Journal of Viral Hepatitis, 2015, 22, 2–7
doi:10.1111/jvh.12348
COMMISSIONED REVIEW
How will we manage acute HCV in men having sex with men in the era of all oral therapy? C. Boesecke and J. K. Rockstroh
Department of Internal Medicine I, Bonn University Hospital, Bonn, Germany
Received August 2014; accepted for publication September 2014
SUMMARY. With the advent of direct-acting antivirals
(DAAs), the treatment of chronic hepatitis C virus (HCV) infection (CHC) has been revolutionized. Modern interferon- and potentially also ribavirin-free combinations consisting of 2 or 3 direct-acting antivirals (DAA) promise sustained virological response rates (SVR) of above 90%. This coincides with much shorter treatment durations and a much more favorable toxicity profile. Some DAAs even work across all HCV genotypes (pangenotypic) [BMJ, 349, 2014, g3308]. And lastly, HCV treatment in HIV-coinfected
INTRODUCTION With the advent of direct-acting antivirals (DAAs), the treatment of chronic hepatitis C virus (HCV) infection (CHC) has been revolutionized. Modern interferon- and potentially also ribavirin-free combinations consisting of 2 or 3 direct-acting antivirals (DAA) promise sustained virological response rates (SVR) of above 90%. This coincides with much shorter treatment durations and a much more favourable toxicity profile. Some DAA even work across all HCV genotypes (pangenotypic) [1]. And lastly, HCV treatment in HIV-coinfected patients will no longer differ from HCV-monoinfected patients as response rates under DAA in the setting of HCV/HIV coinfection have been as good as in HCV-monoinfected patients [2]. Only drug–drug interactions with the new DAAs and concomitant antiretroviral therapy have to be accounted for due to shared metabolizing pathways via the cytochrome p450 system. But what about acute hepatitis C (AHC)? Are we there, yet? Should we be using DAAs in AHC similar to how we have started to use them at the chronic stage? This review will discuss diagnosis of AHC, how, when and whom to treat according to the current treatment recAbbreviations: AHC, acute hepatitis C; ALT, alanine aminotransferases; DAA, direct-acting antiviral; FDC, fix-dose combination; HCV, hepatitis C virus; SVR, sustained virological response rates. Correspondence: J€ urgen Kurt Rockstroh, Department of Medicine I, Bonn University Hospital, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. E-mail: [email protected]
patients will no longer differ from HCV-monoinfected patients as response rates under DAA in the setting of HCV–HIV coinfection have been as good as in HCVmonoinfected patients [J Hepatol, 61, 2014, 373]. Only drug–drug interactions with the new DAAs and concomitant antiretroviral therapy have to be accounted for due to shared metabolization pathways via the cytochrome p450 system. Keywords: Acute hepatitis C, HIV, MSM, DAA.
ommendations as well as outline current and anticipated evidence for the use of DAA in AHC with a focus on (HIV positive) men who have sex with men (MSM) among whom the vast majority of acute HCV infections worldwide have been reported over the last decade [3–11]. Finally, we will also address the public health aspects of a DAAbased IFN-free acute HCV treatment strategy in this highrisk population and its potential to shape the course of the ongoing epidemic.
