M. H. Miller, K. Agarwal, A. Austin, A. Brown, S. T. Barclay, P. Dundas, G. M. Dusheiko, G. R. Foster, R. Fox, P. C. Hayes, C. Leen, C. Millson, S. D. Ryder, J. Tait, A. Ustianowski, J. F. Dillon
Aliment Pharmacol Ther. 2014;39(12):1363-1375.
Abstract and Introduction
Background Therapeutic options for the management of hepatitis C virus (HCV) infection have evolved rapidly over the past two decades, with a consequent improvement in cure rates. Novel therapeutic agents are an area of great interest in the research community, with a number of these agents showing promise in the clinical setting.
Aims To assess and present the available evidence for the use of novel therapeutic agents for the treatment of HCV, updating previous guidelines.
Methods All Phase 2 and 3 studies, as well as abstract presentations from international Hepatology meetings were identified and reviewed for suitable inclusion, based on studies of new therapies in HCV. Treatment-naïve and experienced individuals, as well as cirrhotic and co-infected individuals were included.
Results Sofosbuvir, simeprevir and faldaprevir, along with pegylated interferon and ribavirin, have a role in the treatment of chronic HCV infection. The precise regimens are largely dependent on the patient characteristics, patient and physician preferences, and cost implication.
Conclusions Therapies for chronic HCV have evolved dramatically in recent years. Interferon-free regimens are now possible without compromise in the rate of sustained viral response. The decision as to which regimen is most appropriate is multifactorial, and based on efficacy, safety and cost.
The field of anti-HCV therapy is going through a period of rapid evolution, as numerous highly effective, but expensive, direct-acting anti-viral (DAA) drugs active against different targets become available. This welcome development requires a consensus guideline for treating physicians and health care providers. These expert guidelines are sponsored by the Scottish government and take representative opinion from the British Society of Gastroenterology Liver Committee, British Association for the Study of Liver, the Scottish Society of Gastroenterology, the Scottish Viral Hepatitis group, the Scottish Viral Hepatitis Nurses group and the British Viral Hepatitis group.
The aim of the guideline was to provide treating clinicians and health care providers with an expert opinion of the current best standard of care with available agents. It is anticipated that this advice will rapidly become outdated, but is based on the agents likely to be available in 2014 in the UK and these guidelines will be updated regularly as new agents become available. Over time, the simplest and most effective combinations of agents will become clearer. However any uncertainty over the best therapy or the possibility of better ones in the future is not a reason to defer patients from treatment. It is apparent from modelling and projection work together with empirical observation that we have cured far too few patients of their HCV infection to have an impact on the looming burden of chronic liver disease. Nonetheless annual budgets could limit the numbers of patients that can be treated per year and we may need to stratify patients for immediate treatment. The aim of these guidelines was to help clinicians identify those patients who can be treated efficaciously now and with which therapeutic agents.
We have not considered how much cost differential (i.e. in terms of numbers of patients treated within in a fixed budget) would justify using a cheaper regimen of similar efficacy containing interferon compared to an interferon-free regimen. A significant difference in cost per cure may cause some providers to favour regimens we have regarded as less tolerable for patients. It is hoped that these new efficacious drugs will allow sufficient number of patients to be treated to achieve the desired impact on HCV infection at a population level.
The working group responsible for the preparation of these guidelines consists of members and representatives of leading hepatology and infectious disease societies, selected as experts in the field.
The guidelines are intended to be used to guide clinicians in choice of therapy, once the patient and clinician have decided to proceed to treatment, this decision will of course be guided by the likelihood of cure for an individual patient. These guidelines are based on an expert review of the literature, of phase 2 and 3 studies in HCV-infected patients published in full or abstract reports of large phase 2 or 3 clinical trials published at EASL or AASLD in 2013. They are also based on the assumption that the following drugs are available to be prescribed to HCV-infected patients; pegylated Interferon alpha 2a and 2b, ribavirin, telaprevir, boceprevir, simeprevir, faldaprevir and sofosbuvir. It has been further assumed that these drugs have been deemed cost effective for NHS use by SMC and NICE.
The evidence to formulate recommendations was ranked against a series of criteria. The first and dominant criterion of assessment of a drug regimen was the SVR rate. If SVR rates were equivalent (within the limitations of the evidence), then those regimens that are interferon sparing or interferon free and or reduce other side effects were considered superior. At the time of writing, the costs and pricing structures were not available. However, we have assumed that if the drugs obtained NICE and SMC approval, they are considered cost effective.
Second-generation Direct-acting Anti-viral Therapies. Sofosbuvir: Sofosbuvir (Sovaldi; Gilead Sciences, Foster City, CA, USA) is a HCV-specific uridine nucleotide NS5B polymerase inhibitor with potent pan-genotypic activity. It is a once daily preparation, usually taken at a dose of 400 mg. It is licensed for use in combination with other HCV therapeutic agents, including ribavirin and interferon. There is no associated food effect and CYP3A/4 metabolism of the drug. Sofosbuvir is associated with a well-tolerated safety profile. The most commonly reported adverse events associated with sofosbuvir are headache, anaemia, fatigue and nausea but the rates are little more than placebo. Co-prescription with St John's Wort or rifampicin (potent P-gp inducers) should be avoided as they significantly decrease the plasma concentration of sofosbuvir. Sofosbuvir is predominantly renal eliminated thus use should be cautioned in severe renal impairment.
Simeprevir: Simeprevir (Olysio; Janssen Pharmaceuticals, Beerse, Belgium) is a HCV NS3/4A protease inhibitor with efficacy in genotype 1, 4, 5 and 6. It is a once daily preparation. Simeprevir is well tolerated with a favourable safety profile. The most frequently reported adverse events in patients treated with simeprevir are fatigue, influenza like symptoms, pruritus, headache and nausea, but at rates not dissimilar to placebo. CYP3A4 inducers may significantly decrease plasma concentrations of simeprevir. Polymorphisms for Q80K alter the efficacy of simeprevir. Presence of Q80K mutation significantly reduces the efficacy of simeprevir.
Faldaprevir: Faldaprevir (Boehringer-Ingelheim, Ingelheim am Rhein, Germany) is an HCV NS3/4A protease inhibitor with efficacy in genotype 1, 4, 5 and 6; it is a once daily preparation. The most common adverse events associated with faldaprevir are mild gastrointestinal upset, rash, pruritus and jaundice, but at rates not dissimilar to placebo.
