June 19, 2014

Centers for Disease Control and Prevention (CDC)

Twenty-five years ago CDC played a pivotal role in the discovery of the virus that causes hepatitis C. After the isolation of HCV, implementation of screening of blood products and organs for donation led to a decrease in rates of HCV infection between 1990 and 2009. In spite of these successes, HCV still remains a serious threat, both domestically and abroad. HCV remains the most common chronic blood borne infection in the United States, affecting approximately 3.9 million individuals. However up to 50% of HCV-infected persons are unaware of their infection. Globally, there are 180 million people who are chronically infected with the virus, and 3-4 million new infections occur every year.

Recent therapeutic advances hold the potential to halt the progression of HCV infection and disease. While HCV-infected persons can be effectively treated, more effort is needed to screen, diagnosis, treat and provide continuity of care. This session of Public Health Grand Rounds will discuss how new screening guidelines, testing methods and therapeutic advances will provide us with an opportunity to improve individual outcomes and to eventually eliminate HCV infection.

Transcript The 25th Anniversary of the Discovery of the Hepatitis C Virus Looking Back to Look Forward [2.51 MB, 57 pages]

Source

Alimentary Pharmacology & Therapeutics

Review Article

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

Abstract

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.

Introduction

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.

Methods

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.

The Drugs

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.[1] 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.[2]

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

table1

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.[3] 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[4] 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,[5] 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[6]) and telaprevir .

Simeprevir-based Regimens: The DRAGON study in Japan,[7] 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,[8] 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.[9] 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[10] 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,[9] 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,[10] 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[11] 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.[12]

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).

Treatment Experienced

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[13] 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.[14] 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[15] 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[16] 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.[17]

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,[18] 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.[19] 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,[20] 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,[5] 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,[21] 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.[21] 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 [19] 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 [22] 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%.[23] The FISSION study[3] 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,[21] 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.[3]

The VALENCE trial,[20] 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).[21] 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).[24] 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[25] 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[5] 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.[26]

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).[31] 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.[32]

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%.[33] 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.[34] 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.

Conclusions

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.[39] 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.

References

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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.

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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.

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Source

Drug-Induced Liver Injury Guidelines Released by ACG

Medscape Medical News

Janis C. Kelly
June 18, 2014

Drug-induced liver injury is among the most challenging disorders for gastroenterologists to diagnose and treat, but the American College of Gastroenterology has issued new clinical guidelines to help physicians and other healthcare providers manage this disorder. The guidelines were published online June 17 in the American Journal of Gastroenterology.

Lead author Naga P. Chalasani, MD, writing on behalf of the ACG Practice Parameters Committee, presented an evidence-based approach to diagnosing and managing DILI, "with special emphasis on DILI due to herbal and dietary supplements and DILI occurring in individuals with underlying liver disease."

"[Herbal and dietary supplement] hepatotoxicity has received increasing attention over the past few years, in part owing to the recognition in the United States that among DILI cases HDS are the second most common cause," the authors write.

The authors stress that DILI is a diagnosis of exclusion and requires careful history-taking and workup for possible competing etiologies. "Accurate history of medication exposure and onset and course of liver biochemistry abnormalities is crucial," Dr. Chalasani, who is chief of the Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, said in a news release.

DILI is commonly categorized as intrinsic (because of drugs that predictably cause liver injury in humans or in animal models, such as acetaminophen) and idiosyncratic (affecting only susceptible individuals, having less-consistent dosage relationship, and more varied in presentation). "Despite its low incidence in the general population, gastroenterologists must always consider the possibility of DILI in patients with unexplained acute and chronic liver injury, as well as when prescribing certain gastrointestinal medications (e.g., azathioprine, anti-tumor necrosis factor agents, sulfonamides). Many herbal and dietary supplements...can cause DILI, and thus they must be considered as a cause for DILI," the authors write.

The clinical guideline provides an algorithm for evaluation of suspected DILI, which progresses from abnormal liver enzymes to thorough history and physical with complete review of medications and herbal and dietary supplements, to calculation of the R-value (serum alanine aminotransferase/upper limit of normal divided by serum alkaline phosphatase/upper limit of normal). The guidelines present separate diagnostic pathways for patients with hepatocellular (R ≤ 5), mixed (2 < R < 5), or cholestatic (R ≤ 2) types of liver damage.