HOW TO TEST Acute hepatitis C is defined as the first 6-month period after infection with HCV. As the exact time point of infection in clinical practice is often difficult to determine, it is frequently challenging to distinguish between a true acute hepatitis C and early chronic infection [2,12]. Seroconversion from anti-HCV negativity to anti-HCV positivity reflecting the development of antibodies can be regarded as a definite diagnosis. However, as observable seroconversion is uncommon in clinical care, HCV RNA testing via PCR has to be performed if AHC is suspected and anti-HCV antibodies are still negative. In addition, elevated aminotransferases can be a helpful indicator of an acute hepatitis C although definitions vary from study to study. In contrast to HIV-positive MSM who are seen every 3–6 months for routine control of HIV infection, HIV-negative MSM may consult with their general practitioner on a less-frequent basis. Thus, acute liver transaminase elevations may be missed in the HIVnegative population and only symptomatic patients will be © 2014 John Wiley & Sons Ltd
Management of acute HCV in MSM in the era DAA likely to be diagnosed. More disturbingly, recent data from the UK have shown that of all 3811 HIV-negative MSM attending a London clinic for sexual health screening, only 565 (14.82%) were tested for HCV although there are data also from the UK describing a cohort of 36 HIV-negative MSM with AHC [13,14]. In addition, timely diagnosis is problematic because the majority of individuals with acute HCV infection are asymptomatic. Only around one-third to a half of individuals with acute HCV infection show signs of an acute illness such as lethargy and myalgia, and less frequently jaundice [3,8]. In the German Hep-Net AHC cohort, disease severity was not associated with HCV genotype, viral load, age, sex and BMI [15]. HIV-positive patients are less likely to experience a clinically apparent AHC infection [3,8]. On top, anti-HCV seroconversion may be significantly delayed in HIV-positive patients, with 5% of cases still anti-HCV negative despite ongoing viral replication for 1 year [16]. However, at least annual anti-HCV antibody and 6-month ALT measurements followed by HCV RNA testing in cases of suspected AHC seem to be a reasonable approach for AHC screening in HIV-positive individuals [17]. This recommendation derives from findings from the British St Mary’s Acute Hepatitis C Cohort (SMACC) where 88% of patients experienced elevated alanine aminotransferases (ALT) within three months of infection with peak ALT levels > 5 times the upper limit of normal in 55% [16]. In the absence of consensus recommendations, screening for clinically asymptomatic AHC in other at-risk populations such as HIV-negative MSM should consist of at least annual anti-HCV antibody testing [18].
WHEN TO TREAT Spontaneous HCV clearance happens in up to 15% in HIVcoinfected individuals with around 85% of patients subsequently progressing to chronic hepatitis C [16,19–23]. For both classic treatment with pegIFN + RBV and any new DAA-containing regimen, determination of the point in time until which spontaneous clearance can be expected will be of high interest as this would allow postponement of treatment initiation and prevent unnecessary toxicities (pegIFN + RBV) or substantial costs (DAA). In AHC/HIV coinfection several cohort, data have provided useful answers to the question whether it is possible to predict progression to chronicity of AHC infection by looking at the course of HCV RNA after diagnosis. In a European cohort of 92 HIV-positive patients with acute HCV who did not receive HCV-specific antiviral therapy, the sensitivity and specificity of HCV RNA determination 4 and 12 weeks after diagnosis to predict the outcome of acute HCV was similarly strong [24,25]. Nine of 10 patients showing spontaneous regression of HCV RNA of at least 2 log 4 weeks after diagnosis subsequently cleared HCV. In contrast, 92% of patients who were HCV RNA positive © 2014 John Wiley & Sons Ltd
3
12 weeks after diagnosis developed chronic hepatitis C. Further support comes again from the SMACC cohort in which a rapid decline in HCV RNA (>2 log within 100 days of infection) in 112 HIV-infected patients was also identified as a predictor for spontaneous clearance along with high CD4 T cell count, elevated bilirubin and ALT levels [22]. In the light of the given data, experts such as the European AIDS Treatment Network (NEAT) acute HCV consensus panel recommend that treatment should be offered to all HIV patients who do not spontaneously show a drop in HCV RNA of more than 2 log at week 4 or who are still HCV RNA positive at week 12 after diagnosis (see Fig. 1) [17].
HOW TO TREAT Current guidelines As data on efficacy and safety on DAA in the setting of AHC are still very sparse, the current gold standard of treatment according to the EACS and EASL guidelines still is a combination of pegylated interferons at standard doses (alpha-2b, 1.5 lg/kg/week and alpha-2a, 180 lg/week) and weight-based ribavirin (2log10
Treat
>2log10 Week 8
HCV-RNA
Rise
Treat
Further decay Week 12
HCV-RNA
Positive
Treat
Negative wait: further Wait: further controls controls throughout week 48
Fig. 1 Starting antiviral therapy according to the course of hepatitis C virus RNA in HIV coinfection.