All three drugs are well tolerated with safety profiles more favourable than interferon ribavirin and first-generation protease inhibitor-based regimens.
First-generation Direct-acting Anti-viral Therapies. The use and efficacy of the first-generation protease inhibitors were discussed in detail in the 2012 guidelines produced by this group.
Telaprevir: Telaprevir (Incivek, Incivo; Vertex Pharmaceuticals, Boston, MA, USA and Johnson & Johnson, New Brunswick, NJ, USA) is a first-generation protease inhibitor (NS3/4A). It is currently licensed in the treatment of genotype 1-infected individuals and when used in combination with pegylated interferon and ribavirin has an improved SVR rate. The most common adverse events associated with telaprevir are rash and anaemia which can be significant leading to discontinuation of treatment. Anorectal discomfort is also more frequent. CYP3A4 inducers may significantly decrease plasma concentrations of telaprevir.
Boceprevir: Boceprevir (Victrelis; Merck, NJ, USA) is a serine protease inhibitor which binds reversibly to the NS3 active site. It is licensed in the treatment of genotype 1 HCV-infected individuals, in combination with pegylated interferon and ribavirin. Anaemia is the most common and in some treatment limiting adverse event, although dysgeusia is also reported. CYP3A4 inducers may significantly decrease plasma concentrations of boceprevir.
Interferon. Interferon has been the cornerstone of HCV therapy for almost two decades. Its evolution throughout that time is well documented. The current preparations of pegylated interferon α2a or 2b (Pegasys, PegIntron) are administered as weekly sub-cutaneous injections. The adverse event profile associated with interferon is significant and in many instances results in treatment discontinuation.
Ribavirin. Ribavirin (Copegus, Rebetol, Ribasphere, Vilona, and Virazole) is a nucleoside inhibitor which interferes with RNA metabolism necessary for viral replication. It is an oral preparation taken daily. The most common adverse event associated with interferon is anaemia which can result in a significant symptomatic drop in haemoglobin.
Recommendations. Table 1 is a summary of the recommendations contained within these guidelines.
Table 1. Summary of recommendations for use of direct-acting anti-viral therapies in HCV-infected individuals
Use of Interferon in Treatment Regimens
Evidence Statement. Pegylated interferon alpha 2a or 2b has been the backbone of anti-HCV therapy for two decades and clinicians have become adept at managing its many problems and complications to maximise its efficacy. However the side-effect profile of interferon has made treatment arduous for many patients, becoming a barrier to initiation or completion of therapy for many. In addition, the safety monitoring and support required for interferon therapy limit the situations and environments in which interferon-based anti-HCV therapy can be delivered. However it will remain an effective and relatively low cost anti-viral agent.
Recommendation: Care providers and clinicians when considering choice of treatment regimens that achieve similar rates of SVR, should take into account not only the cost effectiveness of a regimen but also the impact of treatment side effects associated with that regimen on the patient.
HCV Genotype 1a and 1b Naïve
Evidence Statement. Sofosbuvir-based Regimens: The efficacy of sofosbuvir in combination with pegylated interferon and ribavirin (PR) was assessed in a phase 2, randomised double-blind trial. One hundred and twenty two treatment-naïve noncirrhotic genotype 1 individuals were randomly assigned to receive either sofosbuvir 200 mg daily plus PR, sofosbuvir 400 mg daily plus PR or placebo plus PR for 12 weeks, followed by a further 12 weeks of PR alone. SVR24 was achieved in 58% of the placebo group, 85% of the sofosbuvir 200 mg group and 89% of the sofosbuvir 400 mg group. The ATOMIC study, a phase 2 open-label randomised trial sought to ascertain the optimum duration of therapy with sofosbuvir and PR for treatment-naïve genotype 1-infected individuals. The efficacy of 12 and 24 weeks of therapy was assessed, with SVR24 rates comparable at 89% – the cohorts consisted predominately of genotype 1a-infected individuals.
The subsequent phase 3 study, NEUTRINO, assessed the efficacy of sofosbuvir in combination with PR for treatment-naïve chronic HCV. Triple therapy with 180 μg pegylated interferon weekly, weight-based ribavirin and 400 mg once daily sofosbuvir was given for 12 weeks. The study included genotypes 1, 4, 5 and 6, with the majority of the cohort being genotype 1 patients (89%). Of the entire cohort, 17% was cirrhotic. SVR12 was achieved in 90% of the cohort. In sub-group analyses, genotype 1a (n = 225, 69% of entire cohort) achieved an SVR12 in 98% of individuals; genotype 1b (n = 66, 20% of entire cohort) achieved an SVR12 in 82% of individuals. It is not clear whether these differences in SVR between subtypes are clinically significant. Cirrhosis was associated with a slightly reduced SVR12 (80%) compared with the noncirrhotic individuals (92%). Furthermore, IL28b non-CC alleles were associated with a reduced SVR (87% for CT/TT compared with 98% for CC). In the NEUTRINO study, the genotype 1b subtypes achieved an SVR12 of 82% with 12-week therapy of PR plus sofosbuvir. This is an improvement when compared with the first-generation protease inhibitors, boceprevir (70% SVR in genotype 1b individuals treated with 48 weeks of PR and boceprevir) and telaprevir .
Simeprevir-based Regimens: The DRAGON study in Japan, assessed the efficacy of simeprevir in the treatment of naïve noncirrhotic genotype 1b-infected patients in a five arm study (N = 92). All four simeprevir containing arms consisted of PR plus either simeprevir 50 mg per day for 12 weeks plus PR for 24 weeks, or simeprevir 100 mg per day for 12 weeks or for 24 weeks. The control arm (PR for 48 weeks) achieved an SVR of 46%. The groups treated with simeprevir 50 mg for 12 weeks or 24 weeks, as well as the simeprevir 100 mg daily for 12 weeks achieved very similar SVR rates (78%, 77% and 77% respectively). The group treated with simeprevir 100 mg daily for 24 weeks achieved an SVR of 92%.
