Safely treating hepatitis C in patients with HIV or hepatitis B virus coinfection.

Review

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Safely treating hepatitis C in patients with HIV or hepatitis B virus coinfection 1.

Introduction

2.

Method

3.

HCV/HIV coinfection

4.

HBV/HCV coinfection

5.

Expert opinion

Atefeh Jafari, Hossein Khalili†, Mandana Izadpanah & Simin Dashti-Khavidaki †

Tehran University of Medical Sciences, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran, Iran

Introduction: There are several clinical trials and prospective studies which support the use of direct-acting antiviral agents (DAAs) in hepatitis C virus (HCV)-coinfected patients. In this review, the safety of DAAs in HCV patients coinfected with hepatitis B virus (HBV) or HIV has been evaluated. Areas covered: All available prospective studies, clinical trials and congress abstracts in the English language that assessed the safety and efficacy of DAAs in HCV coinfections have been considered. Expert opinion: The newer DAAs in the treatment of HCV/HIV-coinfected patients resolved major limitations of the first-generation protease inhibitors including complex dosing, poor tolerability and interactions with antiretroviral drugs. There are not yet enough data regarding the safety and efficacy of DAAs in some coinfected patients with comorbidities, nor for pregnant, lactating or pediatric patients. Evaluating the safety and efficacy of these agents in these subgroups with HCV coinfection is recommended for future studies. The role of new direct-acting antiviral-based therapy for the treatment of patients with HCV/HBV coinfection remains to be evaluated. Keywords: coinfection, hepatitis B virus, hepatitis C virus, HIV Expert Opin. Drug Saf. [Early Online]

1.

Introduction

Successful treatment of hepatitis C virus (HCV) infection is a worldwide challenge [1]. Among the six major genotypes, HCV genotype 1 is the most common genotype [2]. Until the recent entrance of newer treatment regimen in 2014 guidelines, HCV genotypes 2 and 3 achieved more sustained virologic response (SVR) than the others [3]. HCV-positive patients are frequently coinfected with HIV or hepatitis B virus (HBV) [4]. Coinfection with HIV or HBV accelerates liver damages leading to fibrosis, cirrhosis and hepatocellular carcinoma [5,6] and also affects response to the antiviral therapy [4]. Fibrosis stage, patient’s age at time of infection, duration of infection, consumption of alcohol, HIV coinfection, CD4+ T-cell count < 200 cells/ml, male gender, high body mass index, diabetes and steatosis are other factors consistently associated with progression of fibrosis in patients with HCV infection [7]. Although starting effective antiretroviral therapy (ART) has significantly improved outcomes of coinfected patients [8] and reduced the rate of hepatic decompensation [9], risk of cirrhosis has remained a leading cause of death in these patients. Until recently, first conventional regimen for treatment of HCV-infected patients has been pegylated IFN and ribavirin (pegIFN/RBV). This regimen has three major disadvantages including low rate of SVR, especially in HCV/HIV-coinfected patients, several adverse reactions and potential interactions with antiretroviral drugs. Therefore, the use of pegIFN/RBV is limited in this population. 10.1517/14740338.2015.1019461 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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A. Jafari et al.

Article highlights. .

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Newer direct-acting antiviral agents (DAAs) have improved outcomes with shorter treatment duration, fewer adverse events and better safety profile in hepatitis C virus (HCV)/HIV-coinfected patients. Protease inhibitors (PIs) including telaprevir and boceprevir are off labels for use in HCV/HIV-coinfected patients. Sofosbuvir (SOF) as a new approved DAA with the same efficacy compared with PIs is a considerable option in HCV/HIV-coinfected population. Once-daily regimen including simeprevir plus SOF with or without ribavirine is acceptable regimen for HCV/HIVcoinfected patients. The role of new DAAs for the treatment of patients with HCV/hepatitis B virus infection remains to be evaluated.

This box summarizes key points contained in the article.

The introduction of direct-acting antiviral agents (DAAs) and triple therapy regimens including an HCV protease inhibitor (PI) with pegIFN/RBV dramatically increased efficacy of treatment of HCV infection [10]. DAAs showed a higher SVR rate (~ 40 -- 70%) than pegIFN/RBV in HCVmonoinfected patients with advanced fibrosis or cirrhosis [11,12]. Given that HCV-coinfected patients have decreased response to pegIFN/RBV, considering DAAs is promising. Some classes of DAAs are now placed as the first lines in HCV infection treatment [13,14]. Telaprevir (TPV) and boceprevir (BOC) as NS3/4A PI were the first and the wellstudied DAAs available for treatment of HCV infection. Simeprevir (SMV), a second-generation PI, and sofosbuvir (SOF), an NS5B nucleoside polymerase inhibitors (NPIs), are other currently available DAAs [10]. Recently, the US FDA on 19 December 2014 approved Viekira Pak (ombitasvir/paritaprevir/ritonavir and dasabuvir tablets) as an all-oral, IFN-free regimen, with or without RBV, for the treatment of patients with chronic genotype 1 HCV infection, including those with compensated cirrhosis. There are several clinical trials and prospective studies which support the use of DAAs in HCV-coinfected patients. Although DAAs are effective in HCV coinfections, issues such as safety and drug interactions between the HIV or HBV treatment regimens and these new agents are not well answered. Also, safety of DAAs in coinfected patients with fibrosis/cirrhosis should be discussed in detail. Currently; these new agents provide IFN-free regimens as a new approach in treatment of many coinfected patients. 2.

Method

All available prospective studies, clinical trials and congress abstracts in English language that assessed the safety and efficacy of DAAs and pegIFN/RBV for treatment of HCVcoinfected patients with HIV or HBV have been considered. 2

The data were collected by searching Science direct, Web of knowledge, PubMed, Scopus and Clinical trials. Keywords used as search terms included ‘safety’, ‘drug-drug interaction’, ‘adverse drug reaction’, ‘side-effect’, ‘telaprevir’, ‘boceprevir’ ‘simeprevir’, ‘sofosbuvir’, ‘ledipasvir’, ‘faldaprevir’ ‘daclatasvir’, ‘direct acting agents’, ‘HCV-HIV coinfection’, ‘HCV-HBV coinfection’, ‘NS5B nucleoside polymerase inhibitors’, ‘NS3/4A protease inhibitors’ and ‘pegIFN/RBV’. This search covered all data from year 2009 up to the end of 2014. 3.

HCV/HIV coinfection

Higher rate of chronicity, greater serum HCV-RNA level, accelerated rate of liver fibrosis [3,15] and less chance of resolution of HCV viral infection was reported in HCV/HIV-coinfected patients compared with HCV monoinfection [16]. Also, sustained HCV clearance following 48 weeks pegIFN/RBV treatment has been detected only in 40% of HIV/HCVcoinfected patients [17]. Decreased tolerance and increased risk of hepatotoxicity of ART [6,18] and high prevalence of the metabolic syndrome [15,19] are other issues in HCV/HIV-coinfected individuals. Due to risk of the opportunistic infections and other adverse events, ART is recommended for HCV/HIVcoinfected patients with CD4 counts < 200 cells/ml. Hepatitis C treatment can be considered when the immune status improves and HIV replication is suppressed [13,20]. The primary goal of HCV treatment is to cure the infection, which is generally associated with resolution of liver disease in patients without cirrhosis. Eradication of HCV infection will prevent its complications including liver necroinflammation, fibrosis, cirrhosis, hepatocellular carcinoma and death [13]. Achieving the treatment goals in HCV/HIV-coinfected patients improves liver fibrosis and reduces related morbidity and mortality [21-24]. Fortunately, DAAs improved SVR in HCV-coinfected patients compared with the conventional regimen [25,26]. Also, higher SVR rate of the first-generation PIs and newer DAAs have been detected in HCV/HIV-coinfected patients, especially in the genotype 1 infection [25-33]. Considering these newer agents seems to be essential in HCV/HIV-coinfected patients. Current European Association for the Study of the Liver clinical practice guideline recommends pegIFN/RBV regimen in HCV/HIV-coinfected patients same as patients with HCV monoinfection. Triple therapy with pegIFN/RBV and SOF or SMV is recommended for HCV genotype 1/HIV-coinfected patients [13]. Recommended treatment regimens by the American Association of the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) guideline are also similar [14]. Recommended regimen for HCV/HIV-coinfected patients with genotype 1 who are eligible to receive IFN is 12 weeks treatment with SOF plus pegIFN/RBV. Patients who are IFN ineligible should receive SOF plus RBV for 24 weeks or SOF plus SMV with or without RBV for 12 weeks.