According to the guidelines, liver biopsy can help confirm suspected DILI and should be considered if autoimmune hepatitis is a possible factor and if immunosuppressives are under consideration. Indications for biopsy include unrelenting risk in liver biochemistries or worsening liver function despite stopping the suspected drug; continued peak alanine aminotransferase elevation, if continued exposure or reexposure to the implicated agent is expected; and evaluating for chronic liver disease if liver biochemistry remains abnormal beyond 180 days.

Usual Clinical Tool May Underestimate Risk for Herbal/Diet Supplements

The Roussel Uclaf Causality Assessment Method (RUCAM) scale is widely used for assessing causality in suspected DILI, and the authors warn it might lead to underestimation of risks associated with herbal or dietary supplements. The authors write, "In the RUCAM, the presence of a labeled warning of hepatotoxicity increases the score; as warnings typically do not exist on [herbal or dietary supplement] labels, the highest score could rarely be awarded."

"A lot of consumers have a preconceived notion that if it's a natural product, it must be safe. But that is not necessarily the case," coauthor Herbert Bonkovsky, MD, said in the news release. "Most of these products are not well-regulated and have very little oversight. Traces of heavy metals and prescription drugs have even been found in some herbal and dietary supplements. We encourage patients to talk to their doctor about all medications they are taking, and herbal and dietary supplements should be no exception." Dr. Bonkovsky is professor of medicine and senior advisor for research, Carolinas HealthCare System, Charlotte, North Carolina.

The guidelines include a table of the most common over-the-counter and prescription drugs and supplements that cause DILI, and their usual patterns of liver injury. The table lists antibiotics (amoxicillin/clavulanate is the most commonly associated with DILI) and herbal and dietary supplements.

Green tea extract tops the list of herbal and dietary supplements associated with liver damage. According to Dr. Bonkovsky, the average cup of green tea has around 50 to 150 mg catechins, whereas some green tea extract pills (commonly used for weight loss) have catechin levels more than 700 mg and may be taken multiple times a day.

For more information, the National Institutes of Health has a free database of drugs associated with liver injury, available on their Web site.

Dr. Chalasani has served as a consultant to and received financial compensation from Boehringer Ingelheim, Abbvie, Aegerion, Salix, Bristol-Myers Squibb, and Lilly. He has research support from Cumberland Pharmaceuticals, Intercept Pharmaceuticals, Gilead, and Galectin Pharmaceuticals. Dr. Bonkovsky has served as a consultant and received financial compensation from Alnylam and Clinuvel. He has received research support from Clinuvel, Merck, the National Institutes of Health (National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases), and Vertex. One coauthor has served as a consultant to Glaxo-SmithKline. Another coauthor has served as a consultant to and received financial compensation from Lilly and Novartis and receives research support from Anadys, Bristol-Myers Squibb, Boehringer Ingelheim, Cumberland, Gilead, Vertex, Ocera, and Merck. Another coauthor has received grant support from Gilead and Vertex and served as a paid consultant to Tibotec, Merck, and GlaxoSmithKline.

Am J Gasterenterol. Published online June 17, 2014. Abstract

Source

Press Release

June 19, 2014, 1:36 p.m. EDT

The Majority of Surveyed Primary Care Physicians Expect to Refer HCV Patients to a Specialist for Care, According to Findings from Decision Resources Group

BURLINGTON, Mass., June 19, 2014 /PRNewswire/ -- Decision Resources Group finds that less than one-third of surveyed primary care physicians (PCPs) are familiar with the first-generation hepatitis C virus (HCV) protease inhibitors, Vertex's Incivek and Merck's Victrelis, despite the fact that these direct acting antivirals have been marketed in the U.S. since 2011. Furthermore, approximately three-quarters of surveyed PCPs are unaware that Janssen/Medivir's Olysio and Gilead's Sovaldi recently received FDA approval for the treatment of HCV infections, highlighting an opportunity for drug marketers to increase their prescriber pool by raising awareness of the current HCV treatment options among PCPs.

Other key findings from the U.S. Physician and Payer Forum report entitled: Primary Care Physicians in an Interferon-Free World: How Will the Availability of Safer and More Effective Oral Therapies Impact the Role of PCPs in Treating HCV Patients? :

  • Physician receptivity to emerging all-oral, interferon (IFN) -free therapies: Although more than half of surveyed specialists feel comfortable with the idea of PCPs prescribing all-oral, IFN-free regimens to treatment-naive HCV patients with minimal liver damage, approximately one-third of surveyed PCPs expect to always refer these patients to a specialist for care.

