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You are here: HomeRecommendations for Primary Care PracticePublished RecommendationsRecommendation SummaryOther Supporting Document : Comparative Effectiveness of Antiviral Treatment for Hepatitis C Virus Infection in Adults: A Systematic Review

Comparative Effectiveness of Antiviral Treatment for Hepatitis C Virus Infection in Adults: A Systematic Review

Other Supporting Document for Hepatitis C: Screening

Preface

Release Date: November 2012


By Roger Chou, MD; Daniel Hartung, PharmD, MPH; Basmah Rahman, MPH; Ngoc Wasson, MPH; Erika Barth Cottrell, PhD; and Rongwei Fu, PhD


The information in this article is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This article is intended as a reference and not as a substitute for clinical judgment.

This article may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.

This article was first published in Annals of Internal Medicine on November 27, 2012 (Ann Intern Med 2012; http://www.annals.org).

Abstract

Background: Multiple treatments are available for chronic hepatitis C virus (HCV) infection.

Purpose: To compare benefits and harms of antiviral regimens for chronic HCV infection in treatment-naive adults.

Data Sources: English-language literature from MEDLINE (1947 to August 2012), the Cochrane Library Database, Embase, Scopus, PsychINFO, and clinical trial registries.

Study Selection: Randomized trials of antiviral treatments and cohort studies examining associations between sustained virologic response (SVR) after therapy and clinical outcomes.

Data Extraction: Several investigators abstracted study details and quality by using predefined criteria.

Data Synthesis: No trial evaluated effectiveness of treatment on long-term clinical outcomes. Dual therapy with pegylated interferon alfa-2b plus ribavirin was associated with a lower likelihood of SVR than was pegylated interferon alfa-2a plus ribavirin (absolute difference, 8 percentage points [95% CI, 3 to 14 percentage points]) on the basis of 7 poor- to fair-quality trials. For genotype 2 or 3 infection, dual therapy for 12 to 16 weeks was associated with a lower likelihood of SVR than was therapy for 24 weeks, and lower doses of pegylated interferon alfa-2b were less effective than standard doses (2 to 4 fair-quality trials). For genotype 1 infection, fair-quality trials found that triple therapy with pegylated interferon, ribavirin, and either boceprevir (2 trials) or telaprevir (4 trials) was associated with a higher likelihood of SVR than was dual therapy (absolute difference, 22 to 31 percentage points). Compared with dual therapy, boceprevir triple therapy increased risk for hematologic adverse events and telaprevir triple therapy increased risk for anemia and rash. A large well-designed cohort study and 18 smaller cohort studies found that an SVR after antiviral therapy was associated with lower risk for all-cause mortality than was no SVR.

Limitations: Trials involved highly selected populations. Observational studies did not always adequately control for confounders.

Conclusion: SVR rates for genotype 1 infection are higher with triple therapy that includes a protease inhibitor than with standard dual therapy. An SVR after antiviral therapy appears associated with improved clinical outcomes.

Primary Funding Source: Agency for Healthcare Research and Quality.

Introduction

Chronic hepatitis C virus (HCV) infection is a leading cause of complications from chronic liver disease, including cirrhosis, liver failure, hepatocellular carcinoma, and death1, 2. The goal of antiviral treatment is to eradicate viremia and prevent long-term complications. Genotype 1 infection predominates in the United States (about 75% of cases) but is more difficult to treat than genotype 2 or 3 infection.

In the early 2000s, dual therapy with the combination of pegylated interferon plus ribavirin became the standard HCV treatment3-6. Pegylation refers to the cross-linking of polyethylene glycol molecules to the interferon molecule, which delays renal clearance, permitting once-weekly dosing7. Two pegylated interferons are available: alfa-2a and alfa-2b. Interferon-based treatment is associated with a high rate of adverse effects, including influenza-like symptoms, fatigue, and neuropsychiatric and hematologic adverse effects8. In 2011, the U.S. Food and Drug Administration approved the first direct-acting antiviral agents, boceprevir9 and telaprevir10, for chronic genotype 1 infection.

Understanding the effectiveness of antiviral regimens is critical for making informed treatment decisions for HCV infection. This review focuses on comparative effectiveness in antiviral-naive patients and also examines how effectiveness varies depending on clinical and demographic characteristics.

 

Methods

We developed a review protocol and analytic framework (Appendix Figure 1) that included the following key questions:

1. What is the comparative effectiveness of antiviral treatment in improving health outcomes in patients with HCV infection, and does it vary according to patient subgroup characteristics (including, but not limited to, HCV genotype, age, race, sex, stage of disease, or genetic markers)?

2. What is the comparative effectiveness of antiviral treatments on the rate of sustained virologic response (SVR), and does it vary according to patient subgroup characteristics?

3. What are the comparative harms associated with antiviral treatments, and do they vary according to patient subgroup characteristics?

4. Have improvements in SVR been shown to reduce the risk for or rates of adverse health outcomes from HCV infection?

The protocol was developed by using a standardized process with input from experts and the public. Details, including full search strategies, inclusion criteria, and evidence tables and quality ratings, are provided in the full report, as are results of studies comparing induction versus fixed-dose regimens and study outcomes related to quality of life and histologic changes11.

Data Sources and Searches

A research librarian searched Ovid MEDLINE from 1947 to August 2012, the Cochrane Library Database (through the first quarter of 2012), Embase (1976 to August 2012), Scopus (1960 to August 2012), PsychINFO (1806 to August 2012), clinical trials registries, and grants databases.