Expert Opin. Drug Saf. (2015) 14(5)


Safely treating hepatitis C in patients with HIV or HBV coinfection

Recommended regimen for treatment-experienced patients with HCV genotype 1 is 12 weeks treatment with SOF plus pegIFN/RBV in IFN-eligible patients and SOF plus SMV with or without RBV in those who are IFN ineligible. HCV/ HIV-coinfected patients with genotype 2 or 3 should receive SOF with RBV for 12 and 24 weeks, respectively. SOF with pegIFN/RBV for 12 weeks is also recommended for HCV/ HIV-coinfected patients with either genotype 4, 5 or 6 in those who are eligible for IFN. Also, 24 weeks treatment with SOF plus RBV in coinfected patients with genotype 4 who are not eligible to receive IFN is recommended [14]. In a case series study, TPV showed acceptable virologic response in HCV/HIV-coinfected patients [34,35]. Primary experiences with new DAAs have shown similar SVR rates in HCV-coinfected and -monoinfected patients [25,36]. These acceptable primary results have promoted evaluating safety of current treatment options in this population. Drug interactions between DAAs and ART, overlapping toxicities, patients’ adherence and cost are alerting issues in the management of HCV/HIV-coinfected patients. Adding a PI to the HCV treatment regimen can potentiate the adverse events of pegIFN/RBV. Coadministration of a PI also makes the regimen more complex attributable to the lead-in phases with BOC or increases daily pill burden [20,37,38]. First-generation PIs including TPV and BOC are still off labels for use in HCV/HIV coinfection. However, the newer DAAs, SOF and SMV, were considered milestone for treatment in HCV/ HIV-coinfected patients [14]. Results of available studies are summarized in Table 1. Summary of ongoing studies regarding the efficacy and safety of DAAs in HCV/HIV coinfection is provided in Table 2. 3.1

Drug safety and efficacy Telaprevir

3.1.1

Showing similar SVR rates in coinfected and monoinfected HCV patients potentiate PIs as first lines for HCV treatment. However, adverse events such as anemia, rash, pruritus, dysgeusia and increase in the pill burden may affect considering these agents. Dieterich et al. reported the safety and efficacy of a 12-week regimen of TPV plus pegIFN/RBV, followed by 36 weeks of pegIFN/RBV compared with a 48-week course of pegIFN/ RBV in 60 patients with HCV genotype 1 and HIV coinfection [26]. They also published later results of this Phase IIa, randomized, double-blind, placebo-controlled study [36]. Evaluation of the primary objectives showed undetectable HCV RNA at weeks 4 and 12 in 63% of TPV-treated patients compared with 4.5% of the control arm. Twelve weeks after completion of the treatment course, 74% of the patients in TPV/pegIFN/RBV versus 45% of pegIFN/RBV group showed SVR and undetectable HCV RNA. No HIV RNA breakthrough was reported. Patients in TPV/pegIFN/RBV and pegIFN/RBV groups experienced 3 and 15% of HCV RNA breakthrough, respectively. Although this study included a small number of patients, no significant difference

was found between the patients with or without ART regimen. No significant changes in CD4 cells count or in HIV RNA level was observed in the patients who received either ART regimens compared with the controls. TPV steady state serum concentrations were comparable in the different ART regimens. The overall safety profile in TPV/pegIFN/RBV group was comparable to that previously reported in chronic HCV-monoinfected patients. Among all reported adverse events, skin rash and anemia were the most commonly observed adverse events. Skin rashes that were managed with topical corticosteroids were detected in 29 and 18% of the patients treated with TPV and placebo, respectively. No patient had severe, life-threatening or treatment-limiting rash with TPV. Severe anemia resulted in blood transfusion, which was reported in 11% of patients in TPV/pegIFN/RBV versus 5% of pegIFN/RBV group. Grade 3 or greater of neutropenia was seen in 16 and 27% of the patients treated with TPV and placebo, respectively. Decrease in absolute CD4 cell count without change in the percentage of the CD4 lymphocytes during the treatment was similar between the groups [17]. Other adverse events including abdominal pain, pruritus, headache, dizziness, nausea, rash, pyrexia, depression and insomnia and weight loss were more common in the TPV/pegIFN/RBV than pegIFN/RBV group. Early treatment discontinuation due to the adverse events was reported in three (8%) patients in TPV/pegIFN/RBV group versus no patients in pegIFN/RBV group. Adverse events which caused treatment discontinuation were hemolytic anemia, cholelithiasis and vomiting [26]. However, treatment discontinuation rate because of serious adverse events of TPV in HCV/HIV-coinfected patients was not greater than that reported in HCV-monoinfected individuals [39]. Hepatic decompensation was excluded from the study. As only 10% of the patients in this study had advanced liver fibrosis, the question that whether this triple regimen is effective and safe for HCV/HIV-coinfected patients with more advanced fibrosis stages, remained unanswered. However, high rates of adverse events of DAAs in HCV-monoinfected patients with compensated liver cirrhosis [40] necessities evaluation of the safety of these agents in the cirrhotic-coinfected population. Studies with adequate sample size are needed for characterization of safety of TPV in this population. Use of TPV in coinfected patients with previous HCV treatment failure, those with more advanced HIV infection or receiving some specific ART regimens with potential of interactions with TPV seems ineligible until conducting further studies [36]. As low fixed dose of RBV (800 mg/day) was administered to most patients in this study, anemia was less severe compared with the studies with higher, weight-based RBV [41]. A substantial proportion of treatment-experienced HCV/HIV-coinfected patients achieved SVR24 with a TPV-based regimen. All included patients were infected with HCV genotype 1 and patients with cirrhosis were excluded. Allowed ART regimen in this study were tenofovir, emtricitabine, efavirenz, atazanavir and


3

4


no > 20%

1

6%

20%

Non-cirrhotic

17%

1, 2 & 3

1, 2, 3 & 4

1

1

13%

Non-cirrhotic

1

1

10 -- 12%

Cirrhotic status

1

HCV genotype

SVR12 71 vs 72

SVR12 100

SVR12 Tx-naive: 76(G1), 88(G2), 67(G3) Tx-experienced: 92(G2), 94(G3) SVR12 Between 89(G3) and 84(G4)

SVR12 74

SVR12 63 vs 29

SVR24 80

SVR12 74 vs 45

SVR (%)

Nausea, fatigue, diarrhea, headache and weakness

Fatigue, pain, diarrhea, constipation, headache, myalgia, nausea, coryza

Fatigue, insomnia, headache, nausea and diarrhea

Fatigue, insomnia, nausea and headache

Fatigue, headache and nausea

Anemia, pyrexia, decreased appetite, dysgeusia, vomiting and neutropenia

Rash, anemia, abdominal pain, pruritus, headache, nausea, dizziness, pyrexia, depression, insomnia and weight decrease Cutaneous, psychiatric, hematological

Common ADRs

Maraviroc, raltegravir, efavirenz darunavir/r or atazanavir/r

Efavirenz, tenofovir, emtricitabine, raltegravir, rilpivirine

Tenofovir, rilpivirine, emtricitabine, efavirenz, raltegravir, darunavir/r, atazanavir/r

Atazanavir/r, efavirenz, emtricitabine, darunavir/r, raltegravir, rilpivirine, tenofovir

Lamivudine, abacavir, tenofovir, rilpivirine, enfuvirtide, raltegravir, maraviroc, emtricitabine HIV PIs or efavirenz were not permitted

HIV PI/r boosted + 2 selected NRTIs. NNRTIs, zidovudine or didanosine were not permitted

Tenofovir, raltegravir, emtricitabine, efavirenz, atazanavir

Efavirenz, tenofovir, emtricitabine, atazanavir/r, lamivudine

Allowed ART regimen

ART: Antiretroviral therapy; DAA: Direct-acting antiviral agent; HCV: Hepatitis C virus; NNRTI: Non-nucleoside reverse-transcriptase inhibitors; pegIFN/RBV: Pegylated IFN and ribavirin; PI: Protease inhibitor; SRV: Sustained virologic response; TPV: Telaprevir.

PHOTON-2 [28] SOF/RBV Treatment-naive and treatmentexperienced, n = 274 ERADICATE [31] SOF/ledipasvir Treatment-naive, n = 50 Faldaprevir STARTVerso 4 [29] FDV (120 mg/day) + pegIFN/RBV vs FDV (240 mg/day) + pegIFN/RBV Treatment -naive or relapse, n = 308

Sofosbuvir PHOTON-1 [33] SOF + RBV Treatment-naive and treatmentexperienced, n = 223

ANRSHC26TelapreVIH [42] TPV + pegIFN/RBV Treatment-experienced, n = 69 Boceprevir Sulkowski et al. (2013) [25] BOC + pegIFN/RBV vs placebo + pegIFN/RBV Previously untreated patients, n = 99 Simeprevir Study C212 [27] SMV + pegIFN/RBV Treatment-naive and treatmentexperienced, n = 106

TPV Sulkowski et al. (2013) [36] TPV + pegIFN/RBV vs pegIFN/RBV, n = 62

Study

Table 1. Summary of the studies evaluated efficacy and safety of direct-acting antiviral agents in HIV/HCV coinfection.


