoxanide plus peginterferon alfa-2a and ribavirin in naive patients with genotype 4 chronic hepatitis C To evaluate RVR, or undetectable (< 10 IU/mL) hepatitis C virus RNA at week 4; complete EVR, or undetectable hepatitis C virus RNA at week 12; partial EVR, at least a 2 log drop in viral load at week 12, and ETR, or undetectable viral load at completion of therapy; changes in ALT from baseline to weeks 8,16, end of treatment and end of follow-up

Notes

Funding for this study was provided by Romark Laboratories

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

“ . . . underwent 2:1 randomisation . . . ”

Allocation concealment (selection bias)

Unclear risk

No information about allocation concealment provided

Blinding (performance bias and detection Unclear risk bias) All outcomes

“ . . . in this double-blind, placebo-controlled study . . . ”

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

No information about blinding of participants and personnel provided

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

No information about blinding of outcome assessment provided

Incomplete outcome data (attrition bias) All outcomes

For the 37 placebo participants: “4 discontinued: AEs”, “8 withdrew consent”, “Treatment failure: 6 with . . . 2 hepatitis C virus . . . ”, “17 completed treatment and follow up”. For the 75 nitazoxanide participants: “7 discontinued AEs”, “7 withdrew consent”, “46 completed treatment and follow-up”, “ . . . one patient with genotype 2b erroneously enrolled, and one patient with genotype 1 without subtype . . . ”, “Four subjects (all in standard treatment group) withdrew after poor virological response (≤

Low risk

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1 log10 decrease at week 8)”, “Patients failing to achieve ≥ 2 log decrease in serum hepatitis C virus RNA at week 16 or undetectable hepatitis C virus RNA at week 28 were discontinued from study and treated as failures” Selective reporting (reporting bias)

Low risk

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Quote for primary outcome: “Safety analysis showed no adverse events attributable to NTZ, with the exception of mild intermittent diarrhoea and discoloured urine”, “ . . . there were no significant differences in serious adverse events between the 2 treatment groups”, “Adverse events were characteristic of peginterferon alfa-2a and ribavirin, including anaemia, thrombocytopenia and neutropenia”, “Serious adverse events were reported in 18 patients: 11 (14.7 %) in the NTZ+standard treatment group and 7 (18. 9 %) in the placebo+standard treatment group”, “There were 21 SAEs and no significant differences in AEs between the two treatment groups.” “Addition of NTZ to peginterferon alfa2a and ribavirin was associated with an increase in the SVR rate by more than onethird (44% vs. 32%) in U.S. patients with G1 infection, . . . ”, “Higher SVR12 rates were consistently shown in subsets of patients treated with NTZ+standard treatment, . . . ”, “Results are shown in Table 1. ”, “ . . . SVR rates were also higher in the NTZ (n = 62) vs placebo (n = 31) group (42% vs. 29%).” “ . . . , SVR rates were higher in the NTZ group: 57% (n = 49) vs 49% (n = 24), and 55% vs 35% in patients with high viral load.”, “Across the range of virological responses measured, the changes seen for the addition of NTZ included . . . sustained (SVR12: 32% vs 44%) virological responses.”, “In further subset analyses, there were SVR12 increases in favour of PEG-IFN/RBV treatment with NTZ . . .” Quote for secondary outcomes: “Results of this study are consistent with the previously observed results of treatment with NTZ plus peginterferon alfa-2a and ribavirin in

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naive patients with genotype 4 chronic hepatitis C”, “SVR12 rate for standard treatment group was lower than reported for other clinical trials of peginterferon alfa-2a plus ribavirin (e.g., IDEAL study SVR = 41% vs. 32% SVR12 for the present study) . . . ”, “Consistent with previously reported results in naive genotype 4 patients by more than one third.”, “Moreover, these findings are consistent with the previously observed EVR results in naive genotype 4 patients.” “Patients receiving nitazoxanide had higher response rates than those taking placebo by 12 weeks, but not at 4 weeks: RVR: 12% in nitazoxanide arm vs 19% in placebo arm; complete EVR: 62% vs 49%, respectively; ETR: 63% vs 46%, respectively; SVR: 44% vs 32, respectively.” Results for alanine aminotransferase levels were reported Other bias

High risk

There is probably a vested interest bias as Bacon performed the trial together with EB Keffee (who died in 2011). Keffee was an earlier employee of Romark Institute for Medical Research, Tampa, FL, USA

Basu 2012a Methods

A pilot randomised placebo controlled clinical trial (INTRIGUE-C)

Participants

50 treatment-experienced participants with chronic hepatitis C genotype 1 Exclusion criteria: decompensated cirrhotic, HCC, haemolytic anaemia, severe coronary artery disease, major depression, renal failure, skin rash, active drug, or alcohol abuse

Interventions

All participants received 180 µg peginterferon alfa-2a with a fixed dose of 1200 mg ribavirin daily, for 24 weeks, with 750 mg telaprevir 3 times daily for 12 weeks The 50 participants were divided into 3 groups: Group A (n = 12): received 500 mg nitazoxanide 3 times daily for 12 weeks Group B (n = 12): received 500 mg nitazoxanide twice daily for 12 weeks Group C (n = 12): this was the control group

Outcomes

SVR

Notes Risk of bias

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Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

“Done by random number allocation.”

Allocation concealment (selection bias)

Unclear risk

“Using sealed envelopes.” Note: no information about whether the envelopes were sequentially numbered and opaque

Blinding (performance bias and detection Unclear risk bias) All outcomes

The trial was described as blinded, but no other information was provided about who was blinded

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

No information provided

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

No information provided

Incomplete outcome data (attrition bias) All outcomes

Low risk

“one left the country, the number who left (one subject) was defined”

Selective reporting (reporting bias)

Low risk

“ . . . pre-defined, or clinically relevant and reasonably expected outcomes are reported on”. “This quadruple 24 weeks regimen has excelled the EVR, EVR and ETVR over standard treatment with DAA’s over 11%. SVR of 67% with 3/50 (6%) relapse was noted.”

Other bias

Unclear risk

The trial appears to be free of other components that could put it at risk of bias

Keeffe 2009a Methods

A phase II randomised, double-blinded clinical trial conducted in 1 centre in Egypt

Participants

41 treatment-naive participants with chronic hepatitis C genotype 4 Participants were randomised into three groups No inclusion or exclusion criteria were stated All participants were white Mean age: Group 1 = 32 ± 11 years; Group 2 = 36 ± 9 years; Group 3 = 43 ± 11 years

Interventions

Group 1 (n = 16): received 1350 mg nitazoxanide twice daily for 4 weeks followed by the same regimen of nitazoxanide plus the addition of 180 µg peginterferon alfa-2a weekly and 1000 mg-1200 mg ribavirin daily for 48 weeks

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Group 2 (n = 17): received 675 mg nitazoxanide twice daily for 4 weeks followed by the same regimen of nitazoxanide plus the addition of 180 µg peginterferon alfa-2a weekly and 1000 mg-1200 mg ribavirin daily for 48 weeks Group 3 (control; n = 8): received placebo twice daily for 4 weeks followed by the same regimen of placebo plus the addition of 180 µg peginterferon alfa-2a weekly and 1000 mg-1200 mg ribavirin daily for 48 weeks Outcomes

Primary outcome RVR, cEVR, ETR, and SVR rates

Notes

KN sent EB Keffee an e-mail requesting additional information. EB Keffee resent the email to JF Rossignol, since EB Keffee had left Romark Laboratories, LC on 25 April 2011 and was no longer employed by Romark after that date. No answer was received from J F Rossignol. Later, we were informed that EB Keffee died in 2011

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

“ . . . patients with chronic hepatitis C genotype 4 were randomised to receive . . . ”

Allocation concealment (selection bias)

No information about allocation concealment provided

Unclear risk

Blinding (performance bias and detection Unclear risk bias) All outcomes

No information about blinding provided

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

No information about blinding provided

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

No specification of who was blinded

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

“ . . . there were no serious adverse events or drug discontinuation.”

Selective reporting (reporting bias)

Low risk

Quote for primary outcome: “NTZ was well tolerated with all adverse events being mild to moderate; there were no serious adverse events or drug discontinuation.”, “CR NTZ has the potential to increase SVR rates in comparison to those achieved using standard NTZ in combination with PegIFN plus RBV.”, “This phase 2 trial shows dose-related increases in . . .

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ETR and SVR rates using CR NTZ added to standard of care for treatment of CHC, with good tolerability.”, “Virological response rates are shown: (Table from article)”, “Median Hepatitis C virus RNA reduction of -4,74, -5,11 and -5.57 for the placebo, low-dose and high-dose groups, respectively, were observed at week 16.” Other bias

High risk

There was a vested interest bias as Drs Rossignol and EB Keffee (who died in 2011) are employees of Romark Laboratories, LC, and received grant support for the conduct of this trial. The conflict of interest was declared by the authors. The trial was funded by the Romark Institute for Medical Research, Tampa, FL, USA

Rossignol 2008a Methods

A multicentre, randomised, double-blind, placebo-controlled trial conducted at 3 centres in Egypt (Cairo, Alexandria, and Tanta)

Participants

50 participants aged 18 years or older, randomised into 2 treatment groups Inclusion criteria: adults diagnosed with hepatitis C virus genotype 4, based on the presence of anti-hepatitis C virus and detectable serum hepatitis C virus RNA in combination with liver biopsy, obtained within 3 months of randomisation and showing findings compatible with chronic hepatitis C Exclusion criteria: use of interferon within 90 days, or ribavirin within 30 days prior to enrolment; had any alternative cause of liver disease;had acute hepatitis A or were coinfected with HBV; had history of alcoholism or alcohol consumption more than 40 g/ day; had a history of hypersensitivity or intolerance to nitazoxanide

Interventions

Group 1 (n = 25): received nitazoxanide (Alinia) 500 mg tablet twice daily for 24 weeks Group 2 (n = 25): received 1 matching placebo tablet twice daily for 24 weeks The dose selected for this study was 500 mg, which had been proven to be safe and well tolerated in short- and long-term treatment regimens for parasitic infections. All participants were instructed to take study medications with food Participants were followed up every 4 weeks during the 24-week treatment period and then for 24 weeks after completion of therapy

Outcomes

Primary outcome Evaluation of the safety and efficacy of 24 weeks of nitazoxanide monotherapy for the treatment of chronic hepatitis C genotype 4 by measuring ETR rates Secondary outcomes 1. SVR rates 24 weeks after completion of therapy 2. Serum hepatitis C virus RNA levels 3. Change in ALT levels

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Notes

KN sent E B Keffee an e-mail requesting additional information. EB Keffee resent the email to JF Rossignol, since EB Keffee had left Romark Laboratories, LC on 25 April 2011 and was no longer employed by Romark after that date. No answer was received from JF Rossignol. Later, we were informed that EB Keffee died in 2011

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

“Randomization was performed in a standard fashion using a randomisation list . . . ”

Allocation concealment (selection bias)

“ . . . kept in sealed envelopes”. Note: no information provided about whether the envelopes were sequentially numbered and opaque

Unclear risk

Blinding (performance bias and detection Low risk bias) All outcomes

“ double-blind, placebo-controlled trial” “ . . . matching placebo tablet . . .” “ . . . and the sponsor was blinded until the database was unlocked at the completion of the trial.” Note: no details provided about who was blinded, nor whether the sponsor was one of the “double-blinded” persons or whether it was a triple-blind trial

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

Note: no details provided about who was blinded, nor whether the sponsor was one of the “double-blinded” persons or whether it was a triple-blind trial

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

Note: no details provided about who was blinded, nor whether the sponsor was one of the “double-blinded” persons or whether it was a triple-blind trial

Incomplete outcome data (attrition bias) All outcomes

Low risk

“Three patients dropped out of the trial immediately after enrolment and did not receive any study medication, and one patient did not return for follow-up after week 8”

Selective reporting (reporting bias)