  • Managed care organization (MCO) responsiveness to new HCV treatment guidelines: More than half of surveyed MCO pharmacy and/or medical directors (PDs/MDs) are aware of the American Association for the Study of Liver Diseases' treatment guidelines and the majority of them report that these guidelines have impacted their organization's willingness to reimburse or give favorable formulary status to HCV regimens recommended in these guidelines.

  • Use of formulary restrictions as a mechanism for cost control: Among the majority of PDs/MDs whose MCOs include Gilead's Sovaldi on formulary, these payers estimated that more than one-third of large commercial health plans and nearly half of Medicare Advantage plans restrict Sovaldi to prescription by specialists only, thereby preventing PCPs from utilizing this agent.

Comments from Decision Resources Group Analyst Hannah E. Cummings, Ph.D.:

  • "Most surveyed PCPs follow up with their specialist-referred patients with suspected or confirmed HCV infection and estimate that nearly one quarter of referred patients are lost in follow up. Similarly, most specialists report having PCP-referred patients who never appear for their exam; these physicians estimate 15 percent of PCP-referred patients do not follow up. Our findings suggest that referral to specialists represents a barrier to accessing care for some HCV patients. Therefore, direct HCV treatment by PCPs could help maximize the number of patients retained in care." 

  • "The high price of Sovaldi is a major concern among payers, many of whom have spent tens of millions of dollars on this drug within the first quarter of 2014. Surveyed MCOs anticipate that even greater prescribing restrictions will be placed on emerging interferon-free therapies, which will represent a notable barrier to wider PCP involvement."

About Decision Resources Group Decision Resources Group offers best-in-class, high-value information and insights on critical issues within the healthcare industry. Clients rely on this analysis and data to make informed decisions. Find out more at www.DecisionResourcesGroup.com .

All company, brand, or product names contained in this document may be trademarks or registered trademarks of their respective holders.

For more information, contact:

Decision Resources Group Christopher Comfort
781-993-2597 
ccomfort@dresourcesgroup.com

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SOURCE Decision Resources Group

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Original Research | 18 March 2014

Vincent Lo Re III, MD, MSCE; Michael J. Kallan, MS; Janet P. Tate, ScD; A. Russell Localio, PhD; Joseph K. Lim, MD; Matthew Bidwell Goetz, MD; Marina B. Klein, MD, MS; David Rimland, MD; Maria C. Rodriguez-Barradas, MD; Adeel A. Butt, MD, MS; Cynthia L. Gibert, MD, MS; Sheldon T. Brown, MD; Lesley Park, MPH; Robert Dubrow, MD, PhD; K. Rajender Reddy, MD; Jay R. Kostman, MD; Brian L. Strom, MD, MPH; and Amy C. Justice, MD, PhD

[+-] Article and Author Information

Ann Intern Med. 2014;160(6):369-379. doi:10.7326/M13-1829

Background: The incidence and determinants of hepatic decompensation have been incompletely examined among patients co-infected with HIV and hepatitis C virus (HCV) in the antiretroviral therapy (ART) era, and few studies have compared outcome rates with those of patients with chronic HCV alone.

Objective: To compare the incidence of hepatic decompensation between antiretroviral-treated patients co-infected with HIV and HCV and HCV-monoinfected patients and to evaluate factors associated with decompensation among co-infected patients receiving ART.

Design: Retrospective cohort study.

Setting: Veterans Health Administration.

Patients: 4280 co-infected patients who initiated ART and 6079 HCV-monoinfected patients receiving care between 1997 and 2010. All patients had detectable HCV RNA and were HCV treatment–naive.

Measurements: Incident hepatic decompensation, determined by diagnoses of ascites, spontaneous bacterial peritonitis, or esophageal variceal hemorrhage.