A. Jafari et al.

19% 1

raltegravir. Adverse events, especially severe anemia caused treatment discontinuation in 20% of the patients [42]. ART: Antiretroviral therapy; DAA: Direct-acting antiviral agent; HCV: Hepatitis C virus; NNRTI: Non-nucleoside reverse-transcriptase inhibitors; pegIFN/RBV: Pegylated IFN and ribavirin; PI: Protease inhibitor; SRV: Sustained virologic response; TPV: Telaprevir.

Atazanavir- or raltegravir-containing regimen Fatigue, insomnia, nausea, headache, upper respiratory infection, pruritus, cough, scleral icterus, diarrhea

Abacavir, tenofovir, emtricitabine, raltegravir Fatigue, diarrhea, nausea, and headache

SVR12 With RBV: 97 Without RBV: 90 SVR12 93.5 in 12-week arm 95.0 in 24-week arm Non-cirrhotic 1

Other DAAs C-WORTHY [32] MK-5172 + MK-8742 ± RBV Treatment-naive, n = 59 TURQUOISE-I [30] 12- or 24--week paritaprevir/r/ ombitasvir/dasabuvir+ RBV Treatment-naive and treatmentexperienced, n = 63

Allowed ART regimen Common ADRs SVR (%) Cirrhotic status HCV genotype Study

Table 1. Summary of the studies evaluated efficacy and safety of direct-acting antiviral agents in HIV/HCV coinfection (continued).



Boceprevir Safety and efficacy of BOC were investigated in a multi-center, double-blinded and randomized controlled Phase II trial in 100 previously untreated patients with HCV genotype 1 and HIV coinfection [43]. Although HCVmonoinfected patients were treated for shorter treatment duration, all HIV-positive patients in this trial were assigned to the 48-week regimen. ART regimen was a ritonavirboosted HIV PI plus two selected nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). All patients tolerated this regimen and had stable undetectable HIV viral load. PegIFN/RBV were administered for 4 weeks as a lead-in therapy followed by randomly added 800 mg 3-times-daily BOC or placebo for 44 weeks as a triple regimen for HCV treatment. The control group received pegIFN/RBV for 48 weeks. BOC/pegIFN/RBV substantially increased the likelihood of end-of-treatment response, the higher rate of HCV viral load suppression at all-time points and SVR. Two and three patients taking BOC and placebo experienced HIV viral load rebound by the end of treatment, respectively. The virological relapse rate in the BOC group in this study was lower than the rate noted in monoinfected HCV patients treated with BOC plus pegIFN/RBV. Finally, 63 and 29% of the patients in the BOC and the control group had an SVR at follow-up week 24, respectively. Approximately one-fifth of the participants in both arms experienced serious adverse events, but BOC recipients were about twice as likely to discontinue the therapy due to adverse events (20 vs 9%, respectively). Overall treatment interruption rate due to BOC-induced serious adverse events in monoinfected individuals was reported in 15% of patients [44]. BOC recipients were more likely to report several symptoms, including fever, loss of appetite, vomiting, dysgeusia (unusual taste sensations), anemia and neutropenia than the placebo group. Absolute CD4 T-cell counts decreased in the both groups, but CD4 cell percentages remained stable. Anemia was noted in 41% of BOC treated versus 26% of patients in the control arm. Use of erythropoietin was reported in 38 and 21% of BOC and placebo treated patients, respectively. No patient discontinued treatment because of neutropenia or thrombocytopenia, and none of the cases of neutropenia followed by infection. In this first pilot trial, the safety and tolerability profile of BOC was consistent with that observed in HCVmonoinfected patients. As the majority of patients included in this study were non-cirrhotic (95%), efficacy and safety of BOC in HCV/HIV-coinfected patients with more advanced fibrosis remained unanswered. Although this study did not evaluate the correlation between incidence of anemia and SVR rate, results from the studies of BOC in HCVmonoinfected patients suggested that SVR rates were higher in patients with anemic than in non-anemic patients [11]. Prospective studies are needed to confirm the predictive role of 3.1.2


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Table 2. Summary of the ongoing studies on efficacy and safety of direct-acting antiviral agents in HIV/HCV coinfection. Study (regimen/duration/number of patients)

HCV genotype

SWIFT-C, NCT02128217 (SOF + RBV, 12 weeks) Acute HCV infection (or reinfection) n = 44 NCT02124044 (asunaprevir + daclatasvir) Treatment-naive and treatment-experienced n = 60 ALLY-2, NCT02032888 (daclatasvir + SOF, 8 or 12 weeks) Treatment-naive and treatment-experienced n = 200 QUADRIH, NCT01725542 (asunaprevir, daclatasvir, ribavirin and pegIFN, 8 -- 32 weeks), completed but results not reported Previously null responders to a standard pegIFN/RBV n = 75 C-EDGE, NCT02105662 (grazoprevir [MK-5172] + elbasvir [MK-8742], 12 weeks) Treatment-Naive n = 200 NCT02252016 (grazoprevir 100 mg + elbasvir 50 mg once daily, 12 weeks) n = 200

Genotype not specified

1b 1 -- 6 1 or 4

1, 4, 5, 6

1, 4 and 6

HCV: Hepatitis C virus; pegIFN/RBV: Pegylated IFN and ribavirin; SOF: Sofosbuvir.

anemia in the treatment outcome of HCV/HIV-coinfected patients. Ongoing clinical trial is evaluating the effectiveness of BOC plus pegIFN/RBV in treating HCV/HIV coinfection in adults [45]. The available data regarding the adverse effects of the firstgeneration DAAs show that either TPV- or BOC-induced anemia occurs more frequently and needs to be regularly monitored. With BOC, dysgeusia is seen in half of the patients. With TVR, skin rashes are more frequent, but are mild or moderate in the majority of the cases. Nevertheless, severe rashes can occur that require immediate discontinuation of the treatment [46]. Simeprevir SMV, a second-generation NS3/4A inhibitors with improved pharmacokinetic profile, higher barriers to resistance, fewer adverse events and broader activity against the HCV genotypes is used in regimens with or without pegIFN/RBV. SMV is the first once-daily HCV PI licensed as part of a regimen containing pegIFN/RBV in HCV genotype 1 treatment. The TMC435-C212 was a Phase III, open-label, single-arm study that investigated efficacy and safety of SMV plus pegIFN/RBV in treatment-naive and experienced HCV/HIV-coinfected patients [27]. Each patient received SMV plus pegIFN/RBV for 12 weeks. Non-cirrhotic, treatment-naive patients and patients with prior relapse received response-guided pegIFN/RBV for 24 or 48 weeks, respectively. All prior partial or null responders and patients with cirrhosis received pegIFN/RBV for 48 weeks. Lamivudine, emtricitabine, tenofovir, abacavir, rilpivirine, enfuvirtide, raltegravir or maraviroc were permitted in the ART regimens. Patients who were receiving HIV 3.1.3

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PIs or efavirenz were excluded. Overall, SVR12 of 74% was reported in this trial. This triple regimen was generally safe and adverse events were similar to that of patients with HCV monoinfection, except a higher frequency of pruritus, rash, photosensitivity and increased serum bilirubin concentration was detected in SMV compared with pegIFN/RBV group. The most common side effects were fatigue, headache and nausea. Serious adverse events were similar in patients taking or not taking ART. Six (5.7%) patients had a serious adverse event in the first 12 weeks of treatment, and 10 (9.4%) patients had a serious adverse event during the treatment course. Four patients stopped SMV because of serious adverse event. Neutropenia developed in 37 patients (35%) throughout the treatment. Only 2 out of 105 patients had grade 3 hemoglobin or bilirubin abnormalities. No patient had grade 3 or 4 rash or pruritus. In conclusion, SMV plus pegIFN/RBV led to high virologic response in coinfected patients, regardless of the prior responses. Due to ART--SMV interactions, longer course of pegIFN/ RBV treatment, safety profile, the risk of viral resistance and treatment failure, SMV plus pegIFN/RBV is considered an alternative regimen for treatment-naive individuals and coinfected patients with a history of relapse following pegIFN/ RBV treatment. This regimen is not recommended in prior non-responders or patients with cirrhosis because of the low response rate and the poor tolerability. Due to in vitro diminished activity (for genotypes 2 and 3) and insufficient data (for genotype 4), regimens including TPV or BOC cannot be recommended for these HCV/HIV-coinfected patients [14]. However, this study showed that the safety and efficacy of SMV in HCV/HIV-coinfected patients is similar to those in HCV-monoinfected patients.