The PILLAR study, a phase 2b study designed to assess the efficacy and safety of simeprevir-based regimens used different doses of simeprevir compared with the DRAGON study, but the overall study design was similar. Patients were randomised to receive either simeprevir 75 mg for 12 or 24 weeks, or simeprevir 150 mg for 12 or 24 weeks. Only one cirrhotic individual was included in the study. Each arm consisted of approximately 46% genotype 1a-infected individuals (45.3–48.7%, although the control group consisted of 38.2% genotype 1a). The control group (48-week PR) achieved an SVR of 64.9%. Each of the four treatment arms had significantly higher SVR rates. Those treated with simeprevir 75 mg per day for 12 weeks (and PR for 24 weeks) achieved an SVR of 82.1%. The highest SVR achieved was in the simeprevir 150 mg per day plus PR for 24 weeks – 86.1%. Analysis by subtype of the PILLAR study revealed that those treated with simeprevir 75 mg, regardless of duration (12 weeks vs. 24 weeks) achieved an SVR rate of 88.9% for genotype 1b and 66.2% for genotype 1a. At a dose of 150 mg daily, the genotype 1b-infected individuals achieved an SVR of 83.8% while the genotype 1a-infected individuals achieved an SVR of 82.4%. The higher dose of 150 mg is likely to be the approved dose.
QUEST 1 is a Phase 3 randomised double-blind placebo controlled trial to assess the efficacy of simeprevir in combination with PR. Treatment-naïve genotype 1 patients were randomised to receive simeprevir 150 mg daily for 12 weeks with 24 weeks of PR, or placebo for 12 weeks with 24 weeks of PR. Eligibility criteria for response-guided therapy were applied, with the option to continue for a further 24 weeks of PR in those who failed to meet the criteria (placebo or simeprevir group). The groups consisted of equal numbers of genotype 1a infections (44%) and a similar number of cirrhotic individuals (12% in simeprevir group and 13% in placebo group). The overall SVR in the simeprevir group was 80% compared with 50% for the placebo group. The SVR rates were lower in those with cirrhosis (58% vs. 29%). Of the simeprevir-treated group, 85% were eligible for response-guided therapy, of which 91 subsequently achieved an SVR12. Sub-analysis by HCV sub-genotype showed an SVR of 71% for genotype 1a vs. 90% for genotype 1b.
QUEST 2 is a similar phase 3 trial of simeprevir 150 mg per day for 12 weeks with PR for 24 weeks, with the option of response-guided therapy and a further 24 weeks of PR an option if stopping rules not met. The study was performed in Europe. The treatment arm and placebo arms were well matched, with the exception that there was almost twice the number of cirrhotic individuals in the placebo arm (11.2% vs. 6.9%). The overall SVR for the simeprevir-treated arm was 81.3% compared with 50% in the placebo arm. Each cohort contained approximately 58% genotype 1b-infected individuals. Within the treatment arm, 91% of patients were eligible for response-guided therapy; the eventual SVR was 81.3%. Of note, those treated with pegylated interferon α2a had an improved SVR (88.3%) compared with those treated with pegylated interferon α2b (77.5%). Cirrhotic individuals in the simeprevir group achieved an SVR of 64.7%. Sub-analysis by HCV sub-genotype showed an SVR of 80.4% for genotype 1a and 82% for genotype 1b. A post hoc analysis of the combined results of QUEST1 and QUEST 2 showed an SVR of 75% for genotype 1a. The presence of a Q80K mutation detectable by population sequencing at baseline reduced the SVR rate from 84% to 58%.
In QUEST I, the overall SVR rate in the simeprevir arm was 80% (compared with 50% in the placebo arm). Subgroup analysis of the cohort by sub-genotype (1a vs. 1b) revealed a 90% SVR rate among those with genotype 1b, compared with genotype 1a (71%). In QUEST II, the effect of subtype was not as pronounced, with genotype 1b individuals achieving an SVR rate of 82% vs. 80.4% for genotype 1a. These differences could be due to the differing prevalence of Q80K resistance-associated variants in 1a patients in Europe.
Faldaprevir-based Regimens: The SILEN-C1 study evaluated the efficacy of faldaprevir in combination with PR for the treatment of naïve genotype 1-infected individuals. SILEN-C1 was a phase 2b, randomised double-blind placebo controlled multi-centre study which involved over 400 patients. Patients were randomised to four groups; group 1 received 24 weeks of PR and placebo followed by 24 weeks of PR, group 2 received faldaprevir (240 mg daily) and PR for 24 weeks followed by 24 weeks of PR, group 3 received the same regime as group 2, although had a 3-day lead-in of PR and group 4 received faldaprevir (120 mg daily) for 24 weeks followed by 24 weeks of PR, preceded by a 3-day lead-in with PR. Those receiving 240 mg of faldaprevir who met mRVR criteria (HCV viral load below the lower limit of quantification at week 4, and undetectable from week 8 to 20) were randomised to either continue PR for a further 24 weeks or stop all treatment at week 24. Those in group 1 achieved an SVR of 56%, while the overall SVR for groups 2–4 were 84%, 72% and 72% respectively. Patients in group 2 (240 mg faldaprevir with no lead-in) who met mRVR criteria and were then randomised to 24 weeks of therapy (i.e. stop all treatment at 24 weeks) achieved an SVR of 92% and a relapse rate of 5%. Those who carried on to week 48 of PR therapy also achieved an SVR rate of 92% with a similar relapse rate (2%). However, those patients in group 3 (240 mg faldaprevir daily with a 3-day lead-in of PR) who were then randomised to 24 weeks of therapy achieved an SVR of 81% (compared with 96% if continued to 48 weeks of therapy) and a relapse rate of 17% (compared with 4% if treated to week 48). SVR rates for genotype 1a and genotype 1b were similar in the faldaprevir 240 mg daily, no lead-in group (82% genotype 1a and 84% genotype 1b).
The response-guided therapy aspect of the SILEN-C1 study favoured treating for 24 weeks with faldaprevir 240 mg daily and PR then stopping all treatment if mRVR criteria were met (described above). The faldaprevir approved dose may be 120 mg, although higher SVR rates were reported in SILEN-C1 study at a dose of 240 mg; breakdown analysis of STARTVerso1+2 suggests equivalent SVR rates for both 120 mg and 240 mg doses.
A pooled analysis of the StartVerso 1 and 2 trials which compared placebo + PR to faldaprevir 120 mg + PR to faldaprevir 240 mg plus PR for the treatment of naïve genotype 1 patients. ETS (early treatment success) was defined as HCV RNA <25 IU/mL at week 4 and undetectable at week 8 defined the response-guided therapy rule. SVR rates of 50%, 73% and 72% were achieved in the placebo, faldaprevir 120 mg and faldaprevir 240 mg arms respectively. Higher SVR rates were reported in Asian and European patients than North American patients. Higher breakthrough and relapse rates were reported in subtype 1a vs. 1b.