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C. Boesecke & J. K. Rockstroh
optimal length of therapy in AHC coinfection comes from the European Collaborative Cohort Study [37]. In this observational cohort, patients who were able to achieve a viral load of less than 600 IU/mL at week 4 had a very high chance of reaching SVR. In contrast, patients who did not reach a viral load of less than 600 IU/mL at week 12 were most likely to fail therapy. An additional subanalysis showed that German patients who were treated for at least 20 weeks or longer following a first HCV RNA of less than 600 IU/mL had a 96% chance of cure (SVR), whereas only 20% of patients reached SVR if they were treated less than 20 weeks after a first HCV RNA of less than 600 IU/mL [37]. Although 48 weeks of therapy for acute HCV in HIV-infected patients appeared more efficacious than 24 weeks in another single study [38], other reports in AHC co-infection showed SVR of >70% with no statistically significant difference by length of therapy [29,39,40]. Recent data from the UK support an RVR-driven treatment duration [17,41,42]. The NEAT acute HCV consensus panel therefore recommends considering 24 weeks of therapy sufficient if the patients reach RVR; in patients who do not reach RVR, 48 weeks of therapy may be considered (Fig. 2) [17].
Current studies with DAA To date, there are five licensed DAAs in Europe: two-firstgeneration HCV protease inhibitors (PI; boceprevir, telaprevir), one-second-generation PI (simeprevir), one polymerase inhibitor (sofosbuvir) and one NS5A inhibitor (daclatasvir). In addition, at the end of this year, licensing of two-first fix-dose combinations (FDCs) is expected. The first FDC will be the combination of the NS5A inhibitor ledipasvir and sofosbuvir. The second FDC consists of the ritonavirboosted HCV protease inhibitor ABT-450 coformulated with the NS5A inhibitor ombitasvir. This FDC will in clinical practice be further combined with the polymerase inhibitor (dasabuvir) which is dosed bid. Further DAAs from all three drug classes can be expected to achieve approval in the next 2 years.
Fig. 2 Duration of dual pegIFN/RBV antiviral therapy according to the course of HCV RNA level decreases in HIV coinfection.
At the moment, this allows for three possible treatment strategies beyond pegIFN and RBV using DAA in AHC: 1). pegIFN/RBV + HCV PI Boceprevir Telaprevir 2). 1 DAA + RBV Sofosbuvir + RBV 3). 2 DAAs Sofosbuvir + Daclatasvir Sofosbuvir + Simeprevir Sofosbuvir + Ledipasvir Currently, there are published data only for the first scenario. 19 HIV-positive MSM from New York with AHC were treated with pegIFN + RBV and telaprevir [43]. Overall SVR24 rate was 84% (16/19) in contrast to 63% (30/48) in a comparator group (treated prior to the availability of, or ineligible for, telaprevir) of the same clinic. Retrospective comparison of the two different cohorts that were not matched by baseline characteristics and a notable difference in the distribution of the IL28B CC genotype somewhat limits the conclusion from this trial. Two additional studies with HCV PI containing triple therapy are currently ongoing (see table 1). On treatment, data of the Dutch DAHHS study examining boceprevir-containing HCV triple therapy in AHC have recently been presented. 12 weeks after triple therapy with pegIFN + RBV and boceprevir, a promising 94% (14/15) of HIV-infected patients became HCV RNA undetectable [44]. The CHAT study is the first randomized, controlled study to assess telaprevir containing triple therapy vs standard of care pegIFN + RBV in the setting of AHC genotype (GT) 1 coinfection similar to the DARE-C I study [45]. A special focus in both studies relies on the frequency and severity of toxicities with a much shorter treatment duration now (12 weeks) than in the chronic phase and on HCV resistance. Two patients from the CHAT study have already failed under telaprevir containing triple therapy in the acute phase due to development of HCV PI resistance mutations. Recently, the first report of a transmitted HCV PI resistance between two Spanish HIV-infected MSM has also been published [46]. Thus, one main concern remains, as in all three pilot trials patients can be identified with well-documented virological failure suggesting that not everyone will respond to triple therapy with a first-line HCV PI. In addition, the obvious toxicity of these complex regimens will limit their uptake and ultimately widespread use. Therefore, studies with IFN-free DAA combinations remain of great urgency to further evaluate the role of DAAs in the treatment of acute HCV. Indeed, various studies are underway to further assess IFN-free DAA combinations in AHC mono- and coinfection (see Table 1). Scenario 2 will be addressed by two additional studies currently running in the U.S. and Australia (DARE-C II © 2014 John Wiley & Sons Ltd