3.1.4

Sofosbuvir

Complex dosing, poor tolerability and interaction with ART are major limitations of NS3/4A PIs in the treatment of HCV/HIV-coinfected patients. SOF is an oral nucleotide analogue of NS5B PIs with minimal drug interactions and recently approved for the treatment of all HCV genotypes [14]. IFN-free and SOF-based combinations are associated with a high rate of cure in HCV/HIV-coinfected patients with the safety profile similar to that observed in the subjects with HCV monoinfection. Sulkowski et al. evaluated the rates of SVR and adverse events in patients infected with HIV and HCV genotype 1, 2 or 3 who were treated with the oral regimen of SOF and RBV for 12 or 24 weeks in an open-label, non-randomized, uncontrolled Phase III PHOTON-1 trial [47]. In terms of the safety profile, seven patients (3%) discontinued treatment due to an adverse event. Treatment withdrawal due to the adverse events was detected in 3% of the patients with genotype 1, 4% in treatment-naive genotype 2 and 2% treatment-experienced genotype 2 or 3. Serious adverse events were experienced by 6% of the patients. The incidence of serious adverse events and adverse events leading to discontinuation was similar in the 12- and 24-week treatment regimens. Most of the adverse events were grade 1 or 2 in severity. The most common laboratory abnormalities were anemia and elevation in the patients’ serum indirect bilirubin. Decrease in hemoglobin to < 10 g/dl was detected in 15% of the patients. Only in three patients hemoglobin dropped to < 8.5g/dl. In 19% of all participants, dose reduction of RBV was required. Serum total bilirubin higher than 3.0 mg/dl was recorded in 14% of the patients. Consistent with RBV-associated hemolysis, the maximum increase in serum bilirubin was observed during the first 2 weeks of treatment with SOF plus RBV. Although an increase in serum bilirubin was not associated with elevation in serum liver enzyme levels or other markers of liver injury, ART regimens were changed from atazanavir to darunavir in four patients. CD4 cells percent did not drop, but absolute lymphocyte and CD4 count decreased, probably reflecting the wellknown lymphocyte declining effect of RBV. Similar to the other trials, in this study also percentage of the included patients with cirrhosis is very low. Therefore, efficacy and safety of SOF in this subgroup remain unknown. In addition, relatively few patients with advanced HIV disease were enrolled. Another limitation of this study is the absence of a control group. Patients with either HCV genotype 4, 5 or 6 and coinfected with HIV infection were not included in this study to evaluate the safety and efficacy of SOF. The efficacy of the IFN-free regimen was similar to the results of the regimens consisting of an HCV PI plus pegIFN/RBV [25,36]. The rate of primary discontinuation of SOF because of the adverse events was 34% in both 12- and 24-week regimens that is lower than those observed with BOC and TPV (8 -- 20%).

In another non-randomized, open-label Phase III study, PHOTON-2, 12- or 24-week IFN-free regimen including SOF/RBV was administered in 274 HCV/HIV-coinfected patients with either HCV genotype 1, 2, 3 or 4, with or without HCV treatment experience and presence or absence of compensated cirrhosis in Europe and Australia [28]. The study design of PHOTON-2 was slightly different from the PHOTON-1 because patients with HCV genotype 3 require 24 weeks of treatment. In addition, patients with genotype 4 HCV/HIV coinfection were included in this trial. High SVR12 rates of 84 -- 89% were reported in all four genotypes. In treatment-naive patients with genotype 1 infection, SVR12 rates were higher in patients without than with cirrhosis. Presence of cirrhosis was the only significant risk factor for poorer response in a multivariate analysis. The PHOTON-II was larger than PHOTON-1 study, but the response rates were quite similar. SOF plus RBV regimen tolerated well and was compatible with multiple ART regimens. Treatment of HCV had no significant effect on the CD4 percent or HIV RNA levels in the coinfected patients during the treatment and 12 weeks of follow-up. It was concluded that HCV treatment-naive and experienced patients with HIV coinfection responded well to 12 or 24 weeks of SOF plus RBV. Also, this treatment regimen was associated with a low rate of treatment discontinuation due to the adverse events. Assessment of efficacy and safety of this regimen in pegIFN treatment-experienced patients with HCV/HIV coinfection has been proposed for future studies. Results of PHOTON-1 and PHOTON-2 studies were referred by the AASLD/IDSA recommendation. Due to the lower response in HIV/HCV-coinfected patients with cirrhosis, the use of SOF plus pegIFN/RBV is recommended over SOF plus RBV [14]. Efficacy of treatment of HCV/HIV coinfection with SOF in combination with other anti-HCV regimens such as peg/INF or other DAAs has been studied [48]. The study has evaluated the safety and efficacy of a 12-week course of the combination of once- daily SOF with pegIFN/RBV on 23 non-cirrhotic, genotypes 1 -- 4 and treatment-naive HCV/HIV-coinfected patients receiving concurrent ART. From these 21 patients achieved SVR12 [48]. SVR12 rates of this pilot study were similar to the IFN-free SOF-based regimen. SOF was well tolerated in patients receiving a wide variety of the ART regimens. The most frequently reported adverse effects (> 10%) were fatigue, anemia, thrombocytopenia, neutropenia, hyperbilirubinemia and myalgia. No HIV viral breakthrough or reductions in CD4 cells percent occurred. There was no reported serious adverse event. Abnormality in the laboratory parameters with grade 3 or 4 of severity occurred in 13 and 17% of the patients, respectively. The most common laboratory abnormalities included neutropenia, leukocytopenia and hyperbilirubinemia. All patients received atazanavir as part of the ART regimen that can increase indirect serum bilirubin [48]. The combination of SMV plus SOF with or without RBV is another oral combination therapy that is well studied in


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HCV-monoinfected patients who cannot tolerate the recommended regimens [49]. Although no data are currently available to recommend this combination in patients with HCV/ HIV coinfection, this regimen may be effective for the treatment of HCV genotype 1 infection in HIV patients who are not eligible for IFN. Given the lack of clinical data, it may be prudent to reserve this regimen for the treatment of patients with advanced fibrosis in whom a delay of therapy may lead to adverse clinical outcomes [14]. Faldaprevir Faldaprevir (FDV), an investigational once-daily HCV NS3/4A PI, active against HCV genotypes 1, 4, 5 and 6 in in vitro, was evaluated in HCV/HIV coinfection in a Phase III trial, STARTVerso4 [29]. According to a report of the 21st Conference on Retroviruses and Opportunistic Infections (2014) in Boston, once-daily 120 mg of FDV for 24 weeks (arm A) or once-daily 240 mg for 12 or 24 weeks (arm B) plus pegIFN/RBV were administered in 308 HCV treatment-naive or relapser participants. Most patients in both arms were HCV treatment-naive. A higher proportion of the patients in the arm A had cirrhosis. Patients who were not receiving ART or taking a raltegravir- or maraviroc-based regimen were randomized to 120 or 240 mg of FDV daily. Patients taking efavirenz were assigned to 240 mg FDV daily, and those taking darunavir/ritonavir or atazanavir/ritonavir were assigned to 120 mg FDV daily. Overall, 72% of the patients achieved SVR12. The rate was similar in both the arms (71 vs 72%). SVR12 was significantly higher in relapsers than treatment-naive patients (83 vs 69%) and in the patients with IL28B CC versus non-IL28B CC genotype (88 vs 64%). Age and the baseline HCV viral load were significantly associated with the treatment responses in these groups [50]. HCV genotype 1 subtype (1a or 1b), presence of compensated cirrhosis, FDV dose or duration and duration of pegIFN/RBV treatment had no significant effect on the response rates. Similar proportions in arms A and B (77 and 81%) achieved early treatment response. Almost all the study participants (93% in each arm) had a drug-related adverse event and most side effects being typical of an IFNbased regimen. One patient in the each arm stopped FDV because of an adverse event, while 7% in each arm stopped all the drugs. Serious adverse events were reported in 14 and 8% of patients in the arm A and B, respectively. Only one patient in the each arm showed HIV virologic failure, while a new AIDS defining illness developed in one patient in the arm A and 2 in the arm B. The most detected adverse events in STARTVerso4 were nausea, fatigue, diarrhea, headache and weakness. The most frequent grade 3 or 4 laboratory abnormalities were elevated serum bilirubin (14 and 23% in arms A and B, respectively), absolute neutrophil count < 750/mm3 (18 and 13% in arms A and B, respectively), platelets count < 50,000/mm3 (10 and 6% in arms A and B, respectively), white blood cell count < 1500/mm3 (6 and 4% in arms A and B, respectively) and hemoglobin


3.1.5

8

concentration < 9 g/dl (2% in both the arms). The researchers concluded that FDV was highly effective and well-tolerated in the difficult-to-treat HCV/HIV-coinfected patients and the safety profile similar to that was reported with this regimen in HCV-monoinfected patients. Among the patients treated with FDV plus pegINF/RBV, those who achieved ‘early treatment success’ had similar SVR rates at either 24 or 48 weeks of treatment. Therefore, FDV can shorten the duration of treatment with a good efficacy [51]. The most interesting finding of this study is once-daily administration of FDV that decreases the pill burden in HCV/HIV-coinfected patients and lowers the rate of adverse effects even in the cirrhotic patients. There was no clinically significant effect of FDV on the pharmacokinetic parameters of HIV medications (efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir and tenofovir). These results indicate that FDV 120 or 240 mg once daily can be safely coadministered in combination with ART in HCV/HIV-coinfected patients without the need for ART dose modification [52]. Daclatasvir Daclatasvir, an NS5A inhibitor was approved in Europe in August 2014. Daclatasvir plus SOF was highly effective in HCV-monoinfected patients [53] and its safety and efficacy is being evaluated in HCV/HIV-coinfected patients in the ongoing Phase III study known as ALLY 2 [54]. Another open-label study for assessment of the safety, tolerability and efficacy of asunaprevir 100 mg twice daily (a selective HCV NS3 inhibitor) and daclatasvir 60 mg daily in 20 HCV/HIV-coinfected treatment-naive and treatmentexperienced HCV genotype 1b individuals is ongoing. The findings from this study will be helpful in the understanding of antiviral response to an IFN-free regimen in HCV/HIVcoinfected patients [55]. 3.1.6