Study Selection

At least 2 reviewers independently evaluated studies for inclusion. For the first 3 questions, we included randomized trials of antiviral-naive patients that compared dual therapy with pegylated interferon alfa-2b plus ribavirin versus pegylated interferon alfa-2a plus ribavirin; triple therapy with pegylated interferon (alfa-2a or -2b), ribavirin, and either telaprevir or boceprevir versus dual therapy; or different doses or durations of dual or triple therapy. Dose and duration comparisons of dual therapy focused on genotype 2 or 3 infection. For the last question, we included cohort studies that reported adjusted risk estimates for the association between an SVR after antiviral treatment versus no SVR and clinical outcomes. Clinical outcomes were mortality, cirrhosis, hepatic decompensation, hepatocellular carcinoma, and need for transplantation. SVR, the primary intermediate outcome, was defined as the absence of detectable HCV RNA in the serum 6 months after the end of a course of therapy4. Harms included withdrawals due to adverse events, serious adverse events, neutropenia, anemia, psychological adverse events, influenza-like symptoms, and rash.

We restricted inclusion to English-language articles and included studies published as conference abstracts only in sensitivity analyses. We excluded studies of pregnant women12, patients who received a transplant, HIV-infected patients, patients undergoing hemodialysis, and previously treated patients. We excluded regimens with antiviral drugs not approved in the United States for HCV infection.

Data Extraction and Quality Assessment

One investigator abstracted details about the study design, population, setting, interventions, analysis, follow-up, and results. A second investigator reviewed data for accuracy. Two investigators independently applied predefined criteria13-15 to assess study quality as good, fair, or poor. Discrepancies were resolved through consensus.

Data Synthesis and Analysis

We assessed the overall strength of each body of evidence as “high,” “moderate,” “low,” or “insufficient” in accordance with the AHRQ “Methods Guide for Effectiveness and Comparative Effectiveness Reviews”16 on the basis of the quality of studies, consistency between studies, precision of estimates, and directness of evidence.

We performed meta-analyses of trials that evaluated similar populations, interventions, comparisons, and outcomes to estimate pooled relative risks (RRs) using the DerSimonian–Laird method in a random-effects model17. Heterogeneity was assessed with the I2 statistic18. Statistical heterogeneity was explored through sensitivity and subgroup analyses based on study quality, differences in dosing or drugs, and outlier trials. We did not produce funnel plots because of small numbers10 of studies19, but we performed sensitivity analyses that included studies published only as abstracts. Analyses were performed with Stata software, version 11.0 (Stata Corp, College Station, Texas).

Role of the Funding Source

AHRQ's Effective Health Care Program funded this work. Investigators worked with AHRQ staff to develop and refine the scope, analytic framework, and key questions. AHRQ staff had no role in study selection, quality assessment, synthesis, or development of conclusions. AHRQ staff provided project oversight and reviewed the draft report and manuscript. The investigators are solely responsible for the manuscript's content and the decision to submit it for publication.

Results

Appendix Figure 2 shows the search and selection results and Appendix Table 1 shows the strength of evidence ratings. No study evaluated the comparative effectiveness of current antiviral treatments on long-term clinical outcomes. Three trials found no differences between various dual- or triple-therapy regimens in short-term (6 months after regimen completion) mortality but reported few deaths (20 total)20-22.

Virologic Outcomes

Ten trials (n = 66 to 3070) compared dual therapy with pegylated interferon alfa-2b plus ribavirin versus dual therapy with pegylated interferon alfa-2a plus ribavirin6, 21, 23-30 (Appendix Table 2). Four trials were restricted to genotype 1 infection21, 27, 28, 30. The prevalence of baseline cirrhosis ranged from less than 5% to 20%23, 29, 31, 32, and the prevalence of elevated aminotransferase levels ranged from 60% to 100%23-25, 29, 30, 32. Eleven trials (n = 60 to 1465)33-43 compared different durations of dual therapy, 6 trials (n = 53 to 602)39, 44-48 compared different doses of pegylated interferon as part of dual therapy, and 4 trials (n = 97 to 1831)35, 49-51 compared different doses of ribavirin as part of dual therapy for genotype 2 or 3 infection (Appendix Table 2). One trial was rated as good quality40, 4 trials as poor quality24, 30, 38, 47, and the remainder as fair quality. Methodologic shortcomings included open-label design or inadequately described blinding23-25, 27-29, 33-39, 42-52, high or unclear attrition21, 23, 24, 29, 35, 38, 51, and unclear or inadequate randomization or methods for allocation concealment24, 25, 27-30, 34, 36-39, 41-48.

Dual therapy with standard-dose (1.5 mcg/kg per week) pegylated interferon alfa-2b was associated with a slightly lower likelihood of SVR than was dual therapy with standard-dose (180 mcg per week) pegylated interferon alfa-2a (pooled relative risk [RR], 0.87 [95% CI, 0.80 to 0.95]; I2 = 27%.) (Figure 1), with a pooled absolute difference of 8 percentage points (CI, 3 to 14 percentage points), on the basis of 7 trials (5 fair-quality and 2 poor-quality trials)21, 23-25, 27, 29, 30. Results were similar when the meta-analysis included a trial31 that evaluated triple-therapy regimens, a trial6 published only as an abstract, and 2 trials that evaluated nonstandard doses of pegylated interferon alfa-2b26, 28 or when the analysis excluded poor-quality trials24, 30.