Management of acute HCV in MSM in the era DAA
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Table 1 Current and future studies with DAAs in acute HCV Study name
Coordinator
DAAs
HCV genotype
Duration (weeks)
HIV status
DAHHS CHAT DARE-C I DARE-C II SWIFT-C SOL Hep-Net acute HCV
Erasmus MC UKB Kirby Institute Kirby Institute ACTG UKB MHH
BOC + pegIFN + RBV TPV + pegIFN + RBV TPV + pegIFN + RBV SOF + RBV SOF + RBV SOF + LDV SOF + LDV
1 1 1 all all 1, 4 1
12 12 8–24 6 8 vs 12 6 6
pos pos neg + pos neg + pos pos pos neg
and SWIFT-C). These are the first studies to also include HCV genotypes other than 1. And lastly, two studies currently being planned in Germany will investigate a fixed-dose combination of two DAAs in AHC. The SOL study will examine sofosbuvir and ledipasvir in HIV-coinfected patients with acute HCV genotypes 1 and 4 infection over 6 weeks [45]. The Hep-Net Acute HCV trial will also use a fixed-dose combination of sofosbuvir and ledipasvir over 6 weeks, but only in HIVnegative patients and only in AHC genotype 1 infection. Studies examining the combination of sofosbuvir with either daclatasvir or simeprevir are currently neither planned nor underway.
WHOM TO TREAT NOW IN 2014 The most prominent clinical question at the moment of course is how to manage a patient who experiences an acute hepatitis C just now in this exciting but indecisive transitional phase where the guidelines still recommend a quite successful but rather toxic treatment regimen, and the more efficacious and well-tolerated DAAs have not been properly investigated or recommended for use in this setting, yet, and even more importantly will not be reimbursed by health insurances as there is no approved indication for use of DAAs in AHC, yet. In our opinion, a decision in this situation can only be made on an individual basis in an open discussion between patient and physician. The data from EuroSIDA as well as reports from EASL 2014 tell us that the incidence of AHC and re-infections particularly among HIV-infected MSM are still high [2,47,48]. If the patient is particularly worried about infecting someone else (having gotten used to the concept of hardly being infectious anymore under ART), then treatment with pegIFN + RBV should be discussed highlighting potential side effects and long treatment duration. If side effects occur, treatment should be discontinued as there will be several efficacious and safe treatment options in the next 12–24 months. If the patient is interferon-ineligible or afraid of potential side effects, treatment can be deferred until the chronic phase. If treatment with DAAs over 12 weeks is then initi© 2014 John Wiley & Sons Ltd
ated early at the chronic stage, patients might reach an SVR even earlier than patients with response-guided pegIFN/RBV treatment of at least 24- up to 48-week duration. In addition, recent data from the European AHC Cohort should bring relief to patients and clinicians about the risk of liver fibrosis/cirrhosis after AHC as the investigators found no evidence for faster fibrosis progression rate assessed mainly by transelastography in 41 patients over a median follow-up period of 45 months after diagnosis of AHC [49]. In developed countries with full access to any of the upcoming DAA and not yet restricted financial health resources, it is unlikely that the HCV PIs will play a major role in AHC treatment. The role of a combination of just one DAA plus RBV cannot be defined at this moment in the absence of data from clinical trials. The most likely scenario would be that the gold standard of pegIFN + RBV will be followed by a ‘platinum’ standard consisting of 2 (or 3) DAAs (potentially as fixed-dose combination) given a successful performance in first pilot trials. Most importantly, with the new DAAs, we will have powerful tools to really shape the course of the ongoing AHC epidemic. Data from larger AHC cohorts such as the European PROBE-C study have shown us that treatment uptake in the acute phase is just around 58% (279/478) reflecting concerns about IFN-related toxicities by both patients and physicians [45]. The far less toxic DAA combination regimen with their short treatment duration would allow us to treat almost everyone and thus curtail further viral dissemination particularly in high-risk populations such as MSM and IVDU. In the past, successful HCV treatment in confined settings such as prisons has been shown to have a significant impact on new infections in a high-risk population [50,51]. In addition, modelling data from chronic HCV infection showed a substantial impact on HCV-related morbidity and mortality if screening and treatment uptake with efficacious drugs were increased [52]. Analogously, one should expect to see a similar thwarting effect on AHC incidence if a DAA-containing treatment regimen as prevention strategy is combined with intensified screening efforts.