Paritaprevir/ritonavir/ombitasvir/dasabuvir TURQUOISE-I, an open-label, Phase II/III trial has evaluated the safety and efficacy of 12 or 24 weeks treatment with an investigational novel combination of 3 DAAs containing of a PI (paritaprevir), a boosting dose of ritonavir and an NS5A inhibitor (ombitasvir) plus dasabuvir (a nonnucleoside HCV polymerase inhibitor) and RBV in HCV/ HIV-coinfected patients who receiving atazanavir- or raltegravir-containing ART regimens [30]. Nineteen percent of the recruited patients had cirrhosis. The SVR rate was 94% in the 12-week arm. The participants, who completed 24 weeks of the therapy, reached 95% SVR at week 12. These results appear consistent with that observed in HCVmonoinfected patients. None of the participants experienced serious or treatment-limiting adverse events. Mild-to-moderate fatigue, insomnia, nausea and headache were the most common adverse events. Indirect serum bilirubin elevation was observed in 35 and 19% of the patients receiving atazanavir in the 12- and 24-week arms, respectively. Seven patients 3.1.7




experienced decreases in the hemoglobin concentration (< 10 g/dl) and from them, 6 patients required RBV dose reduction, 5 patients experienced episodes of low-level HIV viral load elevation during the treatment, but all returned to undetectable HIV RNA while remaining on the same ART regimen. There was no significant change in the patients’ CD4 count. The researchers concluded that the three DAA regimen plus RBV was effective and well-tolerated. These results are highly consistent with those previously observed in the patients with HCV monoinfection. Part 2 of the TURQUOISE-I trial will test the three DAA regimen plus RBV in patients with HCV/HIV coinfection receiving ritonavir-boosted HIV PI, darunavir. Ledipasvir SOF works better when combined with other DAAs such as the NS5A inhibitors: ledipasvir or daclatasvir. As an important non-randomized Phase II trial, ERADICATE, evaluated the efficacy and safety of SOF plus an NS5A inhibitor, ledipasvir (with activity against genotypes 1, 4, 5 and 6) for treatment HCV/HIV coinfection in 50 patients including ART-untreated and ART-treated individuals [31]. This oncedaily regimen of 12 weeks of SOF/ledipasvir is simpler than the regimen in TURQUOISE-I study. Acceptable antiretrovirals were tenofovir, emtricitabine, efavirenz, rilpivirine and raltegravir. Patients with stage 3 of liver fibrosis were enrolled in the ART-untreated (38%) or ART-treated (22%) arms. Response rates reached 100% at all time points in the both groups. SOF/ledipasvir was safe and well tolerated. No deaths, grade 4 adverse events and discontinuations due to the adverse events were detected. Most common adverse events included fatigue, pain, diarrhea, constipation and headache. SOF/ledipasvir had no adverse effect on HIV disease and CD4+ cell count or percentage. This regimen also had no significant renal toxicity over time in either arm during HCV treatment. A disadvantage of ledipasvir is that it does not have potent activity against HCV genotypes 2 and 3. It seems that SOF/RBV is an appropriate regimen for HCV/HIVcoinfected patients with HCV genotype 2 or 3 and without cirrhosis. Recently, the FDA on 10 October 2014 announced approval of Harvoni (SOF/ledipasvir) as the first-ever fixeddose combination single tablet (without IFN or RBV) for treatment of HCV genotype 1 infection. Although the study with small sample size showed promising results, this combination did not receive any indication among HCV/HIV-coinfected patients and remained an off-label prescribing until studies in this subgroup become completed. 3.1.8

Newer DAAs Based on the results of the Phase II clinical program (C-WORTHY) and in acknowledgement that MK-5172 (a NS3/4A PI)/MK-8742 (an NS5A PI) is expected to be at least the fourth oral combination on the market, Merck and Co’s Phase III program is enrolling the subgroups which are limited or there are no data regarding the safety and effectiveness 3.1.9

of oral regimens. The C-EDGE program included cirrhotic and non-cirrhotic patients with HCV GT-1/4/5/6 monoinfection and HIV coinfection, as well as patients on opioids replacement therapy. Recently, Sulkowski et al. assessed efficacy and safety of this oral, 12-week once-daily, highly potent regimen of MK-5172/MK-8742 ± RBV in 59 treatmentnaive, non-cirrhotic patients with HCV/HIV-coinfected patients who were on a stable ART regimen (raltegravir + tenofovir or abacavir with either lamivudine or emtricitabine). All patients reached an HCV RNA level < 25 IU/ml at treatment week 4, regardless of RBV therapy. The most common adverse events were fatigue, headache, back pain and asthenia. The incidence of the adverse events was not increased in patients with HIV infection. No patient discontinued treatment due to either an adverse event or the medication intolerance [32]. At week 12, 100% of coinfected patients who received MK-5172/MK-8742 and RBV, and 90% of coinfected patients who received MK-5172/MK-8742 had HCV RNA levels < 25 IU/ml. This rate was 100% in HCVmonoinfected patients who received MK-5172/MK-8742. Only three treatment failures were detected in the HCV/ HIV-coinfected arm [56]. In conclusion, patients with HCV monoinfection and HCV/HIV coinfection achieved rapid viral suppression during the first 4 weeks of therapy with MK-5172/ MK-8742 regimen, regardless of RBV administration [32]. Potentially drug interactions The altered expression and function of the hepatic enzymes and transporters and change in protein binding in HCV infection affects plasma concentration of some DAAs and antiretrovirals. Also, interaction between HCV NS3/4A PIs and antiretrovirals in HCV/HIV-coinfected patients is a serious concern [14]. HCV NS3A/4 PIs and NS5A inhibitors primarily are metabolized by the liver. Several antiretrovirals affect the CYP3A metabolic pathway which can change metabolism of DAAs [57]. Among all antiretrovirals, raltegravir (glucuronidation-mediated metabolism) and tenofovir/ emtricitabine (which are primarily metabolized by the kidneys) do not affect CYP enzyme activity [37]. Therefore, these two agents are more attractive for use as preferred ARTs in HIV/HCV coinfection treatment because of the low potential for drug--drug interactions. Potential drug interactions between DAAs and other antiviral agents, statins, oral contraceptives, antidepressants, anti-psychotics, anxiolytics and sleep aids, opioid replacements, anti-hypertensive agents and immunosuppressants have been reviewed in some studies [57,58]. Drug--drug interactions and practical management of interaction between DAAs and ARTs were summarized in Table 3. Studies on pharmacokinetic properties of first-generation PIs showed that TPV is substrate and inhibitor of CYP3A4 enzyme and drug transporter P-glycoprotein (P-gp). TPV also inhibits organic anion-transporting polypeptide (OATP), which adds to potential drug interactions [5961]. Therefore, coadministration of ARTs with potential of 3.2


9

Safe coadministration and no need for dose change


The pharmacokinetic interactions between TPV and abacavir have not been adequately Studied but TPV can be Safe used in combination with abacavir because of its metabolism pathway

Emtricitabine

Lamivudine

Abacavir

No data

No data Safe coadministration and no need for dose change

No data, but it seems safe because of its metabolism pathway

Recommended without dose adjustment

The pharmacokinetic interactions between BOC and abacavir have not been adequately Studied but BOC can be Safe used in combination with abacavir because of its metabolism pathway

No data

No data

Significant interaction is not expected Safe coadministration and no need for dose change


No data Based on the metabolism pathway, seems that it can be Safe used concomitantly


No clinically meaningful interaction Recommended without dose adjustment No clinically meaningful interaction Recommended without dose adjustment No clinically meaningful interaction Recommended without dose adjustment

Concurrent use at standard doses is recommended -Interactions not expected

No clinically meaningful interaction Recommended without dose adjustment


No data

Safe coadministration Recommended without dose and no need for adjustment dose change


No data

Safe coadministration Safe coadministration and No clinically no need for dose change meaningful and no need for interaction dose change Recommended without dose adjustment


Ledipasvir increases tenofovir levels. Concomitant use of ledipasvir/SOF and ritonavir-boosted PIs or efavirenz may cause tenofovir nephrotoxicity Change HIV treatment to a regimen without tenofovir or close monitoring for signs of tenofovir-induced nephrotoxicity Coadministration of ledipasvir/SOF with the combination regimen of elvitegravir, cobicistat, tenofovir and emtricitabine is not recommended due to increased tenofovir concentration Significant interaction is not expected Safe coadministration and no need for dose change

MK-5172/ MK-8742

Safe coadministration Recommended without dose and no need for adjustment dose change

No effect on pharmacokinetics of BOC Increase in Cmax of tenofovir Safe coadministration and no need for dose change

Paritaprevir/ritonavir/ ombitasvir/dasabuvir

Daclatasvir

Faldaprevir

SOF

Ledipasvir/SOF

Simeprevir

BOC

Direct-acting antiviral agents

BOC: Boceprevir; NNRTI: Non-nucleoside reverse-transcriptase inhibitor; PI: Protease inhibitor; SOF: Sofosbuvir; TPV: Telaprevir.