Low risk

Quote for primary outcome: “No patient had clinical decompensation with ascites, variceal bleeding, or hepatic encephalopathy. No patients in either arm had hepatocellular carcinoma.” “Seventeen patients . . . reported a total of 33 adverse events, with

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two serious adverse events. . . . Both events required hospitalisation and resolved without discontinuing treatment.” “The remaining adverse events were mild-to moderate and transient in nature, with none requiring modification or discontinuation of treatment. Adverse events were similar in the active and placebo groups.” Quote for secondary outcome 1: “Six of the seven virological responders were followedup for 24 weeks after end of treatment, and four of these patients . . . in the nitazoxanide group had an SVR compared to none in the placebo group . . . ” Quote for secondary outcome 2: “The mean reduction in serum Hepatitis C virus RNA from baseline to the end of treatment was greater for the active treatment group . . . than for the placebo group . . . ” Quote for secondary outcome 3: “Mean changes in serum alanine aminotransferase (ALT) levels from baseline to the end of treatment were not significantly different for the active and placebo groups.” Other bias

High risk

There was probably a vested interest bias as Rossignol and Keffee (who died in 2011) worked for Romark Laboratories, LC, and received grant support for the conduct of this trial. The conflict of interest was declared by the authors. The trial was funded by the Romark Institute for Medical Research, Tampa, FL, USA

Rossignol 2009a Methods

A randomised clinical trial (STEALTH C-1 trial) conducted at 2 centres in Egypt

Participants

The initial study enrolled 121 treatment-naive and treatment-experienced participants with chronic hepatitis C genotype 4. The subsequent study enrolled untreated participants with chronic hepatitis C genotype 4 The treatment-experienced patients in the initial study were sequentially randomised to 1 of 2 treatment groups, whereas the treatment-naive patients in both of the studies were sequentially randomised to 1 of 3 treatment groups Inclusion criteria: adults 18 years of age or older with chronic hepatitis C infection (for at least 6 months) evidenced by a positive enzyme immunoassay for anti-hepatitis C virus-antibodies and a positive quantitative RT-PCR amplification of hepatitis C virus RNA, chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral

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hepatitis, and hepatitis C virus genotype 4 Exclusion criteria: previous failure to respond to ≥ 12 weeks of peginterferon alfa-2aribavirin combination therapy; sexually active females who were pregnant, breast-feeding or not using birth control; males whose female partners were pregnant; other causes of liver disease (i.e., autoimmune hepatitis, decompensated liver disease); co-infection with hepatitis A virus, hepatitis B virus or hepatitis D virus; a history of alcoholism or with an alcohol consumption of > 40 g/day; haemoglobinopathies (i.e., thalassaemia major, sickle-cell anaemia); any concomitant condition that, in the opinion of the investigator, would preclude evaluation of response or make it unlikely that the contemplated course of therapy and follow-up could be completed; history of hypersensitivity or intolerance to any of the excipients comprising the nitazoxanide tablets, peginterferon alfa-2a injectionable solution or ribavirin tablets Interventions

Group 1 (n = 40): PegIFN + RBV for 48 weeks (standard care) Group 2 (n = 28): nitazoxanide monotherapy for 12 weeks followed by nitazoxanide + PegIFN for 36 weeks (usual therapy) Group 3 (n = 29): nitazoxanide monotherapy for 12 weeks followed by nitazoxanide + PegIFN + RBV for 36 weeks (triple therapy) Nitazoxanide was administered as one 500 mg tablet twice daily with food;the ribavirin dose was determined by participants’ weight, i.e., 1000 mg/day < 75 kg or 1200 mg/day ≥ 75 kg in divided doses; 180 µg PegIFN was injected once a week Participants were evaluated every 4 weeks during treatment, evaluations included physical examination, standard laboratory haematologic and chemistry tests and determination of hepatitis C virus viral load by RT-PCR The initial study had 12 treatment (interferon)-experienced patients in each of the 2 nitazoxanide groups

Outcomes

Primary outcome SVR rates 24 weeks after the end of treatment Secondary outcomes RVR after 4 weeks of combination therapy; EVR after 12 weeks of combination therapy; ETR; and ALT normalisation 24 weeks after the end of treatment

Notes

KN sent E B Keffee an e-mail requesting additional information. EB Keffee resent the email to JF Rossignol, since EB Keffee had left Romark Laboratories, LC on 25 April 2011 and was no longer employed by Romark after that date. No answer was received from JF Rossignol. Later, we were informed that EB Keffee died in 2011

Risk of bias Bias

Authors’ judgement

Random sequence generation (selection Low risk bias)

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Support for judgement “A computer-generated randomisation list prepared by the sponsor was used to package study medication for each patient with printed labels indicating the patient number.”

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Allocation concealment (selection bias)

High risk

“The investigators enrolled eligible patients and randomised them sequentially to 1 of the 3 treatment groups using the next available numbered package of study medication.”

Blinding (performance bias and detection Low risk bias) All outcomes

“Labaratory personnel were blinded as to treatment group assignment. Participants and investigators were not blinded.”

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

“Labaratory personnel were blinded as to treatment group assignment. Participants and investigators were not blinded.”

Blinding of outcome assessment (detection High risk bias) All outcomes

“Labaratory personnel were blinded as to treatment group assignment.” Note: personnel were not blinded for anything else, but the group assignment

Incomplete outcome data (attrition bias) All outcomes

Low risk

“One patient withdrew immediately, leaving 96 patients for analysis . . . ”, “Because there were a number of patients who discontinued therapy as a result of adverse events . . . , a separate analysis of virological response rates was conducted for the subset of patients after exclusion of these patients . . . ”, “Eight patients discontinued medication because of adverse events . . . Another 11 patients experienced dose reductions . . .”

Selective reporting (reporting bias)

Low risk

Quote for outcome 1: “SVR and interim virological responses rates are displayed in Table 2. Significantly more patients receiving triple therapy . . . experienced SVR compared with the standard of care . . . .”, “The SVR rates for the peginterferon alfa2a plus nitazoxanide group was higher than the standard of care (61% vs 50% . . . ), although this difference was not statistically significant.”, “In this study, triple therapy . . . achieved an SVR rate of 79% . . . , which was superior to the SVR rate achieved with the standard of care . . . ” Quote for outcome 2: “The RVR rate with triple therapy compared with standard of care was significantly higher . . . , whereas complete early virological re-

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sponse and end-of-treatment response rates were significantly different between these 2 treatment groups.”, “Virological responses were observed in some patients during the nitazoxanide monotherapy lead-in-phase. Fifty-three of 56 patients in groups 2 and 3 completed the 12-week nitazoxanide leadin phase . . . ”, “The proportion of patients achieving a RVR with triple therapy . . . was significantly higher than for the standard of care . . . ”, “Changes in alanine aminotransferase (ALT) levels from baseline to week 72 in patients who achieved a SVR are displayed in Table 3. Nearly all patients had normalisation of alanine aminotransferase (ALT) levels . . . ” Other bias

High risk

There was probably a vested interest bias as Rossignol and Keffee (who died in 2011) worked for Romark Laboratories, LC, and received grant support for the conduct of this trial. The conflict of interest was declared by the authors. The trial was funded by the Romark Institute for Medical Research, Tampa, FL, USA

Shehab 2012 Methods

An open-label, randomised clinical trial conducted in 1 centre in Egypt

Participants

100 treatment-naive patients with chronic hepatitis C genotype 4 recruited between November 2010-November 2012 Participants were randomised into 2 treatment groups Inclusion criteria: adults (male or female), 18-65 years of age, with chronic hepatitis C virus infection; BMI < 35; liver biopsy showing chronic hepatitis with significant fibrosis using Ishak scoring system; compensated liver disease; serum bilirubin < 1.5 mg/dL; INR no more than 1.5; serum albumin > 3.4; platelet count > 75,000 mm; no evidence of hepatic decompensation (hepatic encephalopathy or ascites); acceptable haematological and biochemical indices (haemoglobin 13g/dL for men and 12 g/dL for women; neutrophil count 1500/mm3 or more; serum creatinine < 1.5 mg/dL; serum HBsAg negative; negative ANA or titre of < 1:160; serum positive for anti-hepatitis C virus antibodies and hepatitis C virus-RNA; abdominal ultrasound obtained within 3 months prior to entry in the study; electrocardiogram for men aged > 40 years and for women aged > 50 years; normal fundus examination; agree to strict measures to avoid conception by both male and female participants through use of proper contraception measure throughout the course of treatment and for 6 months after; female patients must not breastfeed during therapy Exclusion criteria: previous therapy with interferon; HgbA1c > 7.5 or history of diabetes mellitus; BMI > 34; pregnant or breast-feeding women; men whose female partners were

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sexually active, pregnant, or of child-bearing potential and not using birth control; other causes of liver disease including autoimmune hepatitis; transplant recipients receiving immune suppression therapy; screening tests positive for anti-HAV IgM Ab; HBsAg, anti-HBc IgM Ab or anti-HIV Ab; decompensated cirrhosis; history of variceal bleeding, ascites, hepatic encephalopathy; CTP score > 6 or MELD score > 8; absolute neutrophil count < 1500 cells/mm3 ; platelet count < 135,000 cells/mm3 ; haemoglobin < 12 g/ dL for women and < 13 g/dL for men; or serum creatinine concentration ≥ 1.5 times ULN; hypothyroidism or hyperthyroidism not effectively treated with medication; alcohol consumption of > 40 g/day or an alcohol use pattern that would interfere with the study; serious or severe bacterial infection(s); clinically significant retinal abnormalities. History or other clinical evidence of: significant or unstable cardiac disease; chronic pulmonary disease associated with functional impairment; severe or uncontrolled psychiatric disease, including severe depression, history of suicidal ideation, suicidal attempts or psychosis requiring medication and/or hospitalisation; uncontrolled severe seizure disorder; immunologically-mediated disease requiring more than intermittent anti-inflammatory medications for management or that required frequent or prolonged use of corticosteroids; hypersensitivity or intolerance to nitazoxanide or any of the excipients comprising the nitazoxanide tablets, peginterferon alfa-2a injectable solution or ribavirin tablets Interventions

Participants were randomised in a 1:1 ratio into 2 treatment groups: Group 1 (n = 50): received 500 mg oral nitazoxanide twice daily for 4 weeks followed by ’triple therapy’ of nitazoxanide, pegylated interferon and ribavirin for a further 48 weeks Group 2 (n = 50): received weekly subcutaneous pegylated interferon 160 µg plus weightbased ribavirin (1200 mg ≥ 75 kg, 100 mg < 75 kg) for 48 weeks Participants were evaluated clinically and with laboratory testing every 2 weeks during the first 4 weeks, then every 4 weeks to the end of treatment, and every 12 weeks after the end of treatment. Hepatitis C virus-RNA was recorded at baseline and at week 4, 12, 24, 48, and 6 months after the end of treatment (Cobas Ampliprep/Cobas Taqman, lower limit of detection 15 IU/mL, Roche Molecular Systems, Pleasanton, CA)

Outcomes

Primary outcome SVR at 180 days (± 7 days) after the end of treatment, as defined by an undetectable serum hepatitis C virus RNA 24 weeks after the end of treatment Secondary outcomes RVR 28 to 33 days after start of pegylated interferon and ribavirin treatment, EVR 90 ± 7 days from the start of pegylated interferon and ribavirin treatment, ETR 180 ± 7 days after starting pegylated interferon and ribavirin treatment, defined as serum hepatitis C virus RNA below the limits of detection at 4 weeks and 12 weeks of combination treatment and at the end of treatment respectively Adverse events throughout the period of treatment and up to 90 days after the end of therapy Biochemical response (as defined by an ALT < 30U/L) was also evaluated at 12 weeks and compared with baseline levels. Participants who had less than a 2 log drop in serum hepatitis C virus RNA at 12 weeks of combination therapy or detectable serum hepatitis C virus RNA at 24 weeks of combination therapy were considered as treatment failures and treatment was discontinued

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Notes

This study was not financially, scientifically, or technically supported by any pharmaceutical company or other possible sources. All medications were supplied by the National Railway Hospital in Cairo, Egypt Hany Shehab sent us additional information on the trial 28 November 2012

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection High risk bias)

Allocation depended on admittance numbers

Allocation concealment (selection bias)

High risk

An open-label trial

Blinding (performance bias and detection High risk bias) All outcomes

An open-label trial

Blinding of participants and personnel High risk (performance bias) All outcomes

An open-label trial

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

Statistican was blinded

Incomplete outcome data (attrition bias) All outcomes

Low risk

“Only 2 patients dropped out after completing the treatment in group 1 . . . No withdrawals. In group 1 treatment was discontinued due to adverse events in 3 patients . . . , in group 2 treatment was discontinued in 2 patients . . . ”

Selective reporting (reporting bias)

Low risk

Quote for outcomes of SVR, RVR, EVR and ETR: “The addition of nitazoxanide to pegylated interferon and ribavirin does not improve the virological or biochemical response rates in chronic Hepatitis C virus genotype 4.”, “On an intention-totreat analysis the rates of RVR, CEVR, ETR and SVR were similar in both groups (Table 2). SVR rate was 48% in group 1 and 50% in group 2 (P = 0.84).” Quote for adverse events: “In group 1 treatment was discontinued due to adverse events in 3 patients (2 due to neutropenia at weeks 2 and 24 and 1 due to severe facial palsy at week 24), in group 2 treatment

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was discontinued in 2 patients (1 due to anaemia and 1 due to neutropenia, both at week 2).” Other bias

Low risk

“This is an independent randomised trial not supported by the industry to confirm the efficacy of nitazoxanide in the treatment of chronic HCV genotype 4.”