The largest trial (n = 3070), the Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study, found no difference in likelihood of SVR for genotype 1 infection between 2 doses of pegylated interferon alfa-2b (1.0 mcg/kg per week or 1.5 mcg/kg per week) plus ribavirin, 800 to 1400 mg/d, or pegylated interferon alfa-2a, 180 mcg per week, plus ribavirin, 1000 to 1200 mg/d (range, 38% to 41%)21. Excluding IDEAL because of differential ribavirin dosing had little effect on the pooled estimate but eliminated statistical heterogeneity (6 trials; pooled RR, 0.83 [CI, 0.76 to 0.90]; I2 = 0%)23-25, 27, 29, 30.

Duration Effects

Two fair-quality trials found no difference between 48 and 24 weeks of dual therapy in the likelihood of SVR in genotype 2 or 3 infection (pooled RR, 0.97 [CI, 0.84 to 1.1]; I2= 43%)35, 43. Four trials (1 good-quality trial and 3 fair-quality trials) found that 24 weeks of dual therapy was associated with a higher likelihood of SVR than was 12 to 16 weeks (pooled RR, 1.2 [CI, 1.0 to 1.3]), but the lower limit of the CI nearly crossed 1 and statistical heterogeneity was present (I2= 80%) (Figure 1)36, 38, 40, 42. The 1 trial that found no difference (RR, 1.0 [CI, 0.93 to 1.1]) reported high overall SVR rates (94% to 95%), was restricted to genotype 2 infection, and used a somewhat different ribavirin dosing regimen42. Excluding this trial reduced statistical heterogeneity, but the estimate was similar (3 trials; pooled RR, 1.2 [CI, 1.1 to 1.3]; I2= 47%)36, 38, 40.

Three fair-quality trials of rapid virologic responders (undetectable HCV RNA by week 4) found no difference in the likelihood of SVR between 24 and 12 to 16 weeks of dual therapy (pooled RR, 0.99 [CI, 0.86 to 1.1]; I2= 66%) 34, 39, 41. Absolute differences ranged up to 10 percentage points in either direction.

Dose Effects

Lower-dose pegylated interferon alfa-2b as part of dual therapy was associated with a lower likelihood of SVR than was a higher dose (typically 1.5 mcg/kg per week) in genotype 2 or 3 infection, although the upper limit of the CI nearly crossed 1.0 (pooled RR, 0.90 [CI, 0.81 to 0.99]; I2= 20%), on the basis of 6 trials (4 fair-quality trials and 2 poor-quality trials) (Figure 1)38, 44-48. Excluding the poor-quality trials38, 47 or 1 trial that evaluated an atypical dosing regimen46 had little effect on the pooled estimate.

Two fair-quality trials found no clear difference between induction regimens of pegylated interferon alfa-2b (higher initial doses followed by lower doses) plus ribavirin versus standard fixed-dose dual therapy53, 54.

Two fair-quality trials of pegylated interferon alfa-2a found no difference between 1000 to 1200 and 800 mg of ribavirin daily (n = 492), or between 400 mg and 800 mg daily, in likelihood of SVR (n = 282)35, 49. One fair-quality trial (n = 1831) of pegylated interferon alfa-2b found no difference between ribavirin, 800 mg/d (flat dose), and 800 to 1400 mg/d (weight-dosed)51.

One fair-quality trial (n = 60) that primarily enrolled patients with advanced fibrosis or cirrhosis found pegylated interferon alfa-2a plus ribavirin, 600 to 800 mg/d, to be associated with a lower likelihood of SVR than was ribavirin, 1000 to 1200 mg/d (45% versus 72%; RR, 0.62 [CI, 0.40 to 0.98])50.

Triple Therapy

Two fair-quality trials (n = 1097 and 520) compared triple therapy with boceprevir, pegylated interferon alfa-2b, and ribavirin versus dual therapy for antiviral treatment–naive patients with genotype 1 infection (Appendix Table 3)22, 55. Seven percent to 10% of patients had cirrhosis or severe fibrosis at baseline. Methodologic shortcomings included open-label design55 or high attrition22. A 48-week boceprevir regimen (4 weeks of dual-therapy lead-in followed by 44 weeks of triple therapy) was associated with a higher likelihood of SVR than was 48 weeks of dual therapy (pooled RR, 1.8 [CI, 1.6 to 2.1]; I2= 0%), with a pooled absolute increase of 31 percentage points (CI, 23 to 39 percentage points) (Figure 2)22, 55. Other triple-therapy regimens evaluated in the trials (28 weeks with or without dual-therapy lead-in, 48 weeks without dual-therapy lead-in, or response-guided triple therapy for 28 or 48 weeks) were associated with lower or similar SVR rates compared with the 48-week regimen with lead-in.

One trial (n = 75) found that triple therapy with weight-based ribavirin, 400 to 1000 mg/d, was associated with a trend toward lower likelihood of SVR compared with triple therapy with standard-dose (800 to 1400 mg/d) ribavirin (36% versus 50%; RR, 0.71 [CI, 0.39 to 1.3])55.