No effect on pharmacokinetics of TPV Increase in Cmax of tenofovir Safe coadministration and no need for dose change

TPV

Tenofovir

Antiretroviral therapy

Table 3. Summary of interactions between direct-acting antiviral agents and antiretrovirals.



Coadministration is recommended but caution for QT interval prolongation

Increase in raltegravir AUC TPV levels were unchanged Safe coadministration and no need for dose change

No significant pharmacokinetic interaction between BOC and dolutegravir Safe coadministration and no need for dose change

Etravirine

Rilpivirine

Raltegravir

Dolutegravir

No data

No data

No data

No data

No data

No data

Recommended

No data

No data, but based on data about efavirenz the decreased level of ledipasvir is possible



No data, though significant interaction is not expected

Use of etravirine or nevirapine with SOF has not been studied, though significant interaction not expected

Significant decrease in simeprevir levels expected when used with etravirine Simeprevir is not recommended for use with etravirine Recommended without dose adjustment

Consider on a case-by-case basis

No significant pharmacokinetic interaction between BOC and raltegravir Safe coadministration and no need for dose change


Decrease in raltegravir level, but not significant Recommended without dose adjustment Ral level decreased but no dose adjustment No data but it Use of dolutegravir No significant in patients receiving seems safe and pharmacokinetic no significant simeprevir has not interaction between been studied, though interaction is BOC and raltegravir -Safe coadministration significant interaction expected and no need for dose is not expected change


Decreased AUC and Cmin of daclatasvir Increase dose of daclatasvir to 90 mg/day

Recommended at 240 mg/day

Decreased level of ledipasvir, but not clinically significant Safe coadministration and no need for dose change


Significant decrease in simeprevir levels expected when used with efavirenz and nevirapine SMV is not recommended for use with efavirenz or nevirapine

Decrease in concentration of BOC Combination of BOC and efavirenz or other NNRTIs is not recommended

Safe coadministration

Daclatasvir

Faldaprevir

Ledipasvir/SOF

SOF

Simeprevir

BOC



Decrease in concentration of TPV A higher dose of TPV, 1125 mg thrice daily, suggested in combination with efavirenz

TPV

Efavirenz


Table 3. Summary of interactions between direct-acting antiviral agents and antiretrovirals (continued).



Significantly increased rilpivirine levels Concomitant use with rilpivirine is not recommended due to potential for QT interval prolongation Safe coadministration

NNRTIs other than rilpivirine (efavirenz, etravirine and nevirapine)

Significantly increased levels of efavirenz Concomitant use with efavirenz is not recommended due to poor toleration and elevation in liver enzyme and toxicity


No data

No clinically meaningful interaction Recommended without dose adjustment

No data

Coadministration is not permitted

Decrease in MK-5172 and MK-8742 AUC Coadministration is not permitted

MK-5172/ MK-8742

All of these ritonavirboosted HIV PIs significantly reduce TPV concentrations Reduction in darunavir and fosamprenavir levels No change in lopinavir level Combination of TPV with these ritonavirboosted HIV PIs should be avoided

TPV substantially increase the exposure to maraviroc Decrease in dose of maraviroc to 150 mg twice daily No TPV dose adjustments are needed with maraviroc

Other ritonavir-boosted HIV PIs (such as lopinavir, darunavir and fosamprenavir, tipranavir, etc.)

Maraviroc

BOC substantially increase the exposure to maraviroc Decrease in dose of maraviroc to 150 mg twice daily No BOC dose adjustments are needed with maraviroc

No data

Recommended

No data, though significant interaction is not expected

Use of maraviroc with SOF has not been studied, though significant interaction not expected

No data

Significantly reduced levels of darunavir Concomitant use with darunavir is not recommended Concomitant use with lopinavir-ritonavir is not recommended due to potentially toxic dose of ritonavir Other HIV PIs (e.g., indinavir, saquinavir, tipranavir, lopinavir/ ritonavir) are contraindicated

No data

With darunavir Recommended at 120 mg/day

Safe coadministration of ledipasvir/SOF with ritonavir-boosted PIS and no need for dose change Tipranavir decreases ledipasvir and SOF levels Concommitant use of ritonavir boosted tipranavir with Ledipasvir/SOF is contraindicated

Use of these HIV protease inhibitors with sofosbuvir at standard doses is recommended Exception: coadministration of SOF with tipranavir/ritonavir decreases SOF levels leading to decreased SOF efficacy Coadministration of SOF with tipranavir/ritonavir not recommended

Significantly increased or decreased plasma concentrations of simeprevir when used with any HIV protease inhibitor, when used with or without ritonavir Significant increase in simeprevir levels expected when used with daurnavir/ ritonavir. Simeprevir is not recommended for use with HIV ritonavir-boosted protease inhibitors If used with simeprevir, the dose of maraviroc is decreased to 150 mg twice daily

Safe coadministration The atazanavir should be taken without ritonavir during hepatitis C virus treatment with this fixeddose combination

Increased AUC and Cmin of daclatasvir Decrease dose of daclatasvir to 30 mg daily

Recommended at 120 mg/day



Do not coadminister

Atazanavir/r did not significantly affect BOC exposure BOC coadministration reduces the exposure of atazanavir This combination is not recommended in general but may be considered on a case-by-case basis BOC can lower the serum levels of boosted HIV PIs, and vice versa Combination of BOC with these ritonavirboosted HIV PIs should be avoided


Daclatasvir

Faldaprevir

Ledipasvir/SOF

SOF

Simeprevir

BOC



Atazanavir reduces TPV levels, but the effect is smaller Slightly increase in atazanavir AUC Coadministration is allowed, but monitor for hyperbilirubinemia is recommended

TPV

Atazanavir/r


Table 3. Summary of interactions between direct-acting antiviral agents and antiretrovirals (continued).


No data

Significant increase in AUC of MK-8742 and MK-5172 Coadministration is not permitted

Significant increase in AUC of MK-8742 and MK-5172 Coadministration is not permitted

MK-5172/ MK-8742



CYP3A inducer, efavirenz, may reduce TPV exposure. Use of TPV in the healthy subjects when combined with efavirenz (with increased dose of TPV to 1125 mg every 8 h) [62], tenofovir, emtricitabine, atazanavir/r and raltegravir has been reported as safe [60]. Safe use of TPV in combination with tenofovir/emtricitabine, atazanavir/ritonavir, efavirenz (with a higher dose of TPV) and raltegravir has also been shown in clinical studies in the patients [26]. Although TPV’s inhibition of P-gp increased raltegravir AUC, it seems this interaction is not clinically sound [57]. TPV concentrations with and without concurrent ART were similar, except that the minimum TPV concentration was 31% higher in patients taking ritonavir-boosted atazanavir. However, no increase in the average or maximum TPV concentration was seen in this group. Absence of HIV breakthrough provided additional support for coadministration of TPV with these selected ART regimens [36]. In contrast, combination of TPV with ritonavirboosted HIV PIs, including lopinavir, darunavir and fosamprenavir should be avoided because of their CYP-induction properties and potential for significant reduction in TPV concentration [59,60]. BOC is substrate and inhibitor of CYP3A4 enzyme and P-gp drug transporter [59-61]. BOC is a substrate for breast cancer resistance protein and has weak inhibitory effect on this transporter. In addition, BOC is inhibitor of organic cation transporter and a primary substrate of aldoketo-reductase, as a non-CYP metabolism pathway [61]. On 20 April 2012, the FDA announced an update describing drug--drug interactions between BOC and certain boosted HIV PIs. Concomitant administration of BOC and commonly used ritonavir-boosted HIV PIs and ritonavir is not recommended in this announcement [63]. BOC decreased AUC and Cmin of ritonavir-boosted HIV PIs, including atazanavir, lupinavir and darunavir in healthy subjects. So BOC is not recommended with ritonavir-boosted PIs [64]. As boosted atazanavir had no impact on BOC, it is suggested that different dosages of atazanavir should be tried to reach higher atazanavir levels to compensate the decreased atazanavir exposure induced by BOC [64]. Although BOC can lower the serum levels of some boosted HIV PIs, and vice versa, coinfected participants taking BOC did not show a higher rate of HIV or HCV breakthrough than those taking pegINF/RBV plus placebo [43]. BOC can be safely used in combination with abacavir-lamivudine, tenofovir-emtricitabine plus raltegravir but not efavirenz or other non-nucleoside reverse-transcriptase inhibitors (NNRTIs) due to the significant drug interactions [43,61]. In some trials, the relation between BOC pharmacokinetic parameters and SVR and anemia was examined. The same BOC exposure was achieved irrespective of the ART regimen, although the exposure in patients taking raltegravirbased regimens without PIs was lower than that reported in other groups. As in the healthy individuals, raltegravir did not affect BOC exposure. No significant association between BOC pharmacokinetic parameters and severe anemia was detected [25]. The pharmacokinetic interactions of BOC and