The three new agents in combination with PR therapy offer a significant improvement in SVR compared to the first-generation protease inhibitor-based triple therapies, with fewer side effects. First-generation protease inhibitors, based on efficacy data and side effects, are superseded by the second-generation preparations. There remains a potential role for first-generation protease inhibitors in certain special stratified populations that remain to be defined where they may be more cost effective. There are no head to head comparative trials of these three drugs and it is possible given the variance of previous clinical trials in this area that they are of similar efficacy. The pre-treatment screening of genotype 1a patients for the Q80K resistance mutation in those patients being considered for simeprevir may identify those who will have a lower chance of achieving SVR. Sofosbuvir, together with PR has the shortest duration of interferon therapy and is preferred on that basis.
Recommendation: HCV genotype 1a-naïve patients should be treated with 12 weeks of interferon alpha 2a or b, with ribavirin and sofosbuvir, alternatively they could be treated with 12 weeks of simeprevir and 24 weeks of pegylated interferon alpha 2a or 2b and ribavirin or faldaprevir 120 mg for 12 weeks and pegylated interferon alpha 2a and ribavirin for 24 weeks (or 48 weeks under response-guided rules).
Recommendation: HCV genotype 1b-naïve patients should be treated with either 12 weeks of interferon alpha 2a or b, with ribavirin and sofosbuvir, or treated with 12 weeks of simeprevir and 24 weeks of interferon alpha 2a or b and ribavirin or faldaprevir 120 mg for 12 weeks and pegylated interferon alpha 2a and ribavirin for 24 weeks (or 48 weeks under response-guided rules).
For these guidelines, we have assumed previous treatment was with a formulation of interferon and ribavirin. For HCV genotype 1 patients, we have not divided them by exposure to protease inhibitors, due to the limited evidence in this area currently.
HCV Genotype 1a or 1b Treatment Experienced
Evidence Statement. Simeprevir-based Regimens: The PROMISE trial is a Phase II trial reporting on the efficacy of simeprevir 150 mg daily for 12 weeks with PR for 24 weeks (with the option for response-guided therapy at week 24) for the treatment of genotype 1-infected individuals who have relapsed after previous treatment with an interferon-based regimen. The treatment arm contained 260 participants, 42.3% of whom were genotype 1a and 15.6% were cirrhotic. The overall SVR in the simeprevir arm was 79.2%, compared with 36.8% in the placebo arm. Of patients in the simeprevir arm, 92.7% were eligible for response-guided therapy, of which 83% achieved an SVR. SVR rates were higher among the genotype 1b compared with the genotype 1a (85.3% vs. 70.3%). Cirrhotic individuals treated with simeprevir achieved an SVR rate of 74.4%.
In a phase 2b study, Zeuzem et al. reported on the efficacy of simeprevir in combination with PR in treatment-experienced genotype 1 a- and b-infected individuals. Patients were randomised to receive 12, 24 or 48 weeks of simeprevir 100 mg or 150 mg, with PR for 48 weeks. Prior null responders treated with 48 weeks of simeprevir at 150 mg daily plus PR for 48 weeks achieved an SVR of 58.8% (10/17), however this rose to 86.4% (19/22) and 88.5% (23/26) in prior partial responders and prior relapsers respectively.
The COSMOS trial assessed the efficacy of simeprevir plus sofosbuvir +/- ribavirin in prior null responders, genotype 1. Patients had a Metavir score of F0-2. Treatment was for either 12 or 24 weeks. Patients treated with combination simeprevir and sofosbuvir +/- ribavirin achieved an SVR12 of 96.3% and 92.9% respectively, whereas those treated for 24 weeks achieved an SVR12 of 79.2% and 93.3% respectively.
Faldaprevir-based Regimens: The SILEN-C2 study assessed the efficacy of faldaprevir in combination with PR for treatment of noncirrhotic genotype 1-infected individuals who had had a previous null response or a previous partial response. Three treatment arms were assessed, all lasting 48 weeks. Patients received either 3-day lead-in with PR then combined triple therapy with PR and faldaprevir 240 mg OD, or 3-day lead-in with PR then combined triple therapy with PR and faldaprevir 240 mg BD for 48 weeks, or PR and faldaprevir 240 mg OD for 48 weeks (no lead-in). SVR rates were higher among the previous partial responders (32%, 50% and 42% respectively), with slightly lower SVR rates seen in the previous null responders (21%, 35% and 29% respectively). The impact of sub-genotype (genotype 1a vs. genotype 1b) was not significant among the previous null responders, however the genotype 1b previous partial responders had greater SVR rates when compared with the genotype 1a-infected individuals (44–54% vs. 21–46%, depending on treatment group).
The STARTVerso 3 trial also assessed the efficacy of faldaprevir in combination with PR for treatment-experienced genotype 1 patients. A significant proportion of the 677 enrolled patients had F3 or F4 disease (40%), and 53% were genotype 1b. Treatment was for 48 weeks total, although faldaprevir was assessed over 12 and 24 weeks of therapy. At a dose of 240 mg, faldaprevir achieved SVR12 rates of 70% in prior relapsers, 58% in prior partial responders and 33% in prior null responders. Treatment with 12 weeks of faldaprevir was as efficacious as 24 weeks.
There is a paucity of data to support the use of sofosbuvir in treatment-experienced patients. However at a meeting of the Antiviral Drugs Advisory Committee of the FDA, an analysis was generated comparing the characteristics of patients who did not have an SVR on standard PR therapy and extracted similar patients from the Neutrino study (50 patients in total), compared their SVRs. On this basis, the FDA extrapolated the SVR for 12 weeks of sofosbuvir plus PR to be 79% and approved it for use in treatment-experienced patients.
Overall there is a paucity of data in the treatment-experienced group, the data for simeprevir are limited to relapse patients but probably superior to first-generation PIs in efficacy, duration of therapy and side effects. The faldaprevir data are similar to the first-generation PI's and associated with a prolonged interferon course for all patients (48 weeks) and the evidence for sofosbuvir is entirely based on extrapolation from the treatment-naïve data and historical control data.