Six randomized trials compared triple therapy with telaprevir, pegylated interferon, and ribavirin versus dual therapy for genotype 1 infection (Appendix Table 3)20, 31, 56-59. One trial used pegylated interferon alfa-2b57, 1 evaluated regimens with pegylated interferon alfa-2a or alfa-2b31, and the remainder used pegylated interferon alfa-2a. The prevalence of baseline cirrhosis ranged from 0% to 11%. One trial58 was rated as good quality and the remainder as fair quality. Methodologic shortcomings included open-label design or unclear blinding procedures31, 56, 59, unclear randomization methods56, 58, and unclear attrition57, 58. In all triple-therapy regimens, telaprevir was administered with pegylated interferon plus ribavirin for the first 8 to 12 weeks. For regimens longer than 12 weeks, dual therapy was continued to the end of treatment.

Three trials (n = 189 to 323) found a 24-week fixed-duration telaprevir regimen was associated with a higher likelihood of SVR than was 48 weeks of dual therapy (pooled RR, 1.5 [CI, 1.3 to 1.8]; I2= 0%) (Figure 2), with an absolute increase of 22 percentage points (CI, 13 to 31 percentage points)56-58. Excluding a trial that evaluated pegylated interferon alfa-2b instead of alfa-2a had no effect on the estimate57. Two trials found no difference between 12 weeks of triple therapy and 48 weeks of dual therapy56, 58, and 1 trial found no difference between 48 and 24 weeks of telaprevir triple therapy58.

One trial (n = 1088) found response-guided triple therapy with telaprevir (triple therapy for 8 or 12 weeks followed by dual therapy for a total of 24 or 48 weeks, depending on extended rapid virologic response) to be associated with a higher likelihood of SVR than was dual therapy for 48 weeks (RR, 1.6 [CI, 1.4 to 1.9]), with an absolute increase of 25 to 31 percentage points20.

One trial found similar SVR rates (81% to 85%) for response-guided triple-therapy regimens that varied on telaprevir dose (750 mg 3 times daily versus 1125 mg 2 times daily) and type of pegylated interferon (alfa-2a versus alfa-2b)31. Another trial of extended rapid virologic responders to initial triple therapy with telaprevir reported similar, high SVR rates with 24- and 48-week regimens (92% and 88%, respectively)59.

Effectiveness in Subgroups

In patients with genotype 1 infection, 1 trial of dual therapy with pegylated interferon alfa-2b versus alfa-2a21, 2 trials of 48 weeks of triple therapy with boceprevir and dual-therapy lead-in versus 48 weeks of dual therapy22, 55, and 2 trials of triple therapy with telaprevir (response-guided or fixed duration) versus 48 weeks of dual therapy20, 57 found no clear differences in RR estimates based on race, sex, age, baseline fibrosis, and weight. For boceprevir, the RR estimate was higher with a baseline HCV RNA viral load greater than 600 to 800,000 IU/mL (pooled RR, 2.0 [CI, 1.7 to 2.3]; I2= 0%) than with a lower viral load (pooled RR, 1.3 [CI, 1.0 to 1.5]; I2= 0%)22, 55, but there was no clear difference in RR estimates for telaprevir triple therapy versus dual therapy according to baseline viral load in 2 trials20, 57. Across regimens, absolute SVR rates were lower in older patients, black patients, patients with more advanced fibrosis, and patients with higher viral load. Four trials of dual therapy with pegylated interferon alfa-2b versus alfa-2a found no clear difference in RR estimates according to genotype, although absolute SVR rates were lower by 24% to 42% with genotype 16, 23, 24, 29.

Harms of Antiviral Treatments

Six head-to-head trials of dual therapy with pegylated interferon alfa-2b versus alfa-2a found no difference in risk for withdrawal due to adverse events (6 trials; pooled RR, 1.1 [CI, 0.73 to 1.7]; I2= 42%)21, 23, 24, 28-30. Excluding 1 outlier trial (RR, 4.2 [CI, 1.5 to 12])23 eliminated statistical heterogeneity, but the pooled estimate was similar (5 trials; pooled RR, 0.88 [CI, 0.7 to 1.1]; I2= 0%).

Two trials found dual therapy with pegylated interferon alfa-2b to be associated with lower risk for serious adverse events than was dual therapy with pegylated interferon alfa-2a (pooled RR, 0.76 [CI, 0.61 to 0.95]; I2= 0%) 21, 29. There were no differences between dual-therapy regimens in risk for anemia, thrombocytopenia, depression, fatigue, myalgia, or influenza-like symptoms (Appendix Table 4). Dual therapy with pegylated interferon alfa-2b was associated with higher risk for headache (3 trials; pooled RR, 1.1 [CI, 1.1 to 1.2]; I2= 0%)21, 23, 28 and lower risk for rash (2 trials; pooled RR, 0.79 [CI, 0.71 to 0.88]; I2= 0%)21, 28 and neutropenia (5 trials; pooled RR, 0.61 [CI, 0.46 to 0.83]; I2= 38%). In the largest study (the IDEAL trial), dual therapy with either pegylated interferon was associated with serious adverse events in about 4% of patients, fatigue in 65%, headache in 45%, nausea in 40%, myalgia in 25%, neutrophil count less than 500 cells/mm3 in 5%, and hemoglobin level less than 85 g/L in 3%21.

Excluding the low-dose pegylated interferon alfa-2b group from the IDEAL trial had little effect on pooled estimates, except that pegylated interferon alfa-2b became associated with increased risk for depression (3 trials; pooled RR, 1.2 [CI, 1.0 to 1.4]; I2= 0%)21, 23, 28. Excluding 2 poor-quality trials had little effect on pooled estimates24, 30.