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doi:10.1111/jvh.12348
COMMISSIONED REVIEW
How will we manage acute HCV in men having sex with men in the era of all oral therapy? C. Boesecke and J. K. Rockstroh
Department of Internal Medicine I, Bonn University Hospital, Bonn, Germany
Received August 2014; accepted for publication September 2014
SUMMARY. With the advent of direct-acting antivirals
(DAAs), the treatment of chronic hepatitis C virus (HCV) infection (CHC) has been revolutionized. Modern interferon- and potentially also ribavirin-free combinations consisting of 2 or 3 direct-acting antivirals (DAA) promise sustained virological response rates (SVR) of above 90%. This coincides with much shorter treatment durations and a much more favorable toxicity profile. Some DAAs even work across all HCV genotypes (pangenotypic) [BMJ, 349, 2014, g3308]. And lastly, HCV treatment in HIV-coinfected
INTRODUCTION With the advent of direct-acting antivirals (DAAs), the treatment of chronic hepatitis C virus (HCV) infection (CHC) has been revolutionized. Modern interferon- and potentially also ribavirin-free combinations consisting of 2 or 3 direct-acting antivirals (DAA) promise sustained virological response rates (SVR) of above 90%. This coincides with much shorter treatment durations and a much more favourable toxicity profile. Some DAA even work across all HCV genotypes (pangenotypic) [1]. And lastly, HCV treatment in HIV-coinfected patients will no longer differ from HCV-monoinfected patients as response rates under DAA in the setting of HCV/HIV coinfection have been as good as in HCV-monoinfected patients [2]. Only drug–drug interactions with the new DAAs and concomitant antiretroviral therapy have to be accounted for due to shared metabolizing pathways via the cytochrome p450 system. But what about acute hepatitis C (AHC)? Are we there, yet? Should we be using DAAs in AHC similar to how we have started to use them at the chronic stage? This review will discuss diagnosis of AHC, how, when and whom to treat according to the current treatment recAbbreviations: AHC, acute hepatitis C; ALT, alanine aminotransferases; DAA, direct-acting antiviral; FDC, fix-dose combination; HCV, hepatitis C virus; SVR, sustained virological response rates. Correspondence: J€ urgen Kurt Rockstroh, Department of Medicine I, Bonn University Hospital, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. E-mail: [email protected]
patients will no longer differ from HCV-monoinfected patients as response rates under DAA in the setting of HCV–HIV coinfection have been as good as in HCVmonoinfected patients [J Hepatol, 61, 2014, 373]. Only drug–drug interactions with the new DAAs and concomitant antiretroviral therapy have to be accounted for due to shared metabolization pathways via the cytochrome p450 system. Keywords: Acute hepatitis C, HIV, MSM, DAA.
ommendations as well as outline current and anticipated evidence for the use of DAA in AHC with a focus on (HIV positive) men who have sex with men (MSM) among whom the vast majority of acute HCV infections worldwide have been reported over the last decade [3–11]. Finally, we will also address the public health aspects of a DAAbased IFN-free acute HCV treatment strategy in this highrisk population and its potential to shape the course of the ongoing epidemic.