Recommendation: HCV genotype 1a or 1b treatment-experienced patients should be treated with either simeprevir for 12 weeks plus 24 or 48 weeks (according to RGT rules) of interferon and ribavirin, especially if they relapsed on previous treatment or be treated with 12 weeks of interferon alpha 2 a or b, with ribavirin and sofosbuvir.
Patients With Cirrhosis or Severe Fibrosis
HCV Genotype 1a and 1b. Evidence statement: There is too little data to consider these two sub-genotypes separately. The NEUTRINO study enrolled 54 cirrhotic patients, in whom sofosbuvir with PR achieved an SVR of 80%. The QUEST studies (simeprevir-based regimens) described above reported results for both F3 and F4 stages of fibrosis with 60 of 82 (73%) F3 achieving SVR, but only 29/48 (60%) of F4 achieving SVR. The review group considered this a significant difference within the limitations of comparing trials and were also mindful of the increased rate of interferon-related side effects in patients with cirrhosis, preferring the interferon-sparing regimen. In subgroup analysis of the SPARE trial, 50% (3/6) of treatment-naïve genotype 1 cirrhotic/advanced fibrosis individuals achieved an SVR with 24 weeks of sofosbuvir and weight-based ribavirin therapy. Although based on a small cohort, this study provides a potential regime for situations where interferon is contraindicated.
Recommendation: HCV genotype 1a or b with cirrhosis or severe fibrosis should be treated with 12 weeks of interferon alpha 2a or b, with ribavirin and sofosbuvir.
HCV Genotype 2 Naïve. Evidence Statement: Genotype 2 HCV has been associated with greater rates of SVR than genotype 1/3 infections. In 2007, Yu et al demonstrated that 16 weeks of pegylated interferon and weight-based ribavirin was as efficacious as 24 weeks of the same treatment for genotype 2 infection, with SVR's of 94% and 95% respectively. Sub-group analysis of the patients in this cohort with advanced fibrosis or cirrhosis (F3, 4) revealed SVR rates of 91% for 16 weeks of therapy and 95% for 24 weeks of therapy.
The VALENCE trial, presented at AASLD 2013, is a pan-European Phase 3 trial assessing the efficacy of sofosbuvir and ribavirin for 12 weeks in genotype 2 and 24 weeks in genotype 3 infections. In treatment-naïve, noncirrhotic genotype 2-infected individuals, this regime was associated with an SVR12 of 97%, and in naïve cirrhotic individuals, the SVR12 was 100% (two patients). The FISSION study, designed as a non-inferiority trial of 12 weeks of sofosbuvir and ribavirin vs. 24 weeks of PR reported SVR rates of 97% in the sofosbuvir arm (n = 70) vs. 78% (n = 28) in the PR arm. Cirrhotic patients treated with sofosbuvir had an SVR rate of 48%, compared with 38% in the PR arm.
The combination of sofosbuvir and ribavirin for 12 weeks offers interferon-free therapy with a greater than 90% chance of achieving an SVR. In this group, however 16 weeks of interferon and ribavirin results in 90% SVR rates albeit with higher side effect rates due to the interferon, but may prove more cost effective.
Recommendation: HCV genotype 2-naïve patients should be treated with 12 weeks of ribavirin and sofosbuvir.
HCV Genotype 2 Treatment Experienced. Evidence statement: The POSITRON study, a phase 3 study involving patients with genotype 2 or 3 who had either failed an interferon-based regime or patients for whom interferon was not an option, assessed the efficacy of sofosbuvir and ribavirin for 12 weeks. Patients were considered in the 'interferon not an option' group if they had previously discontinued interferon due to unacceptable adverse effects, had a medical condition precluding the use of interferon or had decided against an interferon-based regime. Among the noncirrhotic genotype 2-infected individuals, the SVR12 was 92% (101/109); this rose slightly to 94% among the cirrhotic cohort (16/17).
The FUSION study (published concomitantly with POSITRON) evaluated the efficacy of sofosbuvir and ribavirin (for 12 and 16 weeks) in patients who had previously failed an interferon-based regimen. Genotype 2 patients receiving 12 weeks of therapy achieved an overall SVR12 of 86% (96% in the noncirrhotic group and 60% in the cirrhotic arm) and those receiving 16 weeks of therapy had an overall SVR12 of 94% (100% in the noncirrhotic arm and 78% in the cirrhotic arm).
Recommendation: HCV genotype 2 patients should be treated with 12 weeks of ribavirin and sofosbuvir.
HCV Genotype 2 Cirrhotic. Evidence statement: Yu et al  assessed the effect of treatment duration with PR in a genotype 2-infected population. Both 16 weeks and 24 weeks of therapy were assessed. The 16-week treatment arm contained 20 individuals with F3–4 fibrosis scores and the 24-week treatment arm contained 11 individuals with F3–4 fibrosis. Among the 24-week treatment arm, 19/20 (95%) achieved SVR, while in the 16-week treatment arm 10/11 (91%) achieved SVR.
The FISSION, POSITRON and VALENCE studies have all demonstrated SVRs in excess of 90% for treatment-naïve cirrhotic patients, with 12 weeks of sofosbuvir and ribavirin. For treatment-experienced patients with cirrhosis, the numbers who have been treated with the same regimen are much smaller and the results more variable with SVRs reported from 60–88%. The addition of interferon (12-week therapy with sofosbuvir and PR) has only so far been reported in a small number in an arm of the LONESTAR-2 study with an SVR of 93% but in only 14 patients.
Recommendation: HCV genotype 2 with cirrhosis or severe fibrosis could be treated with 12 weeks of ribavirin and sofosbuvir.
HCV Genotype 3 Naïve. Evidence Statement: Hadzlyannis et al  described similar SVR rates for PR for patients treated with either 24 weeks of therapy or with 48 weeks of therapy (84–87% and 81–83% respectively). However, these cohorts comprised both genotype 2- and genotype 3-infected individuals. Subsequently, 24 weeks of therapy with peg interferon α2b plus ribavirin in a treatment-naïve genotype 3 cohort achieved an SVR of 79%. The FISSION study compared 12 weeks of sofosbuvir and ribavirin to peg interferon α2a plus ribavirin in the treatment-naïve genotype 3-noncirrhotic cohort. This achieved an SVR of 61% (89/154) and 71%(99/139) respectively which was not statistically different.