Two trials found a 48-week boceprevir regimen with dual-therapy lead-in was associated with higher risk for neutropenia (pooled RR, 1.8 [CI, 1.5 to 2.3]; I2 = 0%), dysgeusia (pooled RR, 2.5 [CI, 2.0 to 3.2]; I2 = 0%), anemia (pooled RR, 2.0 [CI, 1.4 to 2.8]; I2 = 0%), and thrombocytopenia (pooled RR, 3.2 [CI, 1.2 to 8.2]; I2 = 0%) than dual therapy for 48 weeks (Appendix Table 4)22, 55. About 25% of patients receiving triple therapy experienced anemia (4% to 5% severe, defined as hemoglobin level less than 80 or less than 85 g/L) and about 33% neutropenia (8% to 15% severe, defined as neutrophil count < 500 cells/L). There were no differences in risk for withdrawal due to adverse events, serious adverse events, or other adverse events.

A 24-week regimen of triple therapy with telaprevir was associated with higher risk for anemia (3 trials; pooled RR, 1.3 [CI, 1.1 to 1.5]; I2 = 0%) and rash (3 trials; pooled RR, 1.4 [CI, 1.1 to 1.7]; I2 = 0%) than was dual therapy for 48 weeks, but there were no statistically significant differences in risk for serious adverse events, withdrawal due to adverse events, neutropenia, depression, fatigue, headache, chills/rigors, or influenza-like symptoms (Appendix Table 4)56-58. Triple therapy was also associated with increased risk for thrombocytopenia in 1 trial (RR, 1.8 [CI, 1.2 to 2.5])57. About half of the patients randomly assigned to telaprevir experienced rash (severe rash in 7% to 10%) and about half had anemia (severe anemia in 4% to 11%)56-58.

One trial found response-guided therapy with telaprevir for 24 to 48 weeks was associated with higher risk for withdrawal due to adverse events (RR, 3.8 [CI, 2.6 to 5.7]), anemia (RR, 2.0 [CI, 1.6 to 2.5]), rash (RR, 1.5 [CI, 1.2 to 1.8]), and severe rash (5% versus 1%; RR, 4.6 [CI, 1.6 to 13]) than dual therapy for 48 weeks20.

No trial reported harms in patient subgroups. Three trials of dual therapy with pegylated interferon alfa-2b versus alfa-2a for genotype 1 infection reported pooled estimates for harms similar to the estimates based on all trials21, 30, 31.

Association Between SVR and Clinical Outcomes

Nineteen cohort studies (n = 105 to 16,864) evaluated the association between an SVR after antiviral therapy and mortality or complications of chronic HCV infection (Appendix Table 5)60-78. Duration of follow-up ranged from 3 to 9 years. Ten studies were conducted in Asia60, 67-72, 75, 77, 78. Eight64-66, 72, 75-78 were rated as poor quality and the remainder as fair quality. Although all studies reported adjusted risk estimates, only 860, 21, 63, 67-70, 73 evaluated 5 key confounders (age, sex, genotype, viral load, and fibrosis stage). No study clearly described assessment of outcomes blinded to SVR status.

The largest study (n = 16,864) had the fewest methodologic shortcomings61. It adjusted for multiple potential confounders, including age, sex, viral load, presence of cirrhosis, multiple comorbid conditions, aminotransferase levels, and others. It also stratified results by genotype. In a predominantly male, Veterans Affairs population, SVR after antiviral therapy was associated with lower risk for all-cause mortality than was no SVR, after a median of 3.8 years (adjusted hazard ratio, 0.71 [CI, 0.60 to 0.86], 0.62 [CI, 0.44 to 0.87], and 0.51 [CI, 0.35 to 0.75] for genotypes 1, 2, and 3, respectively). Mortality curves began to separate as soon as 3 to 6 months after SVR assessment.

Eighteen other cohort studies also found SVR to be associated with decreased risk for all-cause mortality (adjusted hazard ratios, 0.07 to 0.39)60, 69, 72, 73, 75-78, liver-related mortality (adjusted hazard ratios, 0.04 to 0.27)60, 62, 63, 69, 70, 72, 74, 76, 77, hepatocellular carcinoma (adjusted hazard ratios, 0.12 to 0.46)60, 62, 63, 67, 68, 71, 73-76, 78, and other complications of end-stage liver disease versus no SVR, with effects larger than in the Veterans Affairs study. The subgroup of studies that focused on patients with advanced fibrosis or cirrhosis at baseline62, 63, 65-68, 74-76 or that were conducted in Asia60, 67-72, 75, 77, 78 reported similar ranges of risk estimates.

 

Discussion

Antiviral therapy for chronic HCV infection continues to evolve. No study evaluated comparative effectiveness of antiviral regimens on long-term clinical outcomes. Such trials are a challenge to carry out because of the long time course over which complications of HCV infection develop.

In lieu of direct evidence on long-term clinical outcomes, SVR rates are the primary outcome measure with which to evaluate comparative effectiveness. For treatment-naive patients, dual therapy with pegylated interferon alfa-2b is associated with a lower likelihood of SVR than is dual therapy with pegylated interferon alfa-2a (absolute difference, about 8 percentage points). Although there was no difference between dual-therapy regimens in risk for withdrawals due to adverse events, pegylated interferon alfa-2b was associated with a lower risk for serious adverse events, suggesting potential tradeoffs between benefits and harms. However, serious adverse events were reported in only 2 trials21, 29, the absolute difference was only about 1%, and antiviral-related adverse events are generally self-limited.