antiretrovirals in HCV/HIV-coinfected patients receiving efavirenz, raltegravir, atazanavir/ritonavir, darunavir/ritonavir and lopinavir/ritonavir have also been evaluated. With the exception of increased raltegravir concentration, the effects of BOC on the antiretrovirals pharmacokinetic parameters in these patients were similar to those observed in the healthy volunteers. A greater decline in the BOC Cmin with efavirenz and a reduction in BOC concentration with ritonavir-boosted PIs were expected, but not observed [65]. An ongoing Phase III study assesses the clinical significance and the impact of interactions between BOC and ritonavir-boosted PIs in HCV/ HIV-coinfected individuals (NCT01482767). There is concern about SMV drug interactions as this agent similar to other members of NS3/4A PI family is metabolized by the CYP3A4 isoenzyme in intestine and liver. SMV also inhibits the P-gp and OATP transporters, which increases its potential for drug interactions. SMV concentration significantly decreased when coadministered with efavirenz and increased with darunavir/ritonavir in the healthy subjects. There was no substantial interaction between SMV with either tenofovir or rilpivirine or raltegravir [66]. In C212 study, patients receiving efavirenz or darunavir/ ritonavir as a part of ART were excluded from SMV therapy in the HCV/HIV coinfection [27]. SMV should only be used with antiretrovirals without significant interactions. These agents are raltegravir, rilpivirine, maraviroc, enfuvirtide, tenofovir, emtricitabine, lamivudine and abacavir [14]. Essentially, the use of NNRTIs and ritonavir-boosted HIV PIs is not recommended to coadminister with SMV. Some pharmacokinetic properties of SOF including no metabolism by hepatic CYP450 enzymes and being only a substrate (but not an inhibitor) of the drug transporters such as P-gp place this agent in the category of weak interaction potential. The most common coadministered ART regimens with SOF were emtricitabine/tenofovir plus either efavirenz, atazanavir/ritonavir, darunavir/ritonavir, rilpivirine or raltegravir and no dose adjustment was needed for these drugs [33,48]. These results were similar to the healthy patients [67]. Tipranavir/ritonavir as the main exception is not recommended for concurrent use with SOF due to decreased SOF concentration via induction of the P-gp transporter by tipranavir [47]. Concomitant use of abacavir or dolutegravir with SOF seems safe because these two ARTs have different metabolism pathway from SOF. P-gp transporter is substrate for both agents in ledipasvir/ SOF combination. Pharmacokinetic studies suggest that concomitant use of ritonavir-boosted tipranavir with ledipasvir/ SOF is contraindicated because of its potential for induction of P-gp and subsequently decrease in ledipasvir and SOF [68]. Ledipasvir/SOF is administered with efavirenz, atazanavir/ritonavir, darunavir/ritonavir, rilpivirine or raltegravir with a backbone of emtricitabine/tenofovir without evidence of low efficacy or safety and need for dose adjustment [69]. No clinically significant drug interactions have been either observed or are expected when ledipasvir/SOF is used with


13


A. Jafari et al.

abacavir, ritonavir-boosted darunavir, lamivudine and dolutegravir [68]. The clinical significance and safety of increased tenofovir concentrations in the setting of ledipasvir/SOF and the combination of elvitegravir, cobicistat, emtricitabine and tenofovir has not been certainly established. Therefore, coadministration of ledipasvir/SOF with the combination regimen of elvitegravir, cobicistat, tenofovir and emtricitabine is not recommended [68]. FDV is a substrate for CYP3A4, a moderate inhibitor of CYP3A4 at a dose of 240 mg and a weak inhibitor of CYP3A4 at a dose of 120 mg. FDV also inhibits CYP2C9 and uridine diphosphate glucuronosyl transferase (UGT) [58]. FDV can increase raltegravir AUC by ~ 2.5-fold without any significant effects on the pharmacokinetic parameters of efavirenz, darunavir/ritonavir or tenofovir in the healthy subjects. Analysis of the pharmacokinetic interaction between FDV and ART agents used in coinfected patients showed that FDV had no apparent effect on efavirenz concentration. The trough level of darunavir decreased with FDV. In coinfected patients, FDV with dose of 120 mg had no effect on trough levels of raltegravir and tenofovir, but 240 mg daily dose of FDV decreased the trough levels. In the presence of efavirenz, effect of FDV on the tenofovir trough level disappeared [52]. Antiretrovirals had no consistent effects on the FDV trough concentration in patients who received raltegravir-based ART regimens. FDV trough levels in patients who received FDV 120 mg/day with a darunavir/ritonavir or atazanavir/ritonavir-based ART regimen were 1.8- to 1.9-fold higher than the trough levels in patients who received raltegravir-based ART or in HCV-monoinfected patients with similar demographic characteristics. No apparent increase in the incidence of gastrointestinal events following the addition of FDV to darunavir/ritonavir or atazanavir/ritonavir-based ART regimens was observed [52]. However, increases in serum bilirubin were not markedly different between the groups. There were five and two cases of jaundice in the FDV 120 mg/day arm and the atazanavir/ritonavir subgroup, respectively. The safety profile of FDV plus pegIFN/RBV with concomitant atazanavir/ritonavir therapy was consistent with the overall safety profile of FDV plus pegIFN/RBV in monoinfected individuals. Based on these results, FDV 120 mg once daily and atazanavir/ritonavir or darunavir/ritonavir can be safely coadministered without dose modification in HCV/HIVcoinfected patients [70]. FDV trough levels in patients who received FDV 240 mg daily with an efavirenz-based ART regimen were lower compared with the trough levels in patients who received FDV 240 mg daily with raltegravir-based ART or HCVmonoinfected patients with the similar demographic characteristics. FDV with dose of 240 mg daily is recommended when it is concomitantly administered with efavirenz-based regimen [52]. All agents in the fixed-dose combination of paritaprevir/ ritonavir/ombitasvir/dasabuvir are substrates or inhibitors of 14

CYP enzymes and have potential for drug interactions. Evaluating pharmacokinetic parameters of paritaprevir/a boosting dose of ritonavir/ombitasvir/dasabuvir showed no significant interaction between this regimen and tenofovir, emtricitabine, raltegravir or ritonavir-boosted atazanavir similar to the results of the healthy volunteers [30]. Agents such as lamivudine, dolutegravir and abacavir, whose primary metabolism pathway does not involve CYP enzymes, seem to be safe for concomitant use with paritaprevir/ritonavir/ombitasvir/dasabuvir. This combination significantly reduced level of darunavir and increased levels of rilpivirine and efavirenz when coadministered. Concomitant use of ritonavir-boosted lopinavir is also not recommended due to increase in dose of ritonavir and its potential toxicity [71,72]. Daclatasvir is a substrate of CYP3A4 and substrate and inhibitor of P-gp and OATP1B1. Limited information regarding daclatasvir interactions with antiretrovirals are available. As the AUC and Cmin of daclatasvir when coadministered with atazanavir/ritonavir, the dose of this agent should be decreased when prescribed with these ARTs. The dose of daclatasvir should be increased when coadministered with efavirenz due to decreased AUC and Cmax of daclatasvir. There was no clinically relevant interaction between daclatasvir and tenofovir. No data about other antiretrovirals are available [58]. Evaluating daclatasvir drug interaction in healthy volunteers is generally acceptable for predicting the major interactions. The results of the ongoing trials will be helpful for clinical decision in HCV/HIV-coinfected patients. Table 1 shows ART drugs for concomitant use in regimens consisting of DAAs. MK-5172 and MK-8742 are substrates (but not an inhibitor) of CYP3A4, P-gp and OATP. Also, MK-5172 and MK-8742 are weak inhibitors of UGT1A1. Pharmacokinetic interactions of these two agents are investigated in healthy subjects. There are no clinically significant interactions with MK-8742 and tenofovir or raltegravir [73]. Ritonavir-boosted atazanavir, darunavir and lopinavir caused significant increase in AUC of MK-8742 and MK-5172 [74,75]. Also, no dose adjustment of MK-5172, tenofovir and raltegravir are recommended during coadministration [76]. Decrease in MK-5172 and MK-8742 AUC with efavirenz is likely due to induction of CYP3A4 [76,77]. Allowed ART regimen with MK-5172 and MK-8742 in clinical trial was raltegravir + tenofovir or abacavir with either lamivudine or emtricitabine [32]. Drug interactions with the combination of MK-5172 and MK-8742 and ARTs are ongoing in the C-EDGE coinfection trial (NCT02105662). 4.