Results: The incidence of hepatic decompensation was greater among co-infected than monoinfected patients (7.4% vs. 4.8% at 10 years; P < 0.001). Compared with HCV-monoinfected patients, co-infected patients had a higher rate of hepatic decompensation (hazard ratio [HR] accounting for competing risks, 1.56 [95% CI, 1.31 to 1.86]). Co-infected patients who maintained HIV RNA levels less than 1000 copies/mL still had higher rates of decompensation than HCV-monoinfected patients (HR, 1.44 [CI, 1.05 to 1.99]). Baseline advanced hepatic fibrosis (FIB-4 score >3.25) (HR, 5.45 [CI, 3.79 to 7.84]), baseline hemoglobin level less than 100 g/L (HR, 2.24 [CI, 1.20 to 4.20]), diabetes mellitus (HR, 1.88 [CI, 1.38 to 2.56]), and nonblack race (HR, 2.12 [CI, 1.65 to 2.72]) were each associated with higher rates of decompensation among co-infected patients.

Limitation: Observational study of predominantly male patients.

Conclusion: Despite receiving ART, patients co-infected with HIV and HCV had higher rates of hepatic decompensation than HCV-monoinfected patients. Rates of decompensation were higher for co-infected patients with advanced liver fibrosis, severe anemia, diabetes, and nonblack race.

Primary Funding Source: National Institutes of Health.

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Provided by The Commonwealth Fund

Publication Date:
June 16, 2014

Authors:
Karen Davis, Kristof Stremikis, David Squires, Cathy Schoen

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Executive Summary
Full Report

Executive Summary

The United States health care system is the most expensive in the world, but this report and prior editions consistently show the U.S. underperforms relative to other countries on most dimensions of performance. Among the 11 nations studied in this report—Australia, Canada, France, Germany, the Netherlands, New Zealand, Norway, Sweden, Switzerland, the United Kingdom, and the United States—the U.S. ranks last, as it did in the 2010, 2007, 2006, and 2004 editions of Mirror, Mirror. Most troubling, the U.S. fails to achieve better health outcomes than the other countries, and as shown in the earlier editions, the U.S. is last or near last on dimensions of access, efficiency, and equity. In this edition of Mirror, Mirror, the United Kingdom ranks first, followed closely by Switzerland (Exhibit ES-1).

Expanding from the seven countries included in 2010, the 2014 edition includes data from 11 countries. It incorporates patients’ and physicians’ survey results on care experiences and ratings on various dimensions of care. It includes information from the most recent three Commonwealth Fund international surveys of patients and primary care physicians about medical practices and views of their countries’ health systems (2011–2013). It also includes information on health care outcomes featured in The Commonwealth Fund’s most recent (2011) national health system scorecard, and from the World Health Organization (WHO) and the Organization for Economic Cooperation and Development (OECD).

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The most notable way the U.S. differs from other industrialized countries is the absence of universal health insurance coverage.5 Other nations ensure the accessibility of care through universal health systems and through better ties between patients and the physician practices that serve as their medical homes. The Affordable Care Act is increasing the number of Americans with coverage and improving access to care, though the data in this report are from years prior to the full implementation of the law. Thus, it is not surprising that the U.S. underperforms on measures of access and equity between populations with above- average and below-average incomes.

The U.S. also ranks behind most countries on many measures of health outcomes, quality, and efficiency. U.S. physicians face particular difficulties receiving timely information, coordinating care, and dealing with administrative hassles. Other countries have led in the adoption of modern health information systems, but U.S. physicians and hospitals are catching up as they respond to significant financial incentives to adopt and make meaningful use of health information technology systems. Additional provisions in the Affordable Care Act will further encourage the efficient organization and delivery of health care, as well as investment in important preventive and population health measures.

For all countries, responses indicate room for improvement. Yet, the other 10 countries spend considerably less on health care per person and as a percent of gross domestic product than does the United States. These findings indicate that, from the perspectives of both physicians and patients, the U.S. health care system could do much better in achieving value for the nation’s substantial investment in health.