For genotype 2 or 3 infection, standard doses and durations (24 weeks) of pegylated interferon as part of dual therapy are more effective than shorter regimens or lower doses, lending support to current dosing guidance4, 79, 89. Evidence on differential effects of ribavirin dose is limited, although differences were small in most studies.

The relative ineffectiveness of dual therapy for genotype 1 infection has led to ongoing efforts to identify more effective treatments. Recent trials found triple therapy with boceprevir or telaprevir superior to dual therapy, with SVR rates approaching the 70% to 80% observed in trials of dual therapy for genotype 2 or 3 infection20, 22, 31, 55-59. This has important implications for treatment, as well as for screening, because screening benefits depend in part on the effectiveness of available treatments81.

Triple therapy for genotype 1 infection is also associated with shorter duration of treatment, an important consideration given the high frequency of adverse effects associated with interferon-based therapy. However, triple therapy is also associated with increased risk for hematologic adverse events (neutropenia, anemia, and thrombocytopenia) with boceprevir and anemia and rash (including severe rash in less than 10% of patients) with telaprevir, although there was no clear increase in risk for serious adverse events overall. Across all antiviral regimens, absolute treatment response rates are lower in older patients; black patients; and patients with higher baseline viral load, genotype 1 infection, or more advanced fibrosis.

The strongest evidence on the association between virologic and clinical outcomes is a large Veterans Affairs cohort study that found SVR to be associated with a 30% to 50% reduction in mortality risk, after adjustment for many confounders61. The rapid separation of mortality curves in this study suggests possible residual confounding, given the typically protracted course of HCV infection. Therefore, estimates of benefit may be exaggerated, although it is not possible to determine to what degree. Eighteen other cohort studies also found that SVR was associated with decreased risk for serious complications of chronic HCV infection, but these studies had more methodologic shortcomings than did the Veterans Affairs study.

Our study has limitations. We excluded non–English-language articles. We did not perform formal analyses for publication bias because of the small numbers of trials, but analyses of abstracts and searches of clinical trials registries did not suggest publication bias. Meta-analyses were performed by using the DerSimonian–Laird random-effects model, which results in CIs that are slightly too narrow when heterogeneity is present, so that pooled estimates with 95% CIs close to 1.0 should be interpreted cautiously82. Estimates and conclusions based on small numbers of trials should also be interpreted cautiously. For example, pooled estimates based on 2 trials can be unreliable, particularly when statistical heterogeneity is present. The trials generally met criteria for efficacy studies, which could limit their applicability because of exclusion of patients with comorbid conditions, and greater adherence than typically observed in clinical practice. Almost all of the randomized trials were funded by pharmaceutical companies83, 84.

Additional research would help clarify the comparative effectiveness of antiviral treatments. Studies are needed to understand the long-term clinical outcomes associated with different antiviral treatments, the long-term harms of telaprevir and boceprevir, the comparative effectiveness of triple therapy with telaprevir versus boceprevir, and effective strategies to improve adherence85. Other direct-acting antiviral agents, including second-generation protease inhibitors, polymerase inhibitors, NS5A inhibitors, and others are in active development, with all-oral, interferon-sparing regimens expected within the next few years86.

 

Copyright and Source Information

Source: Agency for Healthcare Research and Quality.

Acknowledgment: The authors thank Robin Paynter, MLIS; Rose Campbell, MLIS; AHRQ Task Order Officer Christine Chang, MD, MPH; and USPSTF Medical Officer Iris Mabry-Hernandez, MD, MPH. They also thank Tracy Dana, MLS; Christina Bougatsos, MPH; and Ian Blazina, MPH, from Oregon Health & Science University, who assisted in data extraction and quality checking.

Grant Support: By the Agency for Healthcare Research and Quality (Contract Number 290-2007-10057-I, Task Order 8), Rockville, Maryland.

Potential Conflicts of Interest: Dr. Chou: Grant (money to institution): AHRQ; Support for travel to meetings for the study or other purposes (money to institution): AHRQ. Dr. Hartung: Grant (money to institution): AHRQ (Institutional career development award 1K12HS019456-01). Dr. Wasson: Grant (money to institution): AHRQ. Dr. Cottrell: Grant: AHRQ. Dr. Fu: Grant (money to institution): AHRQ. Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1085.

Requests for Single Reprints: Roger Chou, MD, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, chour@ohsu.edu.

Current author addresses and author contributions are available at http://www.annals.org.

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Figure 1. Sustained virologic response, comparisons of dual-therapy regimens

 

Select Text Description below for details

Text Description.

Relative risks greater than 1 favor dual therapy with pegylated interferon alfa-2b over dual therapy with pegylated interferon alfa-2a, 24 weeks over 12 to 16 weeks, and lower-dose versus higher dose pegylated interferon alfa-2b.

Figure 2. Sustained virologic response, triple therapy with a protease inhibitor versus dual therapy.

Select Text Description below for details

Text Description.

The boceprevir regimen consisted of 4 weeks of dual-therapy lead-in with pegylated interferon alfa-2b plus ribavirin, followed by the addition of boceprevir for 44 more weeks. The telaprevir regimen consisted of 12 weeks of telaprevir, pegylated interferon alfa-2a or -2b, and ribavirin, followed by 12 weeks of dual therapy (pegylated interferon plus ribavirin without telaprevir). Relative risks greater than 1 favor triple therapy.

Appendix Figure 1. Analytic framework for treatment of hepatitis C infection in adults.