HOW TO TEST Acute hepatitis C is defined as the first 6-month period after infection with HCV. As the exact time point of infection in clinical practice is often difficult to determine, it is frequently challenging to distinguish between a true acute hepatitis C and early chronic infection [2,12]. Seroconversion from anti-HCV negativity to anti-HCV positivity reflecting the development of antibodies can be regarded as a definite diagnosis. However, as observable seroconversion is uncommon in clinical care, HCV RNA testing via PCR has to be performed if AHC is suspected and anti-HCV antibodies are still negative. In addition, elevated aminotransferases can be a helpful indicator of an acute hepatitis C although definitions vary from study to study. In contrast to HIV-positive MSM who are seen every 3–6 months for routine control of HIV infection, HIV-negative MSM may consult with their general practitioner on a less-frequent basis. Thus, acute liver transaminase elevations may be missed in the HIVnegative population and only symptomatic patients will be © 2014 John Wiley & Sons Ltd
Management of acute HCV in MSM in the era DAA likely to be diagnosed. More disturbingly, recent data from the UK have shown that of all 3811 HIV-negative MSM attending a London clinic for sexual health screening, only 565 (14.82%) were tested for HCV although there are data also from the UK describing a cohort of 36 HIV-negative MSM with AHC [13,14]. In addition, timely diagnosis is problematic because the majority of individuals with acute HCV infection are asymptomatic. Only around one-third to a half of individuals with acute HCV infection show signs of an acute illness such as lethargy and myalgia, and less frequently jaundice [3,8]. In the German Hep-Net AHC cohort, disease severity was not associated with HCV genotype, viral load, age, sex and BMI [15]. HIV-positive patients are less likely to experience a clinically apparent AHC infection [3,8]. On top, anti-HCV seroconversion may be significantly delayed in HIV-positive patients, with 5% of cases still anti-HCV negative despite ongoing viral replication for 1 year [16]. However, at least annual anti-HCV antibody and 6-month ALT measurements followed by HCV RNA testing in cases of suspected AHC seem to be a reasonable approach for AHC screening in HIV-positive individuals [17]. This recommendation derives from findings from the British St Mary’s Acute Hepatitis C Cohort (SMACC) where 88% of patients experienced elevated alanine aminotransferases (ALT) within three months of infection with peak ALT levels > 5 times the upper limit of normal in 55% [16]. In the absence of consensus recommendations, screening for clinically asymptomatic AHC in other at-risk populations such as HIV-negative MSM should consist of at least annual anti-HCV antibody testing [18].
WHEN TO TREAT Spontaneous HCV clearance happens in up to 15% in HIVcoinfected individuals with around 85% of patients subsequently progressing to chronic hepatitis C [16,19–23]. For both classic treatment with pegIFN + RBV and any new DAA-containing regimen, determination of the point in time until which spontaneous clearance can be expected will be of high interest as this would allow postponement of treatment initiation and prevent unnecessary toxicities (pegIFN + RBV) or substantial costs (DAA). In AHC/HIV coinfection several cohort, data have provided useful answers to the question whether it is possible to predict progression to chronicity of AHC infection by looking at the course of HCV RNA after diagnosis. In a European cohort of 92 HIV-positive patients with acute HCV who did not receive HCV-specific antiviral therapy, the sensitivity and specificity of HCV RNA determination 4 and 12 weeks after diagnosis to predict the outcome of acute HCV was similarly strong [24,25]. Nine of 10 patients showing spontaneous regression of HCV RNA of at least 2 log 4 weeks after diagnosis subsequently cleared HCV. In contrast, 92% of patients who were HCV RNA positive © 2014 John Wiley & Sons Ltd
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12 weeks after diagnosis developed chronic hepatitis C. Further support comes again from the SMACC cohort in which a rapid decline in HCV RNA (>2 log within 100 days of infection) in 112 HIV-infected patients was also identified as a predictor for spontaneous clearance along with high CD4 T cell count, elevated bilirubin and ALT levels [22]. In the light of the given data, experts such as the European AIDS Treatment Network (NEAT) acute HCV consensus panel recommend that treatment should be offered to all HIV patients who do not spontaneously show a drop in HCV RNA of more than 2 log at week 4 or who are still HCV RNA positive at week 12 after diagnosis (see Fig. 1) [17].
HOW TO TREAT Current guidelines As data on efficacy and safety on DAA in the setting of AHC are still very sparse, the current gold standard of treatment according to the EACS and EASL guidelines still is a combination of pegylated interferons at standard doses (alpha-2b, 1.5 lg/kg/week and alpha-2a, 180 lg/week) and weight-based ribavirin (2log10
Treat
>2log10 Week 8
HCV-RNA
Rise
Treat
Further decay Week 12
HCV-RNA
Positive
Treat
Negative wait: further Wait: further controls controls throughout week 48
Fig. 1 Starting antiviral therapy according to the course of hepatitis C virus RNA in HIV coinfection.