Shiffman 2009/2011 Methods

A randomised, double-blinded, placebo-controlled study (Phase II STEALTH C-2 trial) , conducted at 10 centres in the USA

Participants

64 participants with chronic hepatitis C genotype 1, who were non-responders to peginterferon alfa-2a or ribavirin, or both; 7% were black. Participants underwent a 2:1 randomisation. Mean age: Group 1 = 54 ± 8 years; Group 2 = 53 ± 6 years Inclusion criteria: chronic hepatitis C genotype 1; previously failed to respond to ≥12 weeks of peginterferon alfa-2a and ribavirin (< 2 log drop in hepatitis C virus RNA at week 12 or detectable hepatitis C virus RNA at week 2) Exclusion criteria: sexually active women of child-bearing age who were either pregnant, breast-feeding or not using birth control; men whose female partners were sexually active and pregnant or of child-bearing potential and not using birth control; other causes of liver disease including autoimmune hepatitis; transplant recipients receiving immune suppression therapy; positive screening tests for anti-HAV IgM Ab, HBsAg, anti-HBc IgM Ab or anti-HIV Ab; decompensated cirrhosis; history of variceal bleeding, ascites, hepatic encephalopathy; CTP score > 6 or MELD score > 8; alcohol consumption of > 40 g/day or an alcohol use pattern that would interfere with the study; absolute neutrophil count < 1500 cells/mm3 ; platelet count < 135,000 cells/mm3 ; haemoglobin < 12 g/dL for women and < 13 g/dL for men; serum creatinine concentration ≥ 1.5 times ULN; hypothyroidism or hyperthyroidism not effectively treated with medication; HgbA1c > 7.5 or history of diabetes mellitus; BMI > 28; serious or severe bacterial infection (s); ulcerative or haemorrhagic/ischaemic colitis; pancreatitis. History or other clinical evidence of: significant or unstable cardiac disease; chronic pulmonary disease associated with functional impairment; severe or uncontrolled psychiatric disease, including severe depression, history of suicidal ideation, suicidal attempts or psychosis requiring medication or hospitalisation, or both; uncontrolled severe seizure disorder that required concomitant theophylline or methadone; immunologically-mediated disease requiring more than intermittent anti-inflammatory medications for management or that required frequent or prolonged use of corticosteroids; severe retinopathy or clinically relevant ophthalmological disorder due to diabetes mellitus or hypertension; haemoglobinopathies; hypersensitivity or intolerance to nitazoxanide or any of the excipients comprising the nitazoxanide tablets, peginterferon alfa-2a injectable solution or ribavirin tablets

Interventions

Group 1 (n = 42): nitazoxanide twice daily over a 4-week lead-in followed by continued nitazoxanide plus peginterferon alfa-2a 180 µg weekly and weight-based ribavirin (1000 mg-1200 mg/day) for 48 weeks Group 2 (n = 22): placebo twice daily over a 4-week lead-in followed by continued placebo plus peginterferon alfa-2a 180 µg weekly and weight-based ribavirin (1000 mg-

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1200 mg/day) for 48 weeks Outcomes

Primary outcome SVR rates (hepatitis C virus RNA below lower limit of detection, 24 weeks after end of treatment) Secondary outcomes RVR after 4 weeks of combination treatment, complete and partial EVR after 12 weeks of combination treatment, and ETR at end of treatment Changes in ALT from baseline to weeks 8,16, end of treatment an end of follow-up

Notes

Funding for this study was provided by Romark Laboratories

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

“ . . . underwent 2:1 randomisation . . . ”

Allocation concealment (selection bias)

No information about this was provided

Unclear risk

Blinding (performance bias and detection Unclear risk bias) All outcomes

“ . . . in this double-blind . . . ”

Blinding of participants and personnel Unclear risk (performance bias) All outcomes

No information about this was provided

Blinding of outcome assessment (detection Unclear risk bias) All outcomes

No information about this was provided

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

“Therapy was discontinued if patients failed to achieve an EVR or had detectable hepatitis C virus RNA after 24 weeks of combination therapy.”, “one subject was a prior relapser and excluded from efficacy analysis.”, “ . . . no AE’s required discontinuation of treatment . . . ”

Selective reporting (reporting bias)

Unclear risk

Quote for SVR rates: “Results are shown in table 1.”, “Hepatitis C virus viral load did not change significantly during the 4-week nitazoxanide monotherapy lead-in period”, “SVR: 7% in nitazoxanide arm vs 0 in placebo arm”, “compared with PBO, NTZ added to PegIFN and RBV showed most incremental early virological responses and

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SVR.” Quote for RVR, EVT and ETR:“All 3 patients with SVR has a cEVR, 2 of whom had an RVR . . . ”, “Compared with PBO, NTZ added to pegIFN and RBV showed modest incremental early virological responses and SVR.”, “Patients receiving nitazoxanide had higher response rates than those taking placebo, but rates were low overall and differences did not reach statistical significance: RVR: 5% in nitazoxanide arm vs 0 in placebo arm; complete EVR: 7% vs 0, respectively; partial EVR: 38% vs 29%, respectively; ETR: 14% vs 0, respectively” No information about ALT levels was provided Other bias

High risk

There was probably a vested interest bias as Shiffman performed the trial with EB Keffee (who died in 2011). EB Keffee was previously employed by Romark Institute for Medical Research, Tampa, FL, USA

Abbreviations anti-HAV IgM Ab = anti hepatitis A virus immunoglobulin M antibody anti-HBc IgM Ab = anti hepatitis B core immunoglobulin M antibody anti-HIV Ab = anti human immunodeficiency virus antibody AEs = adverse events ALT = alanine aminotransferase ANA = antinuclear antibodies BMI = body mass index cEVR = complete early virological response CR = controlled release CTP score = Child-Turcotte-Pugh score DAA = direct acting antiviral ETR = virological end-of-treatment response EVR = early virological response HBV = hepatitis B virus HBsAg = hepatitis B surface antigen HgbA1c = haemoglobin A1c HCC = hepatocellular carcinoma IFN = interferon INR = international normalised ratio LOD = limit of detectionMELD score = model for end-stage liver disease LOQ = limit of quantification NTZ = nitazoxanide PBO = placebo Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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PegINF = peginterferon alfa-2a RBV = ribavirin RNA = ribonucleic acid RT-PCR = reverse transcription polymerase chain reaction RVR = rapid virological response SVR = sustained virological response SVR12 = sustained viral response to treatment regimens 12 weeks after therapy ULN = upper limit of normal vs = versus

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Asrani 2010

Not a randomised trial. An open label pilot study of nitazoxanide for the prevention of recurrent hepatitis C infection after liver transplantation

Basu 2009

Not a randomised trial. This study enrolled 33 treatment-naive patients with chronic hepatitis C genotype 1 to receive nitazoxanide plus peginterferon alfa-2a and high-dose ribavirin. The most common adverse events were haematological abnormalities. Anaemia, neutropenia and thrombocytopenia were common. Other adverse events such as skin rash were reported in 9 participants (27%). 11 participants had myalgia, mild changes and mild depression. One participant discontinued because of adverse events, and one participants was lost to follow-up

Kamal 2011

A review article about the latest news on treating hepatitis C

Kanda 2010

A review article about the latest news on treating hepatitis C

Keeffe 2007

A review article about treatment of hepatitis C

Keeffe 2009

A phase I cross-over trial

Keeffe 2009b

A review article about treatment of hepatitis C with nitazoxanide

Mederacke 2009

A review article commenting on Rossignol JF et al Improved virological response in chronic hepatitis C genotype 4 treated with nitazoxanide, peginterferon alfa-2a, and ribavirin (Rossignol 2009a)

Parfieniuk 2009

A review article about treatment of hepatitis C

Pockros 2008a

A review article about future treatment of hepatitis C

Pockros 2008b

A review article

Pockros 2009

A review article

Rossignol 2008b

A review article

Rossignol 2008c

A review article

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Rossignol 2010

A review article

Yoffe 2009

Not a randomised trial. This study enrolled 14 treatment-naive participants with chronic hepatitis C genotype 1 to receive nitazoxanide plus peginterferon alfa-2a and ribavirin. Adverse events were reported as not serious, mild to moderate, and intermittent in nature. Four participants developed adverse events, which included diarrhoea (n = 3), rash (n = 2), cellulitis (n = 3), and laryngitis (n = 1)

Characteristics of ongoing studies [ordered by study ID] Kohla ongoing Trial name or title

Study of the impact of nitazoxanide on chronic hepatitis patients Clinical trials.gov Identifier: NCT01197157

Methods

A phase 2 and 3 randomised, double-blinded trial of placebo for 12 weeks followed by peginterferon alfa-2a plus ribavirin (standard treatment) for 48 weeks versus 12 weeks 500 mg nitazoxanide monotherapy lead-in phase followed by a triple therapy with 500 mg nitazoxanide in combination with peginterferon alfa-2a and ribavirin for 48 weeks. This trial is being conducted in Egypt

Participants

This study is recruiting 200 treatment-naive participants with chronic hepatitis C genotype 4 Inclusion criteria: aged 18-60 years; liver biopsy showing chronic hepatitis with significant fibrosis using Ishak scoring system; compensated liver disease; acceptable haematological and biochemical indices; and willing to be treated and to adhere to treatment requirements Exclusion criteria: major uncontrolled mental illness; solid organ transplantation; autoimmune conditions; untreated thyroid disease; pregnant or unwilling to comply with adequate contraception; severe concurrent medical disease; severe hypertension; heart failure; significant coronary heart disease; poorly controlled diabetes; chronic obstructive pulmonary disease; and known hypersensitivity to drugs used to treat hepatitis C virus Both sexes are eligible for this study

Interventions

Participants in this study will be randomly assigned in a 1:1 ratio to the following 2 groups: Group A (100 CHC patients): oral nitazoxanide 500 mg twice daily with food for an average of 12 weeks followed by the standard treatment, peginterferon alfa-2a once weekly and weight-based ribavirin 1000 mg1200 mg/day (based on body weight < 75 kg or ≥ 75 kg, respectively) in divided doses plus placebo twice daily for 48 weeks Group B (100 CHC patients): monotherapy lead-in phase of placebo twice daily orally with food for an average of 12 weeks followed by triple therapy, 500 mg nitazoxanide twice daily, plus peginterferon alfa-2a once weekly and weight-based ribavirin 1000 mg-1200 mg/day for 48 weeks