The genotype 3 cohort of the POSITRON study, when treated with 12 weeks of sofosbuvir and ribavirin, achieved an SVR12 of 61% (among the group where interferon was not an option), but 21% of patients had cirrhosis. A small phase 2, nonrandomised open-label trial of sofosbuvir and PR for 12 weeks in genotype 3-naïve individuals (n = 25) reported an SVR24 of 92% (23/25), although of the two individuals without SVR, one moved out with the trial area and was lost to follow-up; the other was discounted as the assay was performed in a commercial laboratory which used a different cut-off value.
The VALENCE trial, a pan-European Phase III study, reports an SVR12 of 94% (86/92) for treatment-naïve genotype 3 individuals who received 24 weeks of sofosbuvir and ribavirin, and 92% (12/13) among the cirrhotic cohort.
There are no head to head trials of sofosbuvir and ribavirin for 24 weeks against PR for 24 weeks, but given the magnitude of the difference that is observed in the trials and the known variance, we consider that sofosbuvir and ribavirin regimens will be superior in terms of side effects and may offer increased efficacy compared to peg interferon plus ribavirin PR in patient groups, this preference could be heavily influenced by drug cost. The extrapolation of results obtained in treatment-experienced genotype 3 patients for 12 weeks of triple therapy based on sofosbuvir into naïve patients offers another efficacious and more cost-effective regimen, but again there are no head to head trials.
Recommendation: HCV genotype 3-naïve patients could be treated with either 12 weeks of pegylated interferon and ribavirin and sofosbuvir or could be treated with 24 weeks of pegylated interferon and ribavirin or 24 weeks of sofosbuvir and ribavirin.
HCV Genotype 3 Treatment Experienced. Evidence Statement: The POSITIRON and FUSION studies above reported on the efficacy of sofosbuvir and ribavirin in patients who were either unable to take interferon (POSITRON) or previously failed an interferon-based regimen (FUSION). In the POSITRON study, the overall SVR for 12 weeks of sofosbuvir and ribavirin was 61% in the genotype 3 cohort. In the FUSION study, 12 weeks of sofosbuvir and ribavirin was associated with an SVR12 of 30% whereas 16 weeks of sofosbuvir and ribavirin was associated with an SVR12 of 62%. Patients with genotype 3 infection who have previously failed an interferon-based regimen have limited treatment options. The VALENCE study with larger numbers of treatment-experienced patients (100) demonstrated an SVR of 87%, implying the superiority of 24 weeks of therapy with sofosbuvir and ribavirin. A small pilot study has shown PR plus sofosbuvir triple therapy achieved an SVR of 83% (20/24 patients). However, trials currently underway will address which of three regimens (sofosbuvir & ribavirin for 16 or 24 weeks or triple therapy with peg interferon for 12 weeks) is best for this group of patients, waiting for the outcome of this trial should be considered and discussed with the patient before initiating therapy.
Recommendation: HCV genotype 3 treatment-experienced patients could be offered 24 weeks of sofosbuvir and ribavirin or 12 weeks of pegylated interferon and ribavirin and sofosbuvir.
HCV Genotype 3 Cirrhotic. Evidence statement: The STEPs trial assessed the duration of PR therapy for individuals with genotype 3 and advanced fibrosis or cirrhosis. Patients were randomised to receive either 24 or 48 weeks of PR therapy. There was no benefit achieved with a longer duration of therapy, the group receiving 24 weeks of therapy achieved an SVR rate of 48% compared with 42% in those receiving 48 weeks. The use of sofosbuvir and ribavirin in HCV genotype 3 patients with cirrhosis has been addressed in FISSION, FUSION, POSITRON and VALENCE studies, these are not head to head studies but the differences are such that they show that 24 weeks (SVR 92%) is superior to 12 (SVR 34%) or 16 weeks (SVR 61%). The data for treatment-experienced patients with cirrhosis from the VALENCE and LONESTAR-2 studies suggest that there may be a benefit to adding interferon but numbers are too small and the variances of these separate studies are too large to allow any firm conclusions. An ongoing phase 3 trial (the BOSON study) is designed to address this.
Recommendation: Patients with cirrhosis or severe fibrosis HCV genotype 3 could be offered 24 weeks of sofosbuvir and ribavirin or 12 weeks with sofosbuvir and ribavirin and Interferon alpha, with similar efficacy.
HCV Genotype 4, 5 & 6 Naïve. Evidence Statement: Sofosbuvir-based Regimens. The NEUTRINO study evaluated the efficacy of 12 weeks of treatment with sofosbuvir and PR. A small number of the cohort were infected with genotype 4 (n = 28). This cohort achieved an SVR rate of 96% (27/28). The same study included one individual with genotype 5 and 6 individuals with genotype 6 infection; SVR rates achieved for both genotype 5 and 6 was 100%.
Simeprevir-based Regimens: Simeprevir has activity against HCV genotype 4 and an ongoing phase 3 trial in over 100 genotype 4 patients has promising interim results, with SVR4 rates of 90% in small numbers of limited sub-groups that have reached that time point.
There is very little evidence for treatment with DAAs in genotype 4, but that which exists is positive. Simeprevir and sofosbuvir are active against genotype 4. There is too little evidence to make recommendation for genotype 5 or 6 but in patients unable or unwilling to take 12 months of interferon and ribavirin, the use of sofosbuvir-based triple therapy could be considered, preferably with recording of outcome data in a treatment registry.
Recommendation: HCV genotype 4 patients could be treated with 12 weeks of interferon alpha 2a or 2b, with ribavirin and sofosbuvir. Alternatively, could be treated with simeprevir for 12 weeks plus 24 or 48 weeks (according to RGT rules) of interferon and ribavirin.
HCV Genotype 4, 5, 6 Treatment Experienced. Evidence statement: The interim analysis of the ongoing phase 3 trial of simeprevir in genotype 4 patients includes a high proportion that are treatment experienced, however they have not reached evaluable end-points yet. There is no evidence for the use of these new agents in treatment-experienced genotype 4, 5, 6 patients. Previously they have been considered similar to genotype 1 patients, so by extrapolation it could be assumed that sofosbuvir and PR for 12 weeks or simeprevir for 12 weeks with PR for 24–48 weeks would have some efficacy in this group and there is currently no other treatment option for these patients, so patients with a pressing need for another attempt at cure may benefit from either regimen.
Recommendation: On an individual basis, HCV genotype 4, 5 or 6 treatment-experienced patients could be treated with either 12 weeks of interferon alpha 2a or 2b, with ribavirin and sofosbuvir or simeprevir with 24–48 weeks of interferon alpha 2a or 2b, with ribavirin.