HBV/HCV coinfection

HBV/HCV coinfection has been associated with poorer prognosis of HCV infection [78]. Chronic HCV and active HBV coinfection can lead to severe liver injury and hepatocellular carcinoma [79,80]. There is no established standard of care for HBV/HCV-coinfected patients.




Table 4. Reported rate of serious adverse events and drug discontinuation due to adverse events in the clinical studies of direct-acting antiviral agents. Agent

Reported rate of severe adverse events (%)

Reported rate of treatment discontinuation due to an adverse effect (%)

TPV Sulkowski et al. (2013) [36] TPV ANRS HC26 TelapreVIH 2014 [42] BOC Sulkowski et al. (2013) [25] Simeprevir Study C212 [27] SOF PHOTON-1 [81] SOF PHOTON-2 [28] SOF ERADICATE [31] Faldaprevir STARTVerso 4 [29] MK-5172 + MK-8742 C-WORTHY [32] ABT-450/r/ABT-267 + ABT-333 TURQUOISE-I [30]

5 vs 0 (TPV group vs control group) 20

5 vs 0 (TPV group vs control group) 20

17 vs 21 (BOC group vs control group) 5.7

20 vs 9 (BOC group vs control group) 3.8

7 in patients receiving 24 weeks of therapy 7 in patients receiving 12 weeks of therapy 6

3 in patients receiving 24 weeks of therapy 4 in patients receiving 12 weeks of therapy 2

1 patient with severe adverse event, deemed unrelated to treatment 10

No discontinuation due to adverse event

7 in RBV arm vs 3 in RBV free arm


No serious adverse events


7

BOC: Boceprevir; SOF: Sofosbuvir; TPV: Telaprevir.

It is recommended to initiate individualized treatment in patients with active chronic hepatitis or cirrhosis prior to decompensation. In coinfected patients with low level of HBV viremia, IFN or pegIFN plus RBV has been well studied. The efficacy was as expected as in HCV monoinfection. One of the major concerns in the treatment of HBV/HCV coinfection is ‘flare’ of hepatitis due to the risk of HBV reactivation during or after HCV clearance that may increase risk of liver damage. In the case of HBV replication at a significant level, concurrent HBV nucleoside/nucleotide analogue therapy may be indicated. In patients in whom treatment of HBV infection is required, IFN with or without lamivudine is a reasonable option [13]. In patients with active HBV/ HCV coinfection, treatment of the two infections concurrently with a pegIFN-based regimen is recommended. In addition, future studies are needed to assess the effectiveness of pegIFN as well as triple therapy with lamivudine, IFN and RBV in patients with active coinfection. In dually active HBV/HCV coinfection, further studies regarding adding other oral HBV nucleos(t)ide analogues (such as adefovir and entecavir) to pegIFN/RBV are needed before these agents can be routinely recommended as reasonable options [80]. The addition of lamivudine to pegIFN/RBV has been tested in a small series of dually infected patients. No evidence of significant improvement compared with pegIFN/RBV alone was detected [20]. In patients with active HCV/HBV coinfection, prospective studies on the efficacy and safety of DAAs in patients with active HCV replication must be conducted to confirm their benefits and assess the rate and clinical consequences of HBV rebound. Finally, the role of new DAAs for

the treatment of patients with dual HCV/HBV infection remains to be evaluated. 5.

Expert opinion

The successful treatment of chronic HCV infection with the regimens containing DAAs promote evaluating the safety and efficacy of the current treatment options in HCV/HIVcoinfected patients. Drug interactions between DAAs and ART, overlapping toxicities, regimen complexity and cost also are considerable issues in the management of HCV/ HIV-coinfected patients. Cost of DAAs and affordability of patients are essential issues. These points may affect adherence to DAAs. PIs including TPV and BOC remain off label for use in HIV/HCV coinfection, but the newer DAAs SOF and SMV can be considered in HIV/HCV-coinfected patients. Comparison between first-generation PIs and newer DAAs shows that the newer agents can improve outcomes, shorten duration of treatment, fewer adverse events and better safety profile in HCV/HIV-coinfected patients. SOF as a newer DAA is a considerable option in HIV/HCV-coinfected population due to the minimal adverse effects and drug interaction. First-generation PIs and newer DAAs have similar safety and tolerability profiles in monoinfected and coinfected patients [25,27,29,30,32,36,81]. The adverse effects of the newer agents are lower than the first-generation PIs. We compared rates of serious adverse events and drug discontinuation due to adverse events in clinical studies of DAAs in Table 4. Evaluating safety profile and drug interactions of other newer


15


A. Jafari et al.

agents including daclatasvir, asunaprevir, MK-5172 and MK-8742 are ongoing. Advantages of the newer DAAs are once-daily dosing, IFN free, high response rate, low adverse events and shorter treatment duration. There are also multiple reviews summarizing the drug interactions between approved and upcoming DAAs and commonly used ART agents [58,82,83]. These summaries are practical for selecting an appropriate regimen in HCV/HIV-coinfected patients. In the most studies, HCV-infected patients with the advanced liver diseases, fibrosis or cirrhosis were excluded or limited numbers were enrolled. Therefore, efficacy and safety of DAAs in HCV/HIV-coinfected patients in these subgroups should be determined in future studies. Other conflicting issues are recruitment of special racial groups, middle-aged and male sex individuals in the studies that affect extrapolation of the safety and efficacy data of DAAs in all HCV/ HIV-coinfected patients. These subjects should be considered in designing of future randomized clinical trials. There are no data regarding the safety and efficacy of DAAs in special populations of HCV/HIV-coinfected patients, including patients with comorbidities, pregnancy, lactation and pediatrics. Evaluating the safety and efficacy of DAA-based regimens in these special populations are recommended for future researches. The most important consideration in treatment of HCV/ HIV coinfection is preventing and managing drug--drug interactions between DAAs and ART. Although this issue was addressed for common ART regimens, data for all used antiretrovirals are lacking. Also, concomitant diseases and opportunistic infections are common in HIV patients and many of these patients are using Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

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Affiliation

Atefeh Jafari1, Hossein Khalili†2, Mandana Izadpanah1 & Simin Dashti-Khavidaki3 † Author for correspondence 1 Tehran University of Medical Sciences, Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran, Iran 2 Professor of Clinical Pharmacy, Tehran University of Medical Sciences, Department of Clinical Pharmacy, Faculty of Pharmacy, P.O.Box: 14155/6451, EnghelabAve, Postal Code: 1417614411, Tehran, Iran Tel: +98 912 2979329; E-mail: [email protected] 3 Tehran University of Medical Sciences, Nephrology Research Center, Tehran, Iran

19

HCV coinfection.

Human immunodeficiency virus and coinfection with hepatitis B and C.

Coinfection with HIV-1 alleviates iron accumulation in patients with chronic hepatitis C virus infection.

Update on Hepatitis C Virus and HIV Coinfection.

Clinical outcomes of hepatitis B virus coinfection in a United States cohort of hepatitis C virus-infected patients.

Hepatitis C Virus Coinfection: Improvement of the Liver Function in Chronic Hepatitis C.

Management of psoriasis patients with hepatitis B or hepatitis C virus infection.

Sexual transmission of hepatitis C virus and its relation with hepatitis B virus and HIV.

Immune activation response in chronic HIV-infected patients: influence of Hepatitis C virus coinfection.

Hepatitis B virus surface antigen and anti-hepatitis C virus rapid tests underestimate hepatitis prevalence among HIV-infected patients.

Hepatitis C Coinfection.

Epidemiology and impact of HIV coinfection with hepatitis B and hepatitis C viruses in Sub-Saharan Africa.

HIV Coinfection in the Era of Highly Effective Hepatitis C Virus Direct-Acting Antiviral Therapy.

hepatitis C virus coinfected patients.

Hepatitis B virus markers and antibodies to hepatitis C virus in Japanese patients with hepatocellular carcinoma.

Reactivation of hepatitis B in patients of chronic hepatitis C with hepatitis B virus infection treated with direct acting antivirals.

Human immunodeficiency virus coinfection with hepatitis B virus leads to a decrease in extracellular and intracellular hepatitis B antigen.

Chronic hepatitis B virus coinfection is associated with renal impairment among Zambian HIV-infected adults.

hepatitis B virus coinfection.

or human immunodeficiency virus infections.

hepatitis C virus coinfection ameliorates the atherogenic lipoprotein abnormalities of HIV infection.

Viral (hepatitis C virus, hepatitis B virus, HIV) persistence and immune homeostasis.

Correction: Hepatitis B, Hepatitis C and HIV-1 Coinfection in Two Informal Urban Settlements in Nairobi, Kenya.

Hepatitis B virus and hepatitis C virus dual infection.