Outcomes

The primary objective for this study is to evaluate the efficacy of nitazoxanide as an add-on therapy in terms of achieving SVR after the end of triple therapy (48 weeks from the start of triple therapy). In order to assess this, participants will have their viral load measured at 4 weeks from the start for assessment of SVR. To achieve this, participants must have undetectable levels of virus Secondary outcomes include the assessment of other virological responses; RVR, EVR and ETR. The safety and efficacy of nitazoxanide monotherapy following the lead-in phase will also be assessed

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Kohla ongoing

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Starting date

September 2010

Contact information

Mohamed A Kohla, MD +2/011104684 dr [email protected] Hossam-eldin A Tha, MD +2/0129772285 [email protected]

Notes

This study is sponsored by the National Liver Institute in Egypt

Abbreviations CHC = chronic hepatitis C ETR = virological end-of-treatment response EVR = early virological response RVR = rapid virological response

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DATA AND ANALYSES

Comparison 1. Nitazoxanide versus placebo or no intervention

Outcome or subgroup title 1 All-cause mortality 1.1 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin 2 Chronic hepatitis C-related mortality 2.1 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin 3 Morbidity 4 Adverse events 4.1 Nitazoxanide versus placebo 4.2 Nitazoxanide plus peginterferon and ribavirin versus placebo plus peginterferon and ribavirin 4.3 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin 5 Quality of life 6 Failure of sustained virological response 6.1 Nitazoxanide versus placebo 6.2 Nitazoxanide plus peginterferon and ribavirin versus placebo plus peginterferon and ribavirin 6.3 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin 6.4 Nitazoxanide plus telapravir plus peginterferon and ribavirin versus no intervention plus telapravir plus peginterferon and ribavirin 7 Failure of virological end-of-treatment response

No. of studies

No. of participants

1 1

100 100

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 0.0 [0.0, 0.0]

1

100

Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1

100

Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

0 4 1

0 331 50

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 1.10 [0.71, 1.71] 1.83 [0.80, 4.19]

1

112

Risk Ratio (M-H, Fixed, 95% CI)

0.78 [0.33, 1.84]

2

169

Risk Ratio (M-H, Fixed, 95% CI)

1.00 [0.51, 1.96]

0 7

0 498

Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 0.85 [0.75, 0.97]

1

50

Risk Ratio (M-H, Fixed, 95% CI)

0.84 [0.70, 1.01]

3

217

Risk Ratio (M-H, Fixed, 95% CI)

0.85 [0.72, 1.00]

2

181

Risk Ratio (M-H, Fixed, 95% CI)

0.88 [0.65, 1.19]

1

50

Risk Ratio (M-H, Fixed, 95% CI)

0.79 [0.38, 1.62]

7

498

Risk Ratio (M-H, Fixed, 95% CI)

0.81 [0.69, 0.96]

Statistical method

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Effect size

68

7.1 Nitazoxanide versus placebo 7.2 Nitazoxanide plus peginterferon and ribavirin versus placebo plus peginterferon and ribavirin 7.3 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin 7.4 Nitazoxanide plus telapravir plus peginterferon and ribavirin versus no intervention plus telapravir plus peginterferon and ribavirin 8 Participants without improvement in ALT and/or AST serum levels 8.1 Nitazoxanide versus placebo 8.2 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin 9 Number of participants without histological improvement

1

50

Risk Ratio (M-H, Fixed, 95% CI)

0.73 [0.56, 0.93]

3

217

Risk Ratio (M-H, Fixed, 95% CI)

0.73 [0.60, 0.89]

2

181

Risk Ratio (M-H, Fixed, 95% CI)

1.16 [0.78, 1.73]

1

50

Risk Ratio (M-H, Fixed, 95% CI)

0.54 [0.22, 1.36]

3

192

Risk Ratio (M-H, Fixed, 95% CI)

1.09 [0.84, 1.42]

1

50

Risk Ratio (M-H, Fixed, 95% CI)

0.9 [0.66, 1.23]

2

142

Risk Ratio (M-H, Fixed, 95% CI)

1.24 [0.85, 1.80]

0

0

Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Comparison 2. Subgroup: treatment-naives, relapsers and non-responders

Outcome or subgroup title 1 All-cause mortality 1.1 Treatment-naives 2 Chronic hepatitis C-related mortality 2.1 Treatment-naives 3 Morbidity 4 Adverse events 4.1 Treatment-naives 5 Quality of life 6 Failure of sustained virological response 6.1 Treatment-naives 6.2 Relapsers and non-responders 7 Failure of virological end-of-treatment response 7.1 Treatment-naives

No. of studies

No. of participants

1 1 1

100 100 100

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0]

1 0 3 3 0 6

100 0 281 281 0 412

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.92 [0.54, 1.56] 0.92 [0.54, 1.56] 0.0 [0.0, 0.0] 0.82 [0.69, 0.96]

4 2

322 90

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.78 [0.62, 0.97] 0.91 [0.77, 1.09]

5

386

Risk Ratio (M-H, Fixed, 95% CI)

0.82 [0.67, 1.00]

4

322

Risk Ratio (M-H, Fixed, 95% CI)

0.80 [0.60, 1.06]

Statistical method

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Effect size

69

7.2 Relapsers and non-responders 8 Participants without improvement in ALT and/or AST serum levels 8.1 Treatment-naives 9 Number of participants without histological improvement

1

64

Risk Ratio (M-H, Fixed, 95% CI)

0.87 [0.75, 1.00]

2

142

Risk Ratio (M-H, Fixed, 95% CI)

1.24 [0.85, 1.80]

2 0

142 0

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

1.24 [0.85, 1.80] 0.0 [0.0, 0.0]

Comparison 3. Subgroup: genotype 1 compared to genotype 4

Outcome or subgroup title 1 All-cause mortality 1.1 Genotype 4 2 Chronic hepatitis C-related mortality 2.1 Genotype 4 3 Morbidity 4 Adverse events 4.1 Genotype 1 4.2 Genotype 4 5 Quality of life 6 Failure of sustained virological response 6.1 Genotype 1 6.2 Genotype 4 7 Failure of virological end-of-treatment response 7.1 Genotype 1 7.2 Genotype 4 8 Participants without improvement in ALT and/or AST serum levels 8.1 Genotype 4 9 Number of participants without histological improvement

No. of studies

No. of participants

1 1 1

100 100 100

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 0.0 [0.0, 0.0]

1 0 4 1 3 0 7

100 0 331 112 219 0 498

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 0.0 [0.0, 0.0] 1.10 [0.71, 1.71] 0.78 [0.33, 1.84] 1.24 [0.74, 2.08] 0.0 [0.0, 0.0] 0.85 [0.75, 0.97]

3 4 7

226 272 498

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.88 [0.74, 1.04] 0.83 [0.68, 1.02] 0.81 [0.69, 0.96]

3 4 3

226 272 192

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.76 [0.61, 0.93] 0.88 [0.69, 1.12] 1.09 [0.84, 1.42]

3 0

192 0

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

1.09 [0.84, 1.42] 0.0 [0.0, 0.0]

Statistical method

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Effect size

70

Comparison 4. Subgroup: nitazoxanide dose comparison

Outcome or subgroup title 1 All-cause mortality 1.1 Standard dose (1000 mg/day) 2 Chronic hepatitis C-related mortality 2.1 Standard dose (1000 mg/day) 3 Morbidity 4 Adverse events 4.1 Standard dose (1000 mg/day) 5 Quality of life 6 Failure of sustained virological response 6.1 Standard dose (1000 mg/day) 6.2 Experimental dose (< 1000 mg/day) 7 Failure of virological end-of-treatment response 7.1 Standard dose (1000 mg/day) 7.2 Experimental dose (< 1000 mg/day) 8 Participants without improvement in ALT and/or AST serum levels 8.1 Standard dose (1000 mg/day) 9 Number of participants without histological improvement

No. of studies

No. of participants

1 1

100 100

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 0.0 [0.0, 0.0]

1

100

Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1

100

Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

0 4 4

0 331 331

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 1.10 [0.71, 1.71] 1.10 [0.71, 1.71]

0 7

0 532

Mean Difference (IV, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0] 0.84 [0.73, 0.96]

6

445

Risk Ratio (M-H, Fixed, 95% CI)

0.87 [0.76, 1.00]

2

87

Risk Ratio (M-H, Fixed, 95% CI)

0.57 [0.31, 1.04]

7

532

Risk Ratio (M-H, Fixed, 95% CI)

0.79 [0.67, 0.93]

6

445

Risk Ratio (M-H, Fixed, 95% CI)

0.85 [0.72, 1.00]

2

87

Risk Ratio (M-H, Fixed, 95% CI)

0.36 [0.17, 0.76]

3

192

Risk Ratio (M-H, Fixed, 95% CI)

1.09 [0.84, 1.42]

3

192

Risk Ratio (M-H, Fixed, 95% CI)

1.09 [0.84, 1.42]

0

0

Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Statistical method

Effect size

Comparison 5. Best-worst case scenario analysis

Outcome or subgroup title 1 Failure of sustained virological response

No. of studies

No. of participants

4

307

Statistical method Risk Ratio (M-H, Fixed, 95% CI)

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Effect size 0.81 [0.70, 0.94]

71

Comparison 6. Worst-best case scenario analysis

Outcome or subgroup title

No. of studies

No. of participants

4

307

1 Failure of sustained virological response

Statistical method

Effect size

Risk Ratio (M-H, Fixed, 95% CI)

0.87 [0.76, 1.01]

Analysis 1.1. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 1 All-cause mortality. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 1 Nitazoxanide versus placebo or no intervention Outcome: 1 All-cause mortality

Study or subgroup

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin Shehab 2012

0/50

0/50

Not estimable

Total (95% CI)

50

50

Not estimable

Total events: 0 (Nitazoxanide), 0 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

0.002

0.1

1

Favours nitazoxanide

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

500

Favours PBO/no/other int’

72

Analysis 1.2. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 2 Chronic hepatitis C-related mortality. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 1 Nitazoxanide versus placebo or no intervention Outcome: 2 Chronic hepatitis C-related mortality

Study or subgroup

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin Shehab 2012

0/50

0/50

Not estimable

Total (95% CI)

50

50

Not estimable

Total events: 0 (Nitazoxanide), 0 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

0.01

0.1

1

Favours nitazoxanide

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

100

Favours PBO/no/other int’

73

Analysis 1.4. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 4 Adverse events. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 1 Nitazoxanide versus placebo or no intervention Outcome: 4 Adverse events

Study or subgroup

Nitazoxanide

PBO/no/other intervention

n/N

n/N

11/25

6/25

19.6 %

1.83 [ 0.80, 4.19 ]

25

25

19.6 %

1.83 [ 0.80, 4.19 ]

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Nitazoxanide versus placebo Rossignol 2008a

Subtotal (95% CI)

Total events: 11 (Nitazoxanide), 6 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: Z = 1.44 (P = 0.15) 2 Nitazoxanide plus peginterferon and ribavirin versus placebo plus peginterferon and ribavirin Bacon 2010

11/75

7/37

30.6 %

0.78 [ 0.33, 1.84 ]

75

37

30.6 %

0.78 [ 0.33, 1.84 ]

Subtotal (95% CI)

Total events: 11 (Nitazoxanide), 7 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: Z = 0.58 (P = 0.56) 3 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin Rossignol 2009a Shehab 2012

2/29

11/40

30.2 %

0.25 [ 0.06, 1.05 ]

13/50

6/50

19.6 %

2.17 [ 0.89, 5.25 ]

79

90

49.8 %

1.00 [ 0.51, 1.96 ]

152

100.0 %

1.10 [ 0.71, 1.71 ]

Subtotal (95% CI)

Total events: 15 (Nitazoxanide), 17 (PBO/no/other intervention) Heterogeneity: Chi2 = 6.53, df = 1 (P = 0.01); I2 =85% Test for overall effect: Z = 0.01 (P = 0.99)

Total (95% CI)