HCV Genotype 4, 5 & 6 Cirrhotic. Evidence statement: There is no observed evidence on which to base a recommendation for patients with HCV genotype 4, 5 or 6 who have cirrhosis, but there is a pressing need to treat such patients as they are at high risk of developing complications. Therefore, it is the view of the guideline group that data should be extrapolated from genotype 1 as has been done in the era of dual therapy.
Recommendation: On an individual basis, in experienced centres, HCV genotype 4, 5 or 6 with cirrhosis or severe fibrosis could be treated with 12 weeks of interferon alpha 2a or 2b, with ribavirin and sofosbuvir.
HCV Co-infected. Evidence statement: There is currently limited evidence in the literature for these new agents in HIV/HCV co-infected patients. However it has been observed with previous agents that those co-infected patients who have good control of their HIV disease have response rates to anti-HCV treatments similar to mono-infected patients. Caution must be exercised around possible drug–drug interactions as the evidence base around those for the new anti-HCV agents and standard HIV drugs is still in development.
Telaprevir and boceprevir have both been assessed. Promising SVR rates have been obtained, but drug interactions with anti-retroviral therapy needs assessment.[27,28] Telaprevir can be given for 12 weeks in combination with PEG-IFN and RBV for acute genotype 1 co-infection, a prevalent problem in men who have sex with men.[29,30] IFN-sparing as well as IFN-free regimens have been tested in HIV/HCV co-infected patients. Co-infected genotype 1, 2 and 3 treatment-naïve patients have been treated with sofosbuvir and ribavirin for 24 weeks (genotype 1) vs. 12 weeks (genotype 2 and 3). Sofosbuvir is cleared by renal elimination and drug interactions are less problematic therefore. SVR12 rates of 88% in patients with genotype 2 and 67% and 76% in the genotype 3 and genotype 1 patients respectively have been reported in the preliminary studies.
STARTVerso 4, a phase III trial assessing different doses and durations of faldaprevir for co-infected patients (HCV genotype 1) has shown promising interim results, with overall SVR4 of 74%. The final results from the trial are awaited.
Recommendation: Co-infected HIV/HCV patients with well controlled HIV disease can be considered for therapy according to mono-infected recommendations. Caution should be exercised around drug–drug interactions. Management of such patients should be undertaken by teams expert in both infections.
Patients With Decompensated Liver Disease or With Post-transplant Hepatitis C
The treatment of decompensated HCV-induced liver disease with anti-virals could be lifesaving and obviate the need for liver transplant. Telaprevir and boceprevir have been more effective in treating decompensated or pre-transplant HCV than PEG-IFN and RBV. Anaemia and sepsis, and drug–drug interactions can occur and discontinuation rates, adverse events and deaths are unfortunately high, mainly due to interferon-related side effects. The era of interferon-free therapy could be very beneficial for this patient group; however they have a very limited survival period and cannot wait for the outcome of trials and should be considered for early therapy as agents become available. Data from patients treated in this way should be collected within a national register to inform future therapy.
A report of the use of pre-transplant sofosbuvir and ribavirin for up to 48 weeks, stopping on day of transplant for patients transplanted for HCV and HCC resulted in a 64% post-transplant SVR rate. Similarly sofosbuvir and ribavirin have been used for the treatment of recurrent post-transplant hepatitis C (all genotypes). SVR rates of 77% after 24 weeks of treatment have been reported.[35-38]
Recommendation: Urgent Consideration for therapy should be given to patients in HCV-induced liver failure, in those ineligible or unable to access clinical trials the treatment outcome data should preferably be recorded in a national registry. Such patients should be managed in specialist centres experienced in both HCV treatment and the management of liver failure.
Patients pre- or post-transplant for HCV could be considered for therapy by expert centres.
The landscape of HCV therapy has moved into a new era with interferon-free regimens now a reality for some situations. Treatment options are evolving and the once difficult to treat genotype (genotype 1) has seen significant improvements in SVR rates achieved. This has led many to suggest genotype 3 is the new difficult to treat cohort. Treatment options for patient who have previously failed therapy are now more attractive, associated with impressive cure rates. The newly available drugs are associated with far fewer and less significant side effects than interferon-based regimens. It is now possible to deliver personalised HCV treatment regimens based on favourable treatment response characteristics, informing both physician and patient choice. The favourable side effect profiles of the new drugs improve patient compliance and reduce dropout rates. Cost effectiveness and affordability of these drugs remains a concern and may limit their impact on the burden of HCV-related chronic liver disease.
1. Koff RS. Review article: the efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Aliment Pharmacol Ther 2014; 39: 478–87.
2. Ramachandran P, Fraser A, Agarwal K, et al. UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients. Aliment Pharmacol Ther 2011; 35: 647–62.
3. Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013; 13: 401–8.
4. Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatmentnaive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. The Lancet 2013; 381: 2100–7.
5. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368: 1878–87.
6. Poordad F, McCone J, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195–206.
7. Hayashi N, Seto C, Kato M, Komada Y, Goto S. Once daily simeprevir (TMC435) with peginterferon/ribavirin for treatment naive hepatitis C genotype 1 infected patients in Japan: the DRAGON study. J Gastroenterol 2014; 49: 138–47.
8. Fried MW, Buti M, Dore GJ, et al. Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study. Hepatology 2013; 58: 1918–29.
9. Jacobson I, Dore G, Foster G, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype 1 infection in treatment naive patients: results from QUEST-1, a Phase III Trial. J Hepatol 2013; 58(Supplement 1): S574.
10. Manns M, Marcellin P, Poordad F, et al. Simeprevir with Peginterferon alpha 2a or alpha 2b and ribavirin in treatment naive HCV genotype 1 patients: QUEST-2, a randomized Phase III trial. J Hepatol 2013; 58(Supplement 1): S568.
11. Sulkowski MS, Asselah T, Lalezari J, et al. Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILENAliment C1 trial. Hepatology 2013; 57: 2143–54.
12. Jensen D, Asselah T, Dieterich D, Foster G. A Pooled Analysis of Two Randomized, Double Blind Placebo Controlled Phase III Trials (STARTVerso 1&2) of Faldaprevir Plus Pegylated Interferonalfa 2a and Ribavirin in Treatment Naive Patients With Chronic Hepatits C Genotype 1 Infection. Annual Meeting of the American Association for the Study of Liver Disease (AASLD), Washington DC, 2013; 1088.