Major Findings

  • Quality: The indicators of quality were grouped into four categories: effective care, safe care, coordinated care, and patient-centered care. Compared with the other 10 countries, the U.S. fares best on provision and receipt of preventive and patient-centered care. While there has been some improvement in recent years, lower scores on safe and coordinated care pull the overall U.S. quality score down. Continued adoption of health information technology should enhance the ability of U.S. physicians to identify, monitor, and coordinate care for their patients, particularly those with chronic conditions.
  • Access: Not surprisingly—given the absence of universal coverage—people in the U.S. go without needed health care because of cost more often than people do in the other countries. Americans were the most likely to say they had access problems related to cost. Patients in the U.S. have rapid access to specialized health care services; however, they are less likely to report rapid access to primary care than people in leading countries in the study. In other countries, like Canada, patients have little to no financial burden, but experience wait times for such specialized services. There is a frequent misperception that trade-offs between universal coverage and timely access to specialized services are inevitable; however, the Netherlands, U.K., and Germany provide universal coverage with low out-of-pocket costs while maintaining quick access to specialty services. 
  • Efficiency: On indicators of efficiency, the U.S. ranks last among the 11 countries, with the U.K. and Sweden ranking first and second, respectively. The U.S. has poor performance on measures of national health expenditures and administrative costs as well as on measures of administrative hassles, avoidable emergency room use, and duplicative medical testing. Sicker survey respondents in the U.K. and France are less likely to visit the emergency room for a condition that could have been treated by a regular doctor, had one been available. 
  • Equity: The U.S. ranks a clear last on measures of equity. Americans with below-average incomes were much more likely than their counterparts in other countries to report not visiting a physician when sick; not getting a recommended test, treatment, or follow-up care; or not filling a prescription or skipping doses when needed because of costs. On each of these indicators, one-third or more lower-income adults in the U.S. said they went without needed care because of costs in the past year. 
  • Healthy lives: The U.S. ranks last overall with poor scores on all three indicators of healthy lives—mortality amenable to medical care, infant mortality, and healthy life expectancy at age 60. The U.S. and U.K. had much higher death rates in 2007 from conditions amenable to medical care than some of the other countries, e.g., rates 25 percent to 50 percent higher than Australia and Sweden. Overall, France, Sweden, and Switzerland rank highest on healthy lives.

Summary and Implications

The U.S. ranks last of 11 nations overall. Findings in this report confirm many of those in the earlier four editions of Mirror, Mirror, with the U.S. still ranking last on indicators of efficiency, equity, and outcomes. The U.K. continues to demonstrate strong performance and ranked first overall, though lagging notably on health outcomes. Switzerland, which was included for the first time in this edition, ranked second overall. In the subcategories, the U.S. ranks higher on preventive care, and is strong on waiting times for specialist care, but weak on access to needed services and ability to obtain prompt attention from primary care physicians. Any attempt to assess the relative performance of countries has inherent limitations. These rankings summarize evidence on measures of high performance based on national mortality data and the perceptions and experiences of patients and physicians. They do not capture important dimensions of effectiveness or efficiency that might be obtained from medical records or administrative data. Patients’ and physicians’ assessments might be affected by their experiences and expectations, which could differ by country and culture.

Disparities in access to services signal the need to expand insurance to cover the uninsured and to ensure that all Americans have an accessible medical home. Under the Affordable Care Act, low- to moderate-income families are now eligible for financial assistance in obtaining coverage. Meanwhile, the U.S. has significantly accelerated the adoption of health information technology following the enactment of the American Recovery and Reinvestment Act, and is beginning to close the gap with other countries that have led on adoption of health information technology. Significant incentives now encourage U.S. providers to utilize integrated medical records and information systems that are accessible to providers and patients. Those efforts will likely help clinicians deliver more effective and efficient care.

Many U.S. hospitals and health systems are dedicated to improving the process of care to achieve better safety and quality, but the U.S. can also learn from innovations in other countries—including public reporting of quality data, payment systems that reward high-quality care, and a team approach to management of chronic conditions. Based on these patient and physician reports, and with the enactment of health reform, the United States should be able to make significant strides in improving the delivery, coordination, and equity of the health care system in coming years.

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Counting The Cost: Hepatitis C Treatment In Asia

Provided by Asian Scientist Magazine

By Rebecca Tan | Editorials
June 17, 2014

Counting-The-Cost-Hepatitis-C-Treatment-In-Asia

How should decisions about the cost effectiveness of hepatitis C treatments be made? Rebecca Tan finds out what the experts think at the inaugural Singapore Hepatitis Conference held at Suntec Singapore Convention and Exhibition Center from 6-7 June 2014.