179

Total events: 37 (Nitazoxanide), 30 (PBO/no/other intervention) Heterogeneity: Chi2 = 8.48, df = 3 (P = 0.04); I2 =65% Test for overall effect: Z = 0.41 (P = 0.68) Test for subgroup differences: Chi2 = 2.17, df = 2 (P = 0.34), I2 =8%

0.1 0.2

0.5

Favours nitazoxanide

1

2

5

10

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

74

Analysis 1.6. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 6 Failure of sustained virological response. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 1 Nitazoxanide versus placebo or no intervention Outcome: 6 Failure of sustained virological response

Study or subgroup

Nitazoxanide

PBO/no/other intervention

n/N

n/N

21/25

25/25

16.8 %

0.84 [ 0.70, 1.01 ]

25

25

16.8 %

0.84 [ 0.70, 1.01 ]

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Nitazoxanide versus placebo Rossignol 2008a

Subtotal (95% CI)

Total events: 21 (Nitazoxanide), 25 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: Z = 1.82 (P = 0.069) 2 Nitazoxanide plus peginterferon and ribavirin versus placebo plus peginterferon and ribavirin Bacon 2010

43/75

25/37

22.1 %

0.85 [ 0.63, 1.14 ]

Keeffe 2009a

7/33

4/8

4.2 %

0.42 [ 0.16, 1.10 ]

Shiffman 2009/2011

39/42

22/22

19.3 %

0.94 [ 0.84, 1.05 ]

Subtotal (95% CI)

150

67

45.7 %

0.85 [ 0.72, 1.00 ]

Total events: 89 (Nitazoxanide), 51 (PBO/no/other intervention) Heterogeneity: Chi2 = 5.50, df = 2 (P = 0.06); I2 =64% Test for overall effect: Z = 1.98 (P = 0.048) 3 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin Rossignol 2009a

16/41

20/40

13.4 %

0.78 [ 0.48, 1.28 ]

Shehab 2012

25/50

26/50

17.2 %

0.96 [ 0.65, 1.41 ]

91

90

30.5 %

0.88 [ 0.65, 1.19 ]

Subtotal (95% CI)

Total events: 41 (Nitazoxanide), 46 (PBO/no/other intervention) Heterogeneity: Chi2 = 0.43, df = 1 (P = 0.51); I2 =0.0% Test for overall effect: Z = 0.81 (P = 0.42) 4 Nitazoxanide plus telapravir plus peginterferon and ribavirin versus no intervention plus telapravir plus peginterferon and ribavirin Basu 2012a

8/24

11/26

7.0 %

0.79 [ 0.38, 1.62 ]

24

26

7.0 %

0.79 [ 0.38, 1.62 ]

208

100.0 %

0.85 [ 0.75, 0.97 ]

Subtotal (95% CI)

Total events: 8 (Nitazoxanide), 11 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: Z = 0.65 (P = 0.52)

Total (95% CI)

290

Total events: 159 (Nitazoxanide), 133 (PBO/no/other intervention) Heterogeneity: Chi2 = 5.65, df = 6 (P = 0.46); I2 =0.0% Test for overall effect: Z = 2.34 (P = 0.019) Test for subgroup differences: Chi2 = 0.11, df = 3 (P = 0.99), I2 =0.0%

0.2

0.5

Favours nitazoxanide

1

2

5

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

75

Analysis 1.7. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 7 Failure of virological end-of-treatment response. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 1 Nitazoxanide versus placebo or no intervention Outcome: 7 Failure of virological end-of-treatment response

Study or subgroup

Nitazoxanide

PBO/no/other intervention

n/N

n/N

18/25

25/25

20.1 %

0.73 [ 0.56, 0.93 ]

25

25

20.1 %

0.73 [ 0.56, 0.93 ]

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Nitazoxanide versus placebo Rossignol 2008a

Subtotal (95% CI)

Total events: 18 (Nitazoxanide), 25 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: Z = 2.51 (P = 0.012) 2 Nitazoxanide plus peginterferon and ribavirin versus placebo plus peginterferon and ribavirin Bacon 2010

29/75

20/37

21.1 %

0.72 [ 0.47, 1.08 ]

Keeffe 2009a

3/33

4/8

5.1 %

0.18 [ 0.05, 0.66 ]

Shiffman 2009/2011

36/42

22/22

23.1 %

0.87 [ 0.75, 1.00 ]

Subtotal (95% CI)

150

67

49.3 %

0.73 [ 0.60, 0.89 ]

Total events: 68 (Nitazoxanide), 46 (PBO/no/other intervention) Heterogeneity: Chi2 = 10.22, df = 2 (P = 0.01); I2 =80% Test for overall effect: Z = 3.07 (P = 0.0022) 3 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin Rossignol 2009a

13/41

10/40

8.0 %

1.27 [ 0.63, 2.55 ]

Shehab 2012

21/50

19/50

15.0 %

1.11 [ 0.68, 1.79 ]

91

90

23.0 %

1.16 [ 0.78, 1.73 ]

Subtotal (95% CI)

Total events: 34 (Nitazoxanide), 29 (PBO/no/other intervention) Heterogeneity: Chi2 = 0.10, df = 1 (P = 0.75); I2 =0.0% Test for overall effect: Z = 0.74 (P = 0.46) 4 Nitazoxanide plus telapravir plus peginterferon and ribavirin versus no intervention plus telapravir plus peginterferon and ribavirin Basu 2012a

Subtotal (95% CI)

5/24

10/26

7.6 %

0.54 [ 0.22, 1.36 ]

24

26

7.6 %

0.54 [ 0.22, 1.36 ]

Total events: 5 (Nitazoxanide), 10 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: Z = 1.31 (P = 0.19)

0.05

0.2

Favours nitazoxanide

1

5

20

Favours PBO/no/other int’

(Continued . . . )

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

76

(. . . Study or subgroup

Nitazoxanide

PBO/no/other intervention

n/N

n/N

290

208

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI

Continued) Risk Ratio

M-H,Fixed,95% CI

100.0 %

0.81 [ 0.69, 0.96 ]

Total events: 125 (Nitazoxanide), 110 (PBO/no/other intervention) Heterogeneity: Chi2 = 11.07, df = 6 (P = 0.09); I2 =46% Test for overall effect: Z = 2.48 (P = 0.013) Test for subgroup differences: Chi2 = 5.14, df = 3 (P = 0.16), I2 =42%

0.05

0.2

1

Favours nitazoxanide

5

20

Favours PBO/no/other int’

Analysis 1.8. Comparison 1 Nitazoxanide versus placebo or no intervention, Outcome 8 Participants without improvement in ALT and/or AST serum levels. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 1 Nitazoxanide versus placebo or no intervention Outcome: 8 Participants without improvement in ALT and/or AST serum levels

Study or subgroup

Nitazoxanide

PBO/no/other intervention

n/N

n/N

18/25

20/25

42.3 %

0.90 [ 0.66, 1.23 ]

25

25

42.3 %

0.90 [ 0.66, 1.23 ]

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Nitazoxanide versus placebo Rossignol 2008a

Subtotal (95% CI)

Total events: 18 (Nitazoxanide), 20 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: Z = 0.66 (P = 0.51) 2 Nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin Rossignol 2009a Shehab 2012

7/22

5/20

11.1 %

1.27 [ 0.48, 3.37 ]

27/50

22/50

46.6 %

1.23 [ 0.82, 1.84 ]

72

70

57.7 %

1.24 [ 0.85, 1.80 ]

95

100.0 %

1.09 [ 0.84, 1.42 ]

Subtotal (95% CI)

Total events: 34 (Nitazoxanide), 27 (PBO/no/other intervention) Heterogeneity: Chi2 = 0.00, df = 1 (P = 0.95); I2 =0.0% Test for overall effect: Z = 1.10 (P = 0.27)

Total (95% CI)

97

0.2

0.5

Favours nitazoxanide

1

2

5

Favours PBO/no/other int’

(Continued . . . )

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

77

(. . . Study or subgroup

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Risk Ratio

Weight

M-H,Fixed,95% CI

Continued) Risk Ratio

M-H,Fixed,95% CI

Total events: 52 (Nitazoxanide), 47 (PBO/no/other intervention) Heterogeneity: Chi2 = 1.89, df = 2 (P = 0.39); I2 =0.0% Test for overall effect: Z = 0.67 (P = 0.50) Test for subgroup differences: Chi2 = 1.61, df = 1 (P = 0.20), I2 =38%

0.2

0.5

1

Favours nitazoxanide

2

5

Favours PBO/no/other int’

Analysis 2.1. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 1 Allcause mortality. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 2 Subgroup: treatment-naives, relapsers and non-responders Outcome: 1 All-cause mortality

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Shehab 2012

0/50

0/50

Not estimable

Total (95% CI)

50

50

Not estimable

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Treatment-naives

Total events: 0 (Nitazoxanide), 0 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

0.01

0.1

1

Favours nitazoxanide

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

100

Favours PBO/no/other int’

78

Analysis 2.2. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 2 Chronic hepatitis C-related mortality. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 2 Subgroup: treatment-naives, relapsers and non-responders Outcome: 2 Chronic hepatitis C-related mortality

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Shehab 2012

0/50

0/50

Not estimable

Total (95% CI)

50

50

Not estimable

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Treatment-naives

Total events: 0 (Nitazoxanide), 0 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

0.01

0.1

1

Favours nitazoxanide

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

100

Favours PBO/no/other int’

79

Analysis 2.4. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 4 Adverse events. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 2 Subgroup: treatment-naives, relapsers and non-responders Outcome: 4 Adverse events

Nitazoxanide

PBO/no/other intervention

n/N

n/N

11/75

7/37

38.1 %

0.78 [ 0.33, 1.84 ]

2/29

11/40

37.6 %

0.25 [ 0.06, 1.05 ]

Shehab 2012

13/50

6/50

24.4 %

2.17 [ 0.89, 5.25 ]

Total (95% CI)

154

127

100.0 %

0.92 [ 0.54, 1.56 ]

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Treatment-naives Bacon 2010 Rossignol 2009a

Total events: 26 (Nitazoxanide), 24 (PBO/no/other intervention) Heterogeneity: Chi2 = 6.94, df = 2 (P = 0.03); I2 =71% Test for overall effect: Z = 0.32 (P = 0.75) Test for subgroup differences: Not applicable

0.01

0.1

Favours nitazoxanide

1

10

100

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

80

Analysis 2.6. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 6 Failure of sustained virological response. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 2 Subgroup: treatment-naives, relapsers and non-responders Outcome: 6 Failure of sustained virological response

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Bacon 2010

43/75

25/37

28.5 %

0.85 [ 0.63, 1.14 ]

Keeffe 2009a

7/33

4/8

5.5 %

0.42 [ 0.16, 1.10 ]

Rossignol 2009a

7/29

20/40

14.3 %

0.48 [ 0.24, 0.99 ]

25/50

26/50

22.1 %

0.96 [ 0.65, 1.41 ]

187

135

70.4 %

0.78 [ 0.62, 0.97 ]

4/12

6/14

4.7 %

0.78 [ 0.29, 2.12 ]

39/42

22/22

24.9 %

0.94 [ 0.84, 1.05 ]

54

36

29.6 %

0.91 [ 0.77, 1.09 ]

171

100.0 %

0.82 [ 0.69, 0.96 ]

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Treatment-naives

Shehab 2012

Subtotal (95% CI)

Total events: 82 (Nitazoxanide), 75 (PBO/no/other intervention) Heterogeneity: Chi2 = 4.76, df = 3 (P = 0.19); I2 =37% Test for overall effect: Z = 2.22 (P = 0.027) 2 Relapsers and non-responders Basu 2012a Shiffman 2009/2011

Subtotal (95% CI)

Total events: 43 (Nitazoxanide), 28 (PBO/no/other intervention) Heterogeneity: Chi2 = 0.35, df = 1 (P = 0.55); I2 =0.0% Test for overall effect: Z = 1.02 (P = 0.31)

Total (95% CI)