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optimal length of therapy in AHC coinfection comes from the European Collaborative Cohort Study [37]. In this observational cohort, patients who were able to achieve a viral load of less than 600 IU/mL at week 4 had a very high chance of reaching SVR. In contrast, patients who did not reach a viral load of less than 600 IU/mL at week 12 were most likely to fail therapy. An additional subanalysis showed that German patients who were treated for at least 20 weeks or longer following a first HCV RNA of less than 600 IU/mL had a 96% chance of cure (SVR), whereas only 20% of patients reached SVR if they were treated less than 20 weeks after a first HCV RNA of less than 600 IU/mL [37]. Although 48 weeks of therapy for acute HCV in HIV-infected patients appeared more efficacious than 24 weeks in another single study [38], other reports in AHC co-infection showed SVR of >70% with no statistically significant difference by length of therapy [29,39,40]. Recent data from the UK support an RVR-driven treatment duration [17,41,42]. The NEAT acute HCV consensus panel therefore recommends considering 24 weeks of therapy sufficient if the patients reach RVR; in patients who do not reach RVR, 48 weeks of therapy may be considered (Fig. 2) [17].
Current studies with DAA To date, there are five licensed DAAs in Europe: two-firstgeneration HCV protease inhibitors (PI; boceprevir, telaprevir), one-second-generation PI (simeprevir), one polymerase inhibitor (sofosbuvir) and one NS5A inhibitor (daclatasvir). In addition, at the end of this year, licensing of two-first fix-dose combinations (FDCs) is expected. The first FDC will be the combination of the NS5A inhibitor ledipasvir and sofosbuvir. The second FDC consists of the ritonavirboosted HCV protease inhibitor ABT-450 coformulated with the NS5A inhibitor ombitasvir. This FDC will in clinical practice be further combined with the polymerase inhibitor (dasabuvir) which is dosed bid. Further DAAs from all three drug classes can be expected to achieve approval in the next 2 years.
Fig. 2 Duration of dual pegIFN/RBV antiviral therapy according to the course of HCV RNA level decreases in HIV coinfection.
At the moment, this allows for three possible treatment strategies beyond pegIFN and RBV using DAA in AHC: 1). pegIFN/RBV + HCV PI Boceprevir Telaprevir 2). 1 DAA + RBV Sofosbuvir + RBV 3). 2 DAAs Sofosbuvir + Daclatasvir Sofosbuvir + Simeprevir Sofosbuvir + Ledipasvir Currently, there are published data only for the first scenario. 19 HIV-positive MSM from New York with AHC were treated with pegIFN + RBV and telaprevir [43]. Overall SVR24 rate was 84% (16/19) in contrast to 63% (30/48) in a comparator group (treated prior to the availability of, or ineligible for, telaprevir) of the same clinic. Retrospective comparison of the two different cohorts that were not matched by baseline characteristics and a notable difference in the distribution of the IL28B CC genotype somewhat limits the conclusion from this trial. Two additional studies with HCV PI containing triple therapy are currently ongoing (see table 1). On treatment, data of the Dutch DAHHS study examining boceprevir-containing HCV triple therapy in AHC have recently been presented. 12 weeks after triple therapy with pegIFN + RBV and boceprevir, a promising 94% (14/15) of HIV-infected patients became HCV RNA undetectable [44]. The CHAT study is the first randomized, controlled study to assess telaprevir containing triple therapy vs standard of care pegIFN + RBV in the setting of AHC genotype (GT) 1 coinfection similar to the DARE-C I study [45]. A special focus in both studies relies on the frequency and severity of toxicities with a much shorter treatment duration now (12 weeks) than in the chronic phase and on HCV resistance. Two patients from the CHAT study have already failed under telaprevir containing triple therapy in the acute phase due to development of HCV PI resistance mutations. Recently, the first report of a transmitted HCV PI resistance between two Spanish HIV-infected MSM has also been published [46]. Thus, one main concern remains, as in all three pilot trials patients can be identified with well-documented virological failure suggesting that not everyone will respond to triple therapy with a first-line HCV PI. In addition, the obvious toxicity of these complex regimens will limit their uptake and ultimately widespread use. Therefore, studies with IFN-free DAA combinations remain of great urgency to further evaluate the role of DAAs in the treatment of acute HCV. Indeed, various studies are underway to further assess IFN-free DAA combinations in AHC mono- and coinfection (see Table 1). Scenario 2 will be addressed by two additional studies currently running in the U.S. and Australia (DARE-C II © 2014 John Wiley & Sons Ltd
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Table 1 Current and future studies with DAAs in acute HCV Study name
Coordinator
DAAs
HCV genotype
Duration (weeks)
HIV status
DAHHS CHAT DARE-C I DARE-C II SWIFT-C SOL Hep-Net acute HCV
Erasmus MC UKB Kirby Institute Kirby Institute ACTG UKB MHH
BOC + pegIFN + RBV TPV + pegIFN + RBV TPV + pegIFN + RBV SOF + RBV SOF + RBV SOF + LDV SOF + LDV
1 1 1 all all 1, 4 1
12 12 8–24 6 8 vs 12 6 6
pos pos neg + pos neg + pos pos pos neg
and SWIFT-C). These are the first studies to also include HCV genotypes other than 1. And lastly, two studies currently being planned in Germany will investigate a fixed-dose combination of two DAAs in AHC. The SOL study will examine sofosbuvir and ledipasvir in HIV-coinfected patients with acute HCV genotypes 1 and 4 infection over 6 weeks [45]. The Hep-Net Acute HCV trial will also use a fixed-dose combination of sofosbuvir and ledipasvir over 6 weeks, but only in HIVnegative patients and only in AHC genotype 1 infection. Studies examining the combination of sofosbuvir with either daclatasvir or simeprevir are currently neither planned nor underway.