Select Text Description below for details

 

Key Questions:
1a. What is the comparative effectiveness of antiviral treatment in improving health outcomes in patients with HCV infection?
1b. How does the comparative effectiveness of antiviral treatment for health outcomes vary according to patient subgroup characteristics?
2a. What is the comparative effectiveness of antiviral treatments on intermediate outcomes on the rate of SVR?
2b. How does the comparative effectiveness of antiviral treatment for intermediate outcomes vary according to patient subgroup characteristics?
3a. What are the comparative harms associated with antiviral treatments?
3b. Do these harms differ according to patient subgroup characteristics?
4. Have improvements in SVR been shown to reduce the risk or rates of adverse health outcomes from HCV infection?

*Including but not limited to HCV genotype, age, race, sex, stage of disease, or genetic markers.

Text Description.

This analytic framework outlines the population, interventions, and outcomes considered in the review. It is a modified version of a larger framework depicting the effect of both screening for and treatment of hepatitis C in adults. This figure focuses on the treatment portion of the framework. The population includes adults with chronic hepatitis C virus (HCV) infection. The interventions include pegylated interferon alfa-2a with ribavirin or pegylated interferon alfa-2b with ribavirin, with or without the protease inhibitors telaprevir or boceprevir. Intermediate outcomes include liver function, sustained virologic remission, and histologic changes. Final outcomes include morbidity and mortality from HCV (including hepatic cirrhosis, hepatocellular carcinoma, liver transplantation rates, and quality of life) and harms of antiviral therapies (including influenza-like symptoms, hematologic effects, and psychiatric effects).

Appendix Figure 2. Summary of evidence search and selection

Select Text Description below for details

* Some studies applied to more than 1 key question. Studies of induction versus fixed-dose regimens and outcomes related to quality of life and histologic changes are not reported here but can be found in the full report.11

Text Description.

The study flow diagram summarizes the search and selection of articles for review (for key questions, see Appendix Figure 1). Reproduced from reference.11

Appendix Table 1. Summary of Evidence on Comparative Effectiveness of Treatment for Hepatitis C

Strength of Evidence of Findings* Studies Identified, n
Participants, n
Overall Quality Consistency (High, Moderate, Low) Directness (Direct or Indirect) Precision (High, Moderate, Low) Summary of Findings
Comparative effectiveness of antiviral treatments for SVR
Dual therapy with pegylated interferon α-2a plus ribavirin vs. pegylated interferon α-2b plus ribavirin
Moderate
7 randomized trials
4660
Fair High Direct High Dual therapy with standard-dose pegylated interferon α-2b associated with lower likelihood of achieving SVR than standard-dose pegylated interferon α-2a (pooled RR, 0.87 [95% CI, 0.80–0.95]; I2 = 27%), with an absolute difference of 8 percentage points (95% CI, 3–14 percentage points)
Duration effects, dual therapy with pegylated interferon plus ribavirin (genotype 2 or 3)
SVR: 48 vs. 24 wk
Moderate
2 randomized trials
609
Fair High Direct Moderate No difference in likelihood of achieving SVR (pooled RR, 0.97 [95% CI, 0.84–1.1]; I2 = 43%)
SVR: 24 vs. 12–16 wk
Moderate

 

4 randomized trials
2599

 

Fair High Direct

 

 

Moderate

 

 

24 wk of dual therapy more effective than 12–16 weeks for achieving SVR (pooled RR, 1.2 [95% CI, 1.0–1.3; I2 = 80%); RR estimates ranged from 1.0 to 1.3
SVR: 24 vs. 12–16 wk in patients with rapid virologic response
Moderate
3 randomized trials
583
Fair High Direct

 

 

Moderate

 

 