241

Total events: 125 (Nitazoxanide), 103 (PBO/no/other intervention) Heterogeneity: Chi2 = 11.02, df = 5 (P = 0.05); I2 =55% Test for overall effect: Z = 2.43 (P = 0.015) Test for subgroup differences: Chi2 = 1.26, df = 1 (P = 0.26), I2 =21%

0.01

0.1

Favours nitazoxanide

1

10

100

Favours PBO/no/other int’

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81

Analysis 2.7. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 7 Failure of virological end-of-treatment response. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 2 Subgroup: treatment-naives, relapsers and non-responders Outcome: 7 Failure of virological end-of-treatment response

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Bacon 2010

29/75

20/37

29.8 %

0.72 [ 0.47, 1.08 ]

Keeffe 2009a

3/33

4/8

7.2 %

0.18 [ 0.05, 0.66 ]

Rossignol 2009a

6/29

10/40

9.3 %

0.83 [ 0.34, 2.02 ]

21/50

19/50

21.1 %

1.11 [ 0.68, 1.79 ]

187

135

67.4 %

0.80 [ 0.60, 1.06 ]

36/42

22/22

32.6 %

0.87 [ 0.75, 1.00 ]

42

22

32.6 %

0.87 [ 0.75, 1.00 ]

157

100.0 %

0.82 [ 0.67, 1.00 ]

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Treatment-naives

Shehab 2012

Subtotal (95% CI)

Total events: 59 (Nitazoxanide), 53 (PBO/no/other intervention) Heterogeneity: Chi2 = 7.15, df = 3 (P = 0.07); I2 =58% Test for overall effect: Z = 1.56 (P = 0.12) 2 Relapsers and non-responders Shiffman 2009/2011

Subtotal (95% CI)

Total events: 36 (Nitazoxanide), 22 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: Z = 1.99 (P = 0.047)

Total (95% CI)

229

Total events: 95 (Nitazoxanide), 75 (PBO/no/other intervention) Heterogeneity: Chi2 = 7.84, df = 4 (P = 0.10); I2 =49% Test for overall effect: Z = 2.00 (P = 0.046) Test for subgroup differences: Chi2 = 0.28, df = 1 (P = 0.60), I2 =0.0%

0.01

0.1

Favours nitazoxanide

1

10

100

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

82

Analysis 2.8. Comparison 2 Subgroup: treatment-naives, relapsers and non-responders, Outcome 8 Participants without improvement in ALT and/or AST serum levels. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 2 Subgroup: treatment-naives, relapsers and non-responders Outcome: 8 Participants without improvement in ALT and/or AST serum levels

Study or subgroup

Nitazoxanide

PBO/no/other intervention

n/N

n/N

7/22

5/20

19.2 %

1.27 [ 0.48, 3.37 ]

27/50

22/50

80.8 %

1.23 [ 0.82, 1.84 ]

72

70

100.0 %

1.24 [ 0.85, 1.80 ]

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Treatment-naives Rossignol 2009a Shehab 2012

Total (95% CI)

Total events: 34 (Nitazoxanide), 27 (PBO/no/other intervention) Heterogeneity: Chi2 = 0.00, df = 1 (P = 0.95); I2 =0.0% Test for overall effect: Z = 1.10 (P = 0.27) Test for subgroup differences: Not applicable

0.01

0.1

Favours nitazoxanide

1

10

100

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

83

Analysis 3.1. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 1 All-cause mortality. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 3 Subgroup: genotype 1 compared to genotype 4 Outcome: 1 All-cause mortality

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Shehab 2012

0/50

0/50

Not estimable

Total (95% CI)

50

50

Not estimable

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Genotype 4

Total events: 0 (Nitazoxanide), 0 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

0.01

0.1

1

Favours nitazoxanide

10

100

Favours PBO/no/other int’

Analysis 3.2. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 2 Chronic hepatitis C-related mortality. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 3 Subgroup: genotype 1 compared to genotype 4 Outcome: 2 Chronic hepatitis C-related mortality

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Shehab 2012

0/50

0/50

Not estimable

Total (95% CI)

50

50

Not estimable

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Genotype 4

Total events: 0 (Nitazoxanide), 0 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

0.01

0.1

1

Favours nitazoxanide

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

100

Favours PBO/no/other int’

84

Analysis 3.4. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 4 Adverse events. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 3 Subgroup: genotype 1 compared to genotype 4 Outcome: 4 Adverse events

Study or subgroup

Nitazoxanide

PBO/no/other intervention

n/N

n/N

11/75

7/37

30.6 %

0.78 [ 0.33, 1.84 ]

75

37

30.6 %

0.78 [ 0.33, 1.84 ]

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Genotype 1 Bacon 2010

Subtotal (95% CI)

Total events: 11 (Nitazoxanide), 7 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: Z = 0.58 (P = 0.56) 2 Genotype 4 Rossignol 2008a

11/25

6/25

19.6 %

1.83 [ 0.80, 4.19 ]

Rossignol 2009a

2/29

11/40

30.2 %

0.25 [ 0.06, 1.05 ]

13/50

6/50

19.6 %

2.17 [ 0.89, 5.25 ]

104

115

69.4 %

1.24 [ 0.74, 2.08 ]

152

100.0 %

1.10 [ 0.71, 1.71 ]

Shehab 2012

Subtotal (95% CI)

Total events: 26 (Nitazoxanide), 23 (PBO/no/other intervention) Heterogeneity: Chi2 = 7.20, df = 2 (P = 0.03); I2 =72% Test for overall effect: Z = 0.81 (P = 0.42)

Total (95% CI)

179

Total events: 37 (Nitazoxanide), 30 (PBO/no/other intervention) Heterogeneity: Chi2 = 8.48, df = 3 (P = 0.04); I2 =65% Test for overall effect: Z = 0.41 (P = 0.68) Test for subgroup differences: Chi2 = 0.83, df = 1 (P = 0.36), I2 =0.0%

0.01

0.1

Favours nitazoxanide

1

10

100

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

85

Analysis 3.6. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 6 Failure of sustained virological response. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 3 Subgroup: genotype 1 compared to genotype 4 Outcome: 6 Failure of sustained virological response

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Bacon 2010

43/75

25/37

22.1 %

0.85 [ 0.63, 1.14 ]

Basu 2012a

8/24

11/26

7.0 %

0.79 [ 0.38, 1.62 ]

Shiffman 2009/2011

39/42

22/22

19.3 %

0.94 [ 0.84, 1.05 ]

Subtotal (95% CI)

141

85

48.4 %

0.88 [ 0.74, 1.04 ]

7/33

4/8

4.2 %

0.42 [ 0.16, 1.10 ]

Rossignol 2008a

21/25

25/25

16.8 %

0.84 [ 0.70, 1.01 ]

Rossignol 2009a

16/41

20/40

13.4 %

0.78 [ 0.48, 1.28 ]

Shehab 2012

25/50

26/50

17.2 %

0.96 [ 0.65, 1.41 ]

149

123

51.6 %

0.83 [ 0.68, 1.02 ]

208

100.0 %

0.85 [ 0.75, 0.97 ]

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Genotype 1

Total events: 90 (Nitazoxanide), 58 (PBO/no/other intervention) Heterogeneity: Chi2 = 1.72, df = 2 (P = 0.42); I2 =0.0% Test for overall effect: Z = 1.51 (P = 0.13) 2 Genotype 4 Keeffe 2009a

Subtotal (95% CI)

Total events: 69 (Nitazoxanide), 75 (PBO/no/other intervention) Heterogeneity: Chi2 = 2.54, df = 3 (P = 0.47); I2 =0.0% Test for overall effect: Z = 1.78 (P = 0.074)

Total (95% CI)

290

Total events: 159 (Nitazoxanide), 133 (PBO/no/other intervention) Heterogeneity: Chi2 = 5.65, df = 6 (P = 0.46); I2 =0.0% Test for overall effect: Z = 2.34 (P = 0.019) Test for subgroup differences: Chi2 = 0.15, df = 1 (P = 0.70), I2 =0.0%

0.01

0.1

Favours nitazoxanide

1

10

100

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

86

Analysis 3.7. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 7 Failure of virological end-of-treatment response. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 3 Subgroup: genotype 1 compared to genotype 4 Outcome: 7 Failure of virological end-of-treatment response

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Bacon 2010

29/75

20/37

21.1 %

0.72 [ 0.47, 1.08 ]

Basu 2012a

5/24

10/26

7.6 %

0.54 [ 0.22, 1.36 ]

Shiffman 2009/2011

36/42

22/22

23.1 %

0.87 [ 0.75, 1.00 ]

Subtotal (95% CI)

141

85

51.8 %

0.76 [ 0.61, 0.93 ]

3/33

4/8

5.1 %

0.18 [ 0.05, 0.66 ]

Rossignol 2008a

18/25

25/25

20.1 %

0.73 [ 0.56, 0.93 ]

Rossignol 2009a

13/41

10/40

8.0 %

1.27 [ 0.63, 2.55 ]

Shehab 2012

21/50

19/50

15.0 %

1.11 [ 0.68, 1.79 ]

149

123

48.2 %

0.88 [ 0.69, 1.12 ]

208

100.0 %

0.81 [ 0.69, 0.96 ]

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Genotype 1

Total events: 70 (Nitazoxanide), 52 (PBO/no/other intervention) Heterogeneity: Chi2 = 4.17, df = 2 (P = 0.12); I2 =52% Test for overall effect: Z = 2.59 (P = 0.0096) 2 Genotype 4 Keeffe 2009a

Subtotal (95% CI)

Total events: 55 (Nitazoxanide), 58 (PBO/no/other intervention) Heterogeneity: Chi2 = 9.93, df = 3 (P = 0.02); I2 =70% Test for overall effect: Z = 1.05 (P = 0.29)

Total (95% CI)

290

Total events: 125 (Nitazoxanide), 110 (PBO/no/other intervention) Heterogeneity: Chi2 = 11.07, df = 6 (P = 0.09); I2 =46% Test for overall effect: Z = 2.48 (P = 0.013) Test for subgroup differences: Chi2 = 0.77, df = 1 (P = 0.38), I2 =0.0%

0.01

0.1

Favours nitazoxanide

1

10

100

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

87

Analysis 3.8. Comparison 3 Subgroup: genotype 1 compared to genotype 4, Outcome 8 Participants without improvement in ALT and/or AST serum levels. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 3 Subgroup: genotype 1 compared to genotype 4 Outcome: 8 Participants without improvement in ALT and/or AST serum levels

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Rossignol 2008a

18/25

20/25

42.3 %

0.90 [ 0.66, 1.23 ]

Rossignol 2009a

7/22

5/20

11.1 %

1.27 [ 0.48, 3.37 ]

27/50

22/50

46.6 %

1.23 [ 0.82, 1.84 ]

97

95

100.0 %

1.09 [ 0.84, 1.42 ]

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Genotype 4

Shehab 2012

Total (95% CI)

Total events: 52 (Nitazoxanide), 47 (PBO/no/other intervention) Heterogeneity: Chi2 = 1.89, df = 2 (P = 0.39); I2 =0.0% Test for overall effect: Z = 0.67 (P = 0.50) Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours nitazoxanide

1

2

5

10

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

88

Analysis 4.1. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 1 All-cause mortality. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 4 Subgroup: nitazoxanide dose comparison Outcome: 1 All-cause mortality

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Shehab 2012

0/50

0/50

Not estimable

Total (95% CI)

50

50

Not estimable

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Standard dose (1000 mg/day)

Total events: 0 (Nitazoxanide), 0 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

0.01

0.1

1

Favours nitazoxanide

10

100

Favours PBO/no/other int’

Analysis 4.2. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 2 Chronic hepatitis Crelated mortality. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 4 Subgroup: nitazoxanide dose comparison Outcome: 2 Chronic hepatitis C-related mortality

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Shehab 2012

0/50

0/50

Not estimable

Total (95% CI)

50

50

Not estimable

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Standard dose (1000 mg/day)