AsianScientist (Jun 17, 2014) – When drug manufacturer Gilead announced that its new hepatitis C drug, Solvaldi® (generic name, sofosbuvir) had been approved by the United States Food and Drug Administration, the news was met with both relief and outcry. A simple, once-a-day oral pill compatible with existing therapies and able to treat hepatitis in 90 percent of patients, Solvaldi® is a highly desirable drug that could make a significant difference to the 200 million patients chronically infected with the hepatitis C virus (HCV) around the world. However, many have questioned the price tag of US$84,000 for a standard 12-week course of treatment, which works out to a staggering US$1,000 per pill. From the point of view of the individual patient and governmental health agencies, is Solvaldi® worth it?

As it turns out, the answer to this question is not straightfoward, as Asian Scientist Magazine found out from a panel of experts at the Singapore Hepatitis Conference 2014, held at Suntec Singapore Convention and Exhibition Center from 6-7th June. The pressing issue of the cost effectiveness of HCV therapies was discussed in the session titled Issues in HCV eradication in Asia, chaired by Rajender Reddy, professor at the University of Pennsylvania and director of the Viral Hepatitis Center in the US, and Qin Ning, director of the Institute of Infectious Disease at Tongji Hospital in China.

Peculiarities of the disease

The decision whether or how to treat HCV infection is strongly influenced by features unique to the disease itself. First of all, it is estimated that up to 90 percent of HCV carriers are asymptomatic. This means that carriers go untreated for many years, and only come to know of the underlying HCV infection when they show up at the clinic with liver cirrhosis or end-stage liver cancer. Therefore, doctors have to decide between treating patients with expensive drugs in the absence of symptoms, meaning that some cost would be wasted on individuals who would not have gone on to develop debilitating disease; or waiting until the disease begins to worsen and only treating those patients.

The situation is made more complex by the fact that the cost effectiveness of HCV treatments is also influenced by variables such as life expectancy and the use of transplants to treat liver disease, factors which differ widely across Asia-Pacific.

“One of the more surprising things we found was that a country’s life expectancy decides whether or not HCV treatment is cost effective,” said Dr. Dan Yock Young, head of the Department of Gastroenterology and Hepatology at the National University Health Systems.

“If you have a life expectancy of less than 65 years, you don’t need to treat for HCV. This is because the burden of disease occurs later in life; chronic HCV patients typically manifest symptoms only after the age of 65. In countries with low life expectancy, the chances of dying from violence or diseases such as cholera are much higher. In other words, doctors can cure HCV with drugs, but it would make no difference to survival,” said Dr. Dan.

Counting-The-Cost-Hepatitis-C-Treatment-In-Asia-2

Dr. Dan Yock Young speaking at the panel discussion Issues in HCV eradication in Asia.

However, in countries like Taiwan where the rate of liver transplants is high, treating the disease earlier with drugs is actually more cost effective as the alternative of transplantation surgery and lifelong immunosuppressants is relatively more expensive.

“With less cirrhosis, less liver cancer and less transplants, more expensive drugs can be more cost effective in the long run,” Dr. Dan said. “Furthermore, if you don’t treat, or start with cheaper drugs, there is the added cost of re-treatment at a later stage.”

On a positive note, a polymorphism in the IL-28B gene common in the Asian population favors the clearance of HCV, leading to a high sustained virologic response (SVR), which is the absence of HCV RNA in the blood of patients at least 24 weeks after discontinuing treatment. According to the panelists, this makes it more cost effective to treat patients in an Asian population as they respond better to directly acting antivirals (DAAs), often the first line of treatment for HCV.

Diversity in access to drugs

Naturally, price and purchasing power are major determinants of cost effectiveness as well. However, gross domestic product (GDP) per capita and standards of healthcare vary widely across Asia. Political pressure can bring down the price of HCV drugs, as seen in the successful lobbying for generic versions of the drug Viread in India, China and Thailand which do not observe the patent in force in other countries. While this may benefit developing countries in the short run, it has been argued that it could ultimately hurt drug discovery in the long run as research on new drugs are disincentivized, the panel noted.

Another way that drugs can be made more affordable is through government subvention or subsidies. Whether governments subsidize the treatments or people pay with private insurance, the net cost to society is the same. However, subventions can influence the take up rate, and may help lower the burden of disease.

The devil, of course, is in the details: how much should governments subsidize and for which drugs? Hepatitis is a complex disease with many different genotypes and patient subpopulations. For example, patients with HCV genotype 1 are less responsive to the standard pegylated interferon treatment and require an additional antiviral drug called Ribavarin. Newer drugs such as Solvaldi can be used without interferon treatment, but are much more expensive.