WHOM TO TREAT NOW IN 2014 The most prominent clinical question at the moment of course is how to manage a patient who experiences an acute hepatitis C just now in this exciting but indecisive transitional phase where the guidelines still recommend a quite successful but rather toxic treatment regimen, and the more efficacious and well-tolerated DAAs have not been properly investigated or recommended for use in this setting, yet, and even more importantly will not be reimbursed by health insurances as there is no approved indication for use of DAAs in AHC, yet. In our opinion, a decision in this situation can only be made on an individual basis in an open discussion between patient and physician. The data from EuroSIDA as well as reports from EASL 2014 tell us that the incidence of AHC and re-infections particularly among HIV-infected MSM are still high [2,47,48]. If the patient is particularly worried about infecting someone else (having gotten used to the concept of hardly being infectious anymore under ART), then treatment with pegIFN + RBV should be discussed highlighting potential side effects and long treatment duration. If side effects occur, treatment should be discontinued as there will be several efficacious and safe treatment options in the next 12–24 months. If the patient is interferon-ineligible or afraid of potential side effects, treatment can be deferred until the chronic phase. If treatment with DAAs over 12 weeks is then initi© 2014 John Wiley & Sons Ltd
ated early at the chronic stage, patients might reach an SVR even earlier than patients with response-guided pegIFN/RBV treatment of at least 24- up to 48-week duration. In addition, recent data from the European AHC Cohort should bring relief to patients and clinicians about the risk of liver fibrosis/cirrhosis after AHC as the investigators found no evidence for faster fibrosis progression rate assessed mainly by transelastography in 41 patients over a median follow-up period of 45 months after diagnosis of AHC [49]. In developed countries with full access to any of the upcoming DAA and not yet restricted financial health resources, it is unlikely that the HCV PIs will play a major role in AHC treatment. The role of a combination of just one DAA plus RBV cannot be defined at this moment in the absence of data from clinical trials. The most likely scenario would be that the gold standard of pegIFN + RBV will be followed by a ‘platinum’ standard consisting of 2 (or 3) DAAs (potentially as fixed-dose combination) given a successful performance in first pilot trials. Most importantly, with the new DAAs, we will have powerful tools to really shape the course of the ongoing AHC epidemic. Data from larger AHC cohorts such as the European PROBE-C study have shown us that treatment uptake in the acute phase is just around 58% (279/478) reflecting concerns about IFN-related toxicities by both patients and physicians [45]. The far less toxic DAA combination regimen with their short treatment duration would allow us to treat almost everyone and thus curtail further viral dissemination particularly in high-risk populations such as MSM and IVDU. In the past, successful HCV treatment in confined settings such as prisons has been shown to have a significant impact on new infections in a high-risk population [50,51]. In addition, modelling data from chronic HCV infection showed a substantial impact on HCV-related morbidity and mortality if screening and treatment uptake with efficacious drugs were increased [52]. Analogously, one should expect to see a similar thwarting effect on AHC incidence if a DAA-containing treatment regimen as prevention strategy is combined with intensified screening efforts.
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