Total events: 0 (Nitazoxanide), 0 (PBO/no/other intervention) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Chi2 = 0.0, df = -1 (P = 0.0), I2 =0.0%

0.01

0.1

1

Favours nitazoxanide

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

100

Favours PBO/no/other int’

89

Analysis 4.4. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 4 Adverse events. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 4 Subgroup: nitazoxanide dose comparison Outcome: 4 Adverse events

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Bacon 2010

11/75

7/37

30.6 %

0.78 [ 0.33, 1.84 ]

Rossignol 2008a

11/25

6/25

19.6 %

1.83 [ 0.80, 4.19 ]

Rossignol 2009a

2/29

11/40

30.2 %

0.25 [ 0.06, 1.05 ]

Shehab 2012

13/50

6/50

19.6 %

2.17 [ 0.89, 5.25 ]

Total (95% CI)

179

152

100.0 %

1.10 [ 0.71, 1.71 ]

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Standard dose (1000 mg/day)

Total events: 37 (Nitazoxanide), 30 (PBO/no/other intervention) Heterogeneity: Chi2 = 8.48, df = 3 (P = 0.04); I2 =65% Test for overall effect: Z = 0.41 (P = 0.68) Test for subgroup differences: Not applicable

0.01

0.1

Favours nitazoxanide

1

10

100

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

90

Analysis 4.6. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 6 Failure of sustained virological response. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 4 Subgroup: nitazoxanide dose comparison Outcome: 6 Failure of sustained virological response

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Bacon 2010

43/75

25/37

21.0 %

0.85 [ 0.63, 1.14 ]

Basu 2012a

4/12

11/26

4.4 %

0.79 [ 0.31, 1.97 ]

Rossignol 2008a

21/25

25/25

16.0 %

0.84 [ 0.70, 1.01 ]

Rossignol 2009a

16/41

20/40

12.7 %

0.78 [ 0.48, 1.28 ]

Shehab 2012

25/50

26/50

16.3 %

0.96 [ 0.65, 1.41 ]

Shiffman 2009/2011

39/42

22/22

18.4 %

0.94 [ 0.84, 1.05 ]

Subtotal (95% CI)

245

200

88.9 %

0.87 [ 0.76, 1.00 ]

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Standard dose (1000 mg/day)

Total events: 148 (Nitazoxanide), 129 (PBO/no/other intervention) Heterogeneity: Chi2 = 2.36, df = 5 (P = 0.80); I2 =0.0% Test for overall effect: Z = 1.95 (P = 0.051) 2 Experimental dose (< 1000 mg/day) Basu 2012a

4/12

11/26

4.4 %

0.79 [ 0.31, 1.97 ]

Keeffe 2009a

3/16

4/8

3.3 %

0.38 [ 0.11, 1.29 ]

Keeffe 2009a

4/17

4/8

3.4 %

0.47 [ 0.16, 1.42 ]

45

42

11.1 %

0.57 [ 0.31, 1.04 ]

242

100.0 %

0.84 [ 0.73, 0.96 ]

Subtotal (95% CI)

Total events: 11 (Nitazoxanide), 19 (PBO/no/other intervention) Heterogeneity: Chi2 = 1.04, df = 2 (P = 0.60); I2 =0.0% Test for overall effect: Z = 1.84 (P = 0.066)

Total (95% CI)

290

Total events: 159 (Nitazoxanide), 148 (PBO/no/other intervention) Heterogeneity: Chi2 = 7.41, df = 8 (P = 0.49); I2 =0.0% Test for overall effect: Z = 2.55 (P = 0.011) Test for subgroup differences: Chi2 = 1.89, df = 1 (P = 0.17), I2 =47%

0.02

0.1

1

Favours nitazoxanide

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

10

50

Favours PBO/no/other int’

91

Analysis 4.7. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 7 Failure of virological endof-treatment response. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 4 Subgroup: nitazoxanide dose comparison Outcome: 7 Failure of virological end-of-treatment response

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Bacon 2010

29/75

20/37

19.9 %

0.72 [ 0.47, 1.08 ]

Basu 2012a

2/12

10/26

4.7 %

0.43 [ 0.11, 1.68 ]

Rossignol 2008a

18/25

25/25

18.9 %

0.73 [ 0.56, 0.93 ]

Rossignol 2009a

13/41

10/40

7.5 %

1.27 [ 0.63, 2.55 ]

Shehab 2012

21/50

19/50

14.1 %

1.11 [ 0.68, 1.79 ]

Shiffman 2009/2011

36/42

22/22

21.8 %

0.87 [ 0.75, 1.00 ]

Subtotal (95% CI)

245

200

86.9 %

0.85 [ 0.72, 1.00 ]

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Standard dose (1000 mg/day)

Total events: 119 (Nitazoxanide), 106 (PBO/no/other intervention) Heterogeneity: Chi2 = 5.66, df = 5 (P = 0.34); I2 =12% Test for overall effect: Z = 1.90 (P = 0.057) 2 Experimental dose (< 1000 mg/day) Basu 2012a

3/12

10/26

4.7 %

0.65 [ 0.22, 1.94 ]

Keeffe 2009a

0/16

4/8

4.4 %

0.06 [ 0.00, 0.97 ]

Keeffe 2009a

3/17

4/8

4.0 %

0.35 [ 0.10, 1.22 ]

45

42

13.1 %

0.36 [ 0.17, 0.76 ]

242

100.0 %

0.79 [ 0.67, 0.93 ]

Subtotal (95% CI)

Total events: 6 (Nitazoxanide), 18 (PBO/no/other intervention) Heterogeneity: Chi2 = 2.71, df = 2 (P = 0.26); I2 =26% Test for overall effect: Z = 2.66 (P = 0.0077)

Total (95% CI)

290

Total events: 125 (Nitazoxanide), 124 (PBO/no/other intervention) Heterogeneity: Chi2 = 11.91, df = 8 (P = 0.16); I2 =33% Test for overall effect: Z = 2.86 (P = 0.0042) Test for subgroup differences: Chi2 = 4.80, df = 1 (P = 0.03), I2 =79%

0.002

0.1

Favours nitazoxanide

1

10

500

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

92

Analysis 4.8. Comparison 4 Subgroup: nitazoxanide dose comparison, Outcome 8 Participants without improvement in ALT and/or AST serum levels. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 4 Subgroup: nitazoxanide dose comparison Outcome: 8 Participants without improvement in ALT and/or AST serum levels

Nitazoxanide

PBO/no/other intervention

n/N

n/N

Rossignol 2008a

18/25

20/25

42.3 %

0.90 [ 0.66, 1.23 ]

Rossignol 2009a

7/22

5/20

11.1 %

1.27 [ 0.48, 3.37 ]

27/50

22/50

46.6 %

1.23 [ 0.82, 1.84 ]

97

95

100.0 %

1.09 [ 0.84, 1.42 ]

Study or subgroup

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

1 Standard dose (1000 mg/day)

Shehab 2012

Total (95% CI)

Total events: 52 (Nitazoxanide), 47 (PBO/no/other intervention) Heterogeneity: Chi2 = 1.89, df = 2 (P = 0.39); I2 =0.0% Test for overall effect: Z = 0.67 (P = 0.50) Test for subgroup differences: Not applicable

0.01

0.1

Favours nitazoxanide

1

10

100

Favours PBO/no/other int’

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

93

Analysis 5.1. Comparison 5 Best-worst case scenario analysis, Outcome 1 Failure of sustained virological response. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 5 Best-worst case scenario analysis Outcome: 1 Failure of sustained virological response

Nitazoxanide

PBO or no intervention

n/N

n/N

Bacon 2010

41/75

25/37

30.8 %

0.81 [ 0.60, 1.10 ]

Rossignol 2008a

18/25

25/25

23.5 %

0.73 [ 0.56, 0.93 ]

Rossignol 2009a

15/41

20/40

18.7 %

0.73 [ 0.44, 1.22 ]

Shiffman 2009/2011

39/42

22/22

27.0 %

0.94 [ 0.84, 1.05 ]

183

124

100.0 %

0.81 [ 0.70, 0.94 ]

Study or subgroup

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

Total events: 113 (Nitazoxanide), 92 (PBO or no intervention) Heterogeneity: Chi2 = 8.10, df = 3 (P = 0.04); I2 =63% Test for overall effect: Z = 2.85 (P = 0.0044) Test for subgroup differences: Not applicable

0.2

0.5

Favours nitazoxanide

1

2

5

Favours PBO or no intervention

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

94

Analysis 6.1. Comparison 6 Worst-best case scenario analysis, Outcome 1 Failure of sustained virological response. Review:

Nitazoxanide for chronic hepatitis C

Comparison: 6 Worst-best case scenario analysis Outcome: 1 Failure of sustained virological response

Nitazoxanide

PBO or no intervention

n/N

n/N

Bacon 2010

43/75

25/37

31.8 %

0.85 [ 0.63, 1.14 ]

Rossignol 2008a

21/25

24/25

22.8 %

0.88 [ 0.72, 1.06 ]

Rossignol 2009a

16/41

20/40

19.2 %

0.78 [ 0.48, 1.28 ]

Shiffman 2009/2011

39/42

21/22

26.2 %

0.97 [ 0.86, 1.10 ]

183

124

100.0 %

0.87 [ 0.76, 1.01 ]

Study or subgroup

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

Total events: 119 (Nitazoxanide), 90 (PBO or no intervention) Heterogeneity: Chi2 = 3.11, df = 3 (P = 0.37); I2 =4% Test for overall effect: Z = 1.88 (P = 0.060) Test for subgroup differences: Not applicable

0.1 0.2

0.5

Favours nitazoxanide

1

2

5

10

Favours PBO or no intervention

ADDITIONAL TABLES Table 1. Summary of the included studies

Study

Place study

of Medication groups (what was studied?)

Rossignol 2008a

3 centres in Group 1: Egypt NTZ Group 2: PBO Participants were followed up every 4 weeks, and

NumDose of Primary ber of par- medication outcomes ticipants included (on an intention-totreat basis)

Secondary outcomes

Results Results for for primary secondary outcomes outcomes

A total of 50 randomised participants: Group 1: 25 participants Group 2: 25 participants Participants were

SVR rates 24 weeks after therapy completion, reduction in serum hepatitis C virus RNA levels and changes

30.4% NTZ participants had an ETR, and in contrast, the 16 non-responders generally had less than a 1

NTZ: 500 ETR mg/twice daily for 24 weeks PBO: 500 mg/twice daily for 24 weeks

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

17.4 % NTZ participants had a SVR compared to none in the PBO group There were

95

Table 1. Summary of the included studies

24 weeks after completion of therapy

(Continued)

infected by hepatitis C virus genotype 4

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

in ALT levels log10 reduction in serum hepatitis C virus RNA levels on repeated testing every 4 weeks during therapy. The mean reduction in serum hepatitis C virus RNA levels was greater for the NTZ group 17 participants reported a total of 33 adverse events (11 from the NTZ group, and 5 in the placebo group. 1 patient in the NTZ group experienced melena with endoscopy showing a duodenal ulcer. This event required hospitalisation. The remaining adverse events were mild to moder-

no significant changes in ALT levels between the 2 groups

96

Table 1. Summary of the included studies

(Continued)

ate and transient in nature with none requiring modification or discontinuation of treatment Rossignol 2009a (STEALTH C-1)

2 centres in Group 1: Egypt PegIFN plus RBV (standard care) Group 2: NTZ monotherapy for 12 weeks then PegIFN added for 36 weeks Group 3: NTZ monotherapy for 12 weeks then PegIFN and RBV added for 36 weeks Participants were followed up every 4 weeks during treatment and at weeks 4, 8, 12, and at 24 weeks after completion of therapy

A total of 121 randomised participants: 40 treatment-naive participants to Group 1 28 treatment-naive participants to Group 2 29 treatment-naive participants to Group 3 12 treatment-experienced participants to Group 2 12 treatment-experienced participants to Group 3