“Two percent of the world’s population is infected with HCV. One of the biggest ironies is that 90 percent of those patients are outside the US and Europe, but access to care mainly occurs within US and Europe and the drugs that are being developed cater to that market,” said Dr. Shamir Shah, director of Global Hospitals in Mumbai, India.

Another barrier preventing patients in Asia from accessing newly developed hepatitis drugs are stringent regulatory requirements. Many countries in Asia require clinical trials to be done in their own populations before the drug can be approved. Therefore, it may take years for drugs already in the market in the US and Europe to reach Asia. Participants at the discussion suggested that this might be expedited by collaborations with Asian universities and research institutions, or multi-center trials where some of the trials are done in Asia.

In the meantime, Gilead has made statements indicating that it might retail Solvaldi® in India at 42 times less than the US price, or US$2,000 for a full course of treatment. However, whether or not a significant drop in price is sufficient to make treatment cost effective also depends on many other factors. As the discussion showed, the price of the treatment ultimately needs to be weighed against the burden of the disease to make an accurate assessment of cost effectiveness.

Asian Scientist Magazine is a media partner of Suntec Singapore Convention & Exhibition Center.

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Provided by ScienceDaily

Date: June 17, 2014

Source: American College of Gastroenterology (ACG)

Summary: New clinical guidelines on the diagnosis and management of idiosyncratic drug-induced liver injury (DILI) have now been released. DILI is a rare adverse drug reaction, challenging to diagnose, and can lead to jaundice, liver failure and even death. The frequency of DILI incidence is increasing, as the use of herbal and dietary supplements has drastically increased over the last 10 years.

New clinical guidelines on the diagnosis and management of idiosyncratic drug-induced liver injury (DILI) appear in the July issue of The American Journal of Gastroenterology. DILI is a rare adverse drug reaction, challenging to diagnose, and can lead to jaundice, liver failure and even death. The frequency of DILI incidence is increasing, as the use of herbal and dietary supplements has drastically increased over the last 10 years.

The new guidelines from the American College of Gastroenterology, intended for use by physician and other health-care providers, include an overview of risk factors, diagnosis evaluation and causality assessment, prognosis factors, and management of hepatotoxicity due to pre-existing chronic liver disease or herbal/dietary supplement intake. One of the key focuses of the guidelines is on herbal and dietary supplements, which many doctors warn should be used with caution.

"A lot of consumers have a preconceived notion that if it's a natural product, it must be safe. But that is not necessarily the case," said Herbert Bonkovsky, MD, FACG, co-author of the guidelines. "Most of these products are not well-regulated and have very little oversight. Traces of heavy metals and prescription drugs have even been found in some herbal and dietary supplements. We encourage patients to talk to their doctor about all medications they are taking, and herbal and dietary supplements should be no exception."

The guidelines include a table of the most common over-the-counter and prescription drugs and supplements that cause DILI, and their usual patterns of liver injury. The table lists antibiotics (amoxicillin/clavulanate is the most commonly associated with DILI) and herbal and dietary supplements.

Of the herbal and dietary supplements, green tea extract tops the list as one of the most common dietary supplements associate with DILI injury. To give context, Dr. Bonkovsky says that the average cup of green tea has around 50-150 mgs of catechins, a group of polyphenols that are the major active ingredients. In some green tea extract pills, known to help with weight loss and other factors, the levels of such catechins can be over 700 mg. This can be particularly dangerous when the pills are taken multiple times a day.

It is important to note that DILI remains a "diagnosis of exclusion," which underscores the importance of patients giving their doctors a full history of all medications and supplement use. "Accurate history of medication exposure and onset and course of liver biochemistry abnormalities is crucial," says lead guideline author Naga P. Chalasani, MD, FACG.

Story Source:

The above story is based on materials provided by American College of Gastroenterology (ACG). Note: Materials may be edited for content and length.

Journal Reference:

  1. Naga P Chalasani, Paul H Hayashi, Herbert L Bonkovsky, Victor J Navarro, William M Lee, Robert J Fontana. ACG Clinical Guideline: The Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury. The American Journal of Gastroenterology, 2014; DOI: 10.1038/ajg.2014.131

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Also See: Drug-Induced Liver Injury Guidelines Released by ACG