13. Lawitz E, Forns X, Zeuzum S, et al. Simeprevir With Peginterferon/Ribavirin for Treatment of Chronic HCV Genotype 1 Infection in Patients Who Relapsed After Previous Interferon Based Therapy: Results From PROMISE, a Phase III Trial. Annual Meeting of the American Association for the Study of Liver Disease (AASLD), Washington DC, 2013; 1092.
14. Zeuzem S, Berg T, Gane E, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology 2014; 146: 430–41.e6.
15. Jacobson I, Ghalib R, Rodriguez-Torres M, et al. SVR Results of a Once-Daily Regimen of Simeprevir (TMC435) Plus Sofosbuvir (GS-7977) With or Without Ribavirin in Cirrhotic and non-Cirrhotic HCV Genotype 1 Treatment Naive and Prior Null Repsonder Patients: The COSMOS Study. Annual Meeting of the American Association for the Study of Liver Disease (AASLD), Washington DC, 2013; LB–3.
16. Sulkowski MS, Bourli_ere M, Bronowicki J-P, et al. Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial. Hepatology 2013; 57: 2155–63.
17. Jacobson I, Asselah T, Perenci P, Foster G. STARTVerso 3: A Randomized, Double Blind Placebo Controlled Phase III Trial of Faldaprevir in Combination With Pegylated Interferon Alfa 2a and Ribavirin in Treatment Experienced Patients With Chronic Hepatitis C Genotype 1 Infection. Annual Meeting of the American Association for the Study of Liver Disease (AASLD), Washington DC, 2013; 1100.
18. Osinusi A, Meissner EG, Lee Y, et al. Sofosbuvir and ribavirin for hepatitis c genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA 2013; 310: 804–11.
19. Yu ML, Dai CY, Huang JF, et al. A randomised study of peginterferon and ribavirin for 16 weeks versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut 2007; 56: 553–9.
20. Zeuzem S, Dusheiko G, Salupere R, et al. Sofosbuvir and Ribavirin for 12 or 24 Weeks for Patients With HCV Genotype 2 or 3: The VALENCE Trial. Annual Meeting of the American Association for the Study of Liver Disease (AASLD), Washington DC, 2013; 1085.
21. Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368: 1867–77.
22. Hadziyannis SJ, Sette JH, Morgan TR, et al. Peginterferon-Î ± 2a and Ribavirin combination therapy in chronic hepatitis C A randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140: 346–55.
23. Zeuzem S, Hultcrantz R, Bourliere M, et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004; 40: 993–9.
24. Lawitz E, Poordad F, Brainard D. Sofosbuvir in Combination With PegIFN and Ribavirin for 12 Weeks Provides High SVR Rates in HCV-Infected Genotype 2 or 3 Treatment Experienced Patients With and Without Compensated Cirrhosis: Results From the LONESTAR-2 Study. Annual Meeting of the American Association for the Study of LIver Disease (AASLD), Washington DC, 2013; LB–4.
25. Foster G, Shoeb D, Weatherall A, et al. Randomized controlled trial of 24 and 48 weeks of pegylated interferon alfa 2A plus ribavirin with genotype 3 HCV and cirrhosis. J Hepatol 2013; 58(Supplement): S335.
26. Moreno C, Hezode C, Marcellin P. Simeprevir with peginterferon/ribavirin in treatment-naive or experienced patients with chronic HCV 4 infection: interim results of a phase III trial. European Aids Conference, Brussels, Belgium, 2013; LBPS9/6.
27. Rockstroh JBS. Managing HIV/hepatitis C con-infection in the era of direct acting antivirals. BMC Med 2013; 11: 234.
28. Lacombe KVN, Stitou H. Efficacy and tolerance of telaprevir in HIV-hepatitis C virus genotype 1 coinfected patients failing previous antihepatitis C virus therapy: 24-week results. AIDS 2013; 15: 1356–9.
29. Sulkowski MS, Sherman KE, Dieterich DT, et al. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIVA randomized trial. Ann Intern Med 2013; 159: 86–96.
30. Fierer DS, Dieterich DT, Mullen MP, et al. Telaprevir in the treatment of acute hepatitis C virus infection in HIV-infected men. Clin Infect Dis 2014; 58: 873–9.
31. Sulkowski M, Rodriquez-Torres M, Lalezari J. All Oral Therapy With Sofosbuvir Plus Ribavirin for the Treatment of HCV Genotype 1, 2 and 3 Infection in Patients Coinfected With HIV (PHOTON-1). Annual Meeting of the American Association for the Study of Liver Disease (AASLD), Washington DC, 2013; 212.
32. Chastain C, Naggie S. Treatment of genotype 1 HCV infection in the HIV coinfected patient in 2014. Current HIV/AIDS Report 2013; 10: 408–19.
33. Rockstroh J, Nelson M, Soriano V, et al. STARTVerso 4 Phase III Trial of Faldaprevir Plus peg Interferon Alfa-2a and Ribavirin (PR) in Patients With HIV and HCV Genotype 1 co-Infection: End of Treatment Repsonse. Annual Meeting of the American Association for the Study of Liver Disease (AASLD), Washington DC, 2013; 1099.
34. Joshi D, Carey I, Agarwal K. Review article: the treatment of genotype 1 chronic hepatitis C virus infection in liver transplant candidates and recipients. Aliment Pharmacol Ther 2013; 37: 659–71.
35. Charlton M. Telaprevir, boceprevir, cytochrome P450 and immunosuppressive agents — A potentially lethal cocktail. Hepatology 2011; 54: 3–5.
36. Coilly A, Roche B, Dumortier J, et al. Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: a multicenter experience. J Hepatol 2014; 60: 78–86.
37. Curry MPFX, Chung RT. Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection After Liver Transplantation. AASLD, Washington DC, 2013; poster 1091.
38. Charlton M, Gane E, Manns M. Sofosbuvir and Ribavirin for the Treatment of Established Recurrent Hepatitis C Infection After Liver Transplant: Preliminary Results of a Prospective Multicentre Study. Annual Meeting of the American Association for the Study of Liver Disease (AASLD), Washington DC, 2013; LB2.
39. Ampuero J, Romero-Gómez M, Reddy KR. Review article: HCV genotype 3 – the new treatment challenge. Aliment Pharmacol Ther 2014; 39:686–98.