NTZ: 500 mg/twice daily RBV: 1000 mg-1200 mg/ day (weight based) PegIFN: 180 µg/ weekly for 48 weeks

SVR at 24 weeks after end of treatment

Keeffe 2009

1 centre in Group 1: Egypt PBO monotherapy for 4 weeks, then

A total of 41 participants were randomised; Group 1: 8

NTZ (low RVR, cEVR, ETR, and Dose-dependent reductions dose) SVR rates in serum hepatitis C virus : 675 mg/ RNA were observed 4 days twice daily after starting combination

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Rates of virological responses, defined as serum hepatitis C virus RNA below the limits of detection. Also the ALT rates of normalisation

Significally more participants receiving triple therapy experienced SVR compared to those receiving standard care. The SVR rates for Group 2 were higher than for the standard care group, but not statistically significant Treatmentexperienced participants had lower SVR rates compared to the treatmentnaive participants

There was a total of 41 participants with SVR that had changes in ALT levels from baseline to week 72 There was a modest but statistically significant gradual decrease in serum HCV RNA levels in Groups 2 and 3 during the 12week lead in phase. The higher SVR rates in the NTZ groups were associated with mean reductions in serum hepatitis C virus RNA levels

97

Table 1. Summary of the included studies

Shiffman 2009/2011 (STEALTH C-)

(Continued)

PegIFN plus RBV added for 48 weeks Group 2: NTZ (low dose) monotherapy for 4 weeks, then PegIFN plus RBV added for 48 weeks Group 3: NTZ (high dose) monotherapy for 4 weeks, then pegIFN plus RBV added for 48 weeks

participants Group 2: 17 participants Group 3: 16 participants

NTZ (high dose) : 1350 mg/ twice daily PBO: for both low dose and high dose twice daily PegIFN: 180 µg/ weekly RBV: 1000mg1200 mg/ day (weight based)

10 centres in Group 1: the USA NTZ monotherapy for 4 weeks, then PegIFN plus RBV added for 48 weeks Group 2: PBO monotherapy for 4 weeks, then PegIFN plus RBV added for 48 weeks

A total of 64 participants were randomised : Group 1: 42 participants Group 2: 22 participants

NTZ: 500 mg/twice daily PBO: 500 mg/twice daily. RBV: 1000mg1200 mg/ day (weight based). PegIFN: 180 µg/ weekly.

therapy. Median reductions were -5.11 and -5.57 for the low- and high doses, respectively. There were 76% with SVR in the low-dose group compared to 81% with SVR in the high-dose group

SVR rates and detection of a < 2 log hepatitis C virus RNA decrease at week 12 or hepatitis C virus RNA detectable at week 4

Nitazoxanide for chronic hepatitis C (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

RVR, complete and partial EVR, and ETR

Median baseline serum hepatitis C virus RNA was 6. 8 log10 IU/ mL in the NTZ group compared to 6. 5 log10 IU/ mL in the PBO group 7% of participants in the NTZ group had SVR versus none in PBO group

Participants receiving NTZ had higher response rates than those taking PBO, but rates were low overall and differences did not reach statistical significance Compared with PBO, NTZ added to PegIFN and RBV showed modest incremental EVR and SVR

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Table 1. Summary of the included studies

(Continued)

Bacon 2010 13 centres in Group 1: NTZ (STEALTH Egypt monotherC-3) apy for 4 weeks, then PegIFN plus RBV added for 48 weeks Group 2: PBO monotherapy for 4 weeks, then PegIFN plus RBV added for 48 weeks Participants were followed up 24 weeks after completion of therapy

A total of 112 participants were randomised: Group 1: 75 participants Group 2: 37 participants

NTZ: 500 mg/twice daily PBO: 500 mg/twice daily RBV: 1000 mg-1200 mg/ day (weight based) PegIFN: 180 µg/ weekly

Primary objective was to determine and evaluate the efficacy of NTZ plus PegIFN and RBV in treatmentnaive participants with CHC genotype 1 in the USA. The primary outcome was SVR, or continued undetectable hepatitis C virus viral load 24 weeks after the end of treatment

The researchers also looked at RVR, or undetectable hepatitis C virus RNA; complete EVR, or undetectable hepatitis C virus RNA at week 12; partial EVR, at least a 2 log drop in viral load at week 12, and ETR or undetectable viral load at completion of therapy

SVR rates were higher in the NTZ group versus PBO group. The addition of NTZ increased SVR rate in genotype 1 naive participants by more than one-third There were no significant differences in adverse events, except for mild diarrhoea in participants receiving NTZ

Participants receiving NTZ had higher response rates than those taking PBO by 12 weeks, but not at 4 weeks

Shehab 2012

A total of 100 participants were randomised: Group 1: 50 participants Group 2: 50 participants

NTZ: oral 500 mg/ twice daily RBV: 1200 mg if ≥ 75 kg and 1000 mg if < 75 kg PegIFN: 160 µg/ weekly, subcutaneously

SVR 180 days (± 7 days) after the end of treatment

RVR 28 to 33 days after start of PegINF and RBV treatment, EVR 90 ± 7 days from the start of pegINF and RBV treatment, ETR 180 ± 7 days after starting pegINF and RBV treatment Occurrence of adverse events

The addition of NTZ to pegINF and RBV did not improve the virological or biochemical response rates in chronic hepatitis C virus genotype 4

In Group 1 treatment was discontinued due to adverse events in 3 participants (2 due to neutropenia at weeks 2 and 24 and 1 due to severe facial palsy at week 24) , in Group 2 treatment was discontinued

1 centre in Group 1: Egypt PegINF plus weight based RBV for 48 weeks Group 2: NTZ for 4 weeks, then triple therapy, i.e., NTZ, PegIFN and RBV for a further 48 weeks

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Table 1. Summary of the included studies

(Continued)

throughout the period of treatment and up to 90 days after the end of triple therapy Basu 2012a

Not Group stated in the A: 500 mg trial report NTZ 3 times daily for 12 weeks Group B: 500 mg NTZ twice daily for 12 weeks Group C: PegINF plus RBV plus TPR

50 participants; Group A: 12 participants Group B: 12 participants Group C: 26 participants

PegIFN: 180 µg every other week RBV: fixed dose of 1200 mg/day TPR: 750 mg three times daily

SVR in treatmentexperienced participants

No information provided about secondary outcomes

in 2 participants (1 due to anaemia and 1 due to neutropenia, both at week 2)

This quadruple 24 weeks regimen excelled the EVR, EVR and ETVR over standard treatment with DAAs over 11% SVR of 67% with 3/50 (6%) relapse was noted

No information about secondary outcomes provided

Abbreviations ALT = alanine aminotransferase CHC = chronic hepatitis C CR = controlled release DAAs = directly acting antivirals ETR = virological end-of-treatment response EVR = early virological response NTZ = nitazoxanide PBO = placebo PegINF = pegylated interferon RBV = ribavirin RNA = ribonucleic acid RVR = rapid virological response SVR = sustained virological response TPR = telaprevir

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Table 2. Summary of characteristics of the included trials

Risk of bias

Trial duration (weeks)

Follow-up duration (weeks)

High

24

24

Bacon 2010

High

52

24

Shiffman 2009/2011

High

52

24

Keeffe 2009a

High

52

24

High

48

24

High

48

24

Trial Nitazoxanide versus placebo or no intervention for 24 weeks Rossignol 2008a

Nitazoxanide 4 weeks monotherapy plus nitazoxanide plus peginterferon and ribavirin versus placebo 4 weeks monotherapy plus placebo plus peginterferon and ribavirin

Nitazoxanide 12 weeks monotherapy plus nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin Rossignol 2009a*

Nitazoxanide 12 weeks monotherapy plus nitazoxanide plus peginterferon versus no intervention plus peginterferon and ribavirin Rossignol 2009a*

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Table 2. Summary of characteristics of the included trials

(Continued)

Nitazoxanide 4 weeks monotherapy plus nitazoxanide plus peginterferon and ribavirin versus no intervention plus peginterferon and ribavirin Shehab 2012

High

Nitazoxanide plus telapravir High plus peginterferon and ribavirin versus no intervention plus telapravir plus peginterferon and ribavirin

52

24

uncertain

unclear

Basu 2012a Rosignol 2009* trial had three intervention groups

APPENDICES Appendix 1. Search strategy

Database

Search date

Search strategy

Cochrane Hepato-Biliary Group Con- April 2013 trolled Trials Register

(nitazoxanid* OR alinia OR annita OR daxon OR dexidex OR kidonax OR pacovanton OR paramix OR nitax OR zox OR nitazox OR toza) AND (’hepatitis c’ OR Hepatitis C virus OR hepacivir*)

The Cochrane Central Register of Con- Issue 3 of 12, 2013 trolled Trials (CENTRAL)

#1 MeSH descriptor: [Antiprotozoal Agents] this term only #2 (nitazoxanid* or alinia or annita or daxon or dexidex or kidonax or pacovanton or paramix or nitax or zox or nitazox or toza) #3 #1 or #2 #4 MeSH descriptor: [Hepatitis C] explode all trees #5 hepatitis c or Hepatitis C virus or hepacivir* #6 #4 or #5 #7 #3 and #6

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(Continued)

MEDLINE (Ovid SP)

1948 to April 2013

1. Antiprotozoal Agents/ 2. (nitazoxanid* or alinia or annita or daxon or dexidex or kidonax or pacovanton or paramix or nitax or zox or nitazox or toza).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier] 3. 1 or 2 4. exp Hepatitis C/ 5. (hepatitis c or Hepatitis C virus or hepacivir*).mp. [mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier] 6. 4 or 5 7. 3 and 6

EMBASE (Ovid SP)

1980 to April 2013

1. exp NITAZOXANIDE/ 2. (nitazoxanid* or alinia or annita or daxon or dexidex or kidonax or pacovanton or paramix or nitax or zox or nitazox or toza).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] 3. 1 or 2 4. exp hepatitis C/ 5. (hepatitis c or Hepatitis C virus or hepacivir*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer] 6. 4 or 5 7. 3 and 6

LILACS

1983 to April 2013

(nitazoxanide or alinia or annita or daxon or dexidex or kidonax or pacovanton or paramix or nitax or zox or nitazox or toza) [Words]

Expanded 1900 to April 2013

#3 #2 AND #1 #2 TS=(hepatitis c or Hepatitis C virus or hepacivir*) #1 TS=(nitazoxanid* or alinia or annita or daxon or dexidex or kidonax or pacovanton or paramix or nitax or zox or nitazox or toza)

(Science Citation Index www.thomsonscientific.com)

WHAT’S NEW Last assessed as up-to-date: 8 March 2014.

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Date

Event

Description

16 April 2014

Amended

In some phrases describing combinations of interventions, ‘plus’ is replaced with ‘and’ for better understanding

CONTRIBUTIONS OF AUTHORS Kristiana Nikolova and Berit Grevstad selected studies for inclusion and extracted data independently. Kristiana Nikolova, Janus Christian Jakobsen, and Christian Gluud drafted the review, following the protocol plan. All authors revised and approved of the final review version for publication.

DECLARATIONS OF INTEREST Kristiana Nikolova: nothing to declare. Christian Gluud: nothing to declare. Berit Grevstad: nothing to declare. Janus C Jakobsen: nothing to declare.

SOURCES OF SUPPORT Internal sources • The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark. • The Cochrane Hepato-Biliary Group, Denmark.

External sources • No sources of support supplied

DIFFERENCES BETWEEN PROTOCOL AND REVIEW We planned in the protocol to do worst-best and best-worse sensitivity analyses on the first three primary outcomes; all-cause mortality, chronic hepatitis C-related mortality, and morbidity. The analyses were described under ’Dealing with missing data’. Since there were not enough data on these outcomes, we performed sensitivity analysis on the secondary outcome sustained virological response (Analysis 5.1 and Analysis 6.1).

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Nitazoxanide for chronic hepatitis C.

Hepatitis C infection is a disease of the liver caused by the hepatitis C virus. The estimated number of chronically infected people with hepatitis C ...
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