No differences between 24 vs. 12–16 wk of dual therapy (pooled RR, 0.99 [95% CI, 0.86 to 1.1]; I2 = 66%); RR estimates ranged from 0.89 to 1.1
Dose effects, dual therapy with pegylated interferon plus ribavirin (genotype 2 or 3)
SVR: Lower- vs. higher-dose pegylated interferon
Moderate
6 randomized trials
865
Fair High Direct Moderate Lower doses of pegylated interferon α-2b associated with lower likelihood of achieving SVR than higher doses (pooled RR, 0.90 [95% CI, 0.81–0.99]; I2 = 20%)
SVR: Lower- vs. higher-dose ribavirin
Moderate
3 randomized trials
2605
Fair Moderate Direct Moderate No clear difference in likelihood of SVR between lower versus higher doses of ribavirin
SVR: Lower- vs. higher-dose ribavirin, patients with advanced fibrosis or cirrhosis
Low
1 randomized trial
60
Fair Unknown (1 study) Direct Low 600–800 mg of ribavirin daily associated with lower likelihood of SVR than 1000–1200 mg daily (45% vs. 72%; RR, 0.62 [95% CI, 0.40–0.98])
Triple therapy with boceprevir for genotype 1 infection
SVR: Triple therapy with boceprevir vs. dual therapy
Moderate
2 randomized trials
1608
Fair High Direct Moderate Triple therapy with boceprevir for 48 wk associated with higher likelihood of SVR than dual therapy for 48 wk (pooled RR, 1.8 [95% CI, 1.6–2.1]; I2 = 0%), with an absolute increase in SVR rate of 31 (95% CI, 23–39) percentage points
Triple therapy with telaprevir for genotype 1 infection
SVR: 24 wk of fixed-duration triple therapy with telaprevir vs. 48 wk of dual therapy
Moderate
3 randomized trials
506
Fair High Direct Moderate Triple therapy with telaprevir for 24 wk associated with higher likelihood of SVR than dual therapy for 48 wk (pooled RR, 1.5 [95% CI, 1.3– 1.8]; I2 = 0%), with an absolute increase in SVR rate of 22 (95% CI, 13 to 31) percentage points
SVR: response-guided triple therapy with telaprevir vs. dual therapy
Low
1 randomized trial
1088
Fair Unknown (1 study) Direct Low Response-guided triple therapy with telaprevir associated with higher likelihood of SVR than dual therapy for 48 wk (RR, 1.6 [95% CI, 1.4–1.9]), with an absolute increase in SVR rate ranging from 25 to 31 percentage points
Effectiveness in patient subgroups
SVR: Effects of race, sex, age, baseline fibrosis stage, or baseline viral load
Low to moderate†
9 randomized trials
7116
Fair High (low for viral load and telaprevir) Direct Moderate to high Across regimens, absolute SVR rates were lower in older patients, black patients, patients with more advanced fibrosis, and patients with higher viral load
Harms of antiviral treatments
Harms: Dual therapy with pegylated interferon α-2b plus ribavirin vs. pegylated interferon α-2a plus ribavirin
Moderate
5 randomized trials, depending on specific harm
4047
Fair High Direct Moderate Dual therapy with pegylated interferon α-2b was associated with slightly higher risk for headache (3 trials; pooled RR, 1.1 [95% CI, 1.1–1.2]; I2 = 0%), and lower risk for serious adverse events (2 trials; pooled RR, 0.74 [95% CI, 0.57–0.95]; I2 = 0%), neutropenia (5 trials; pooled RR, 0.61 [95% CI, 0.46–0.83]), rash (2 trials; pooled RR, 0.79 [95% CI, 0.71–0.88]; I2 = 0%) than dual therapy with pegylated interferon α-2a
Harms: Triple therapy with boceprevir for 48 wk (4-wk lead-in plus 44 wk dual therapy) vs. dual therapy for 48 wk
Moderate
2 randomized trials
3501
Fair High Direct Moderate Triple therapy with boceprevir for 48 wk was associated with higher risk for neutropenia (2 trials; pooled RR, 1.8 [95% CI, 1.5– 2.3]; I2 = 0%), dysgeusia (2 trials; pooled RR, 2.5 [95% CI, 2.0–3.2]; I2 = 0%), anemia (2 trials; pooled RR, 2.0 [95% CI, 1.4–2.8]; I2 = 0%), and thrombocytopenia (2 trials; pooled RR, 3.2 [95% CI, 1.2–8.2]) than dual therapy for 48 wk
Harms: 24 wk of fixed duration triple therapy with telaprevir vs. 48 wk of dual therapy
Moderate
3 randomized trials
3591
Fair High Direct Moderate Triple therapy with telaprevir for 24 wk was associated with increased risk for anemia (3 trials; pooled RR, 1.3 [95% CI, 1.1–1.5]; I2 = 0%) and rash (3 trials; pooled RR, 1.4 [95% CI, 1.1–1.7]) versus dual therapy for 48 wk
Harms: Response-guided triple therapy with telaprevir vs. dual therapy
Low
1 randomized trial
189
Fair Unknown (1 study) Direct Low Response-guided triple therapy with telaprevir was associated with increased risk for withdrawal due to adverse events (RR, 3.8 [95% CI, 2.6–5.7]), anemia (RR, 2.0 [95% CI, 1.6–2.5]), any rash (RR, 1.5 [95% CI, 1.2–1.8]), and severe rash (RR, 4.6 [95% CI, 1.6–13]) vs. dual therapy for 48 wk
Association between SVR and clinical outcomes
Mortality and long-term hepatic complications
Moderate
19 cohort studies
27,992
Fair High Direct High One large study that controlled well for potential confounders found SVR after antiviral therapy associated with lower risk for all-cause mortality vs. no SVR (adjusted HR, 0.71 [95% CI, 0.60–0.86], 0.62 [95% CI, 0.44–0.87], and 0.51 [95% CI, 0.35–0.75] for genotypes 1, 2, and 3, respectively); 18 other cohort studies found SVR associated with decreased mortality and liver complications than no SVR but did not control as well for confounders

HCV = hepatitis C virus; HR = hazard ratio; RR = relative risk; SVR = sustained virologic response.
* Outcomes related to quality of life and histologic changes are not reported in this publication but can be found in the full report11.
† Details about strength of evidence for subgroup effects for specific drug comparisons are available in the full report11.

Appendix Table 2. Trials Comparing Dual-Therapy Regimens

Study, Year, Country (Reference)
Quality
Sample Sizes, I Cirrhosis at Baseline, % Elevated Aminotransferase Levels at Baseline, % Genotype Mix, % Weekly Pegylated Interferon Dose Daily Ribavirin Dose, mg Duration, wk Sustained Virologic Response Rate, %
Pegylated interferon α-2a plus ribavirin versus pegylated interferon α-2b plus ribavirin
Ascione et al, 2010, Italy23
Fair
A: 160
B: 160
A: 21
B: 16
100 ~60 genotype 1 or 4 A: α-2a, 180 mcg
B: α-2b, 1.5 mcg/kg
1000–1200 24–48 by genotype* A: 69
B: 54
Escudero et al, 2008, Spain24
Poor
A: 91
B: 92
Not reported 100 ~75 genotype 1 or 4 A: α-2a, 180 mcg
B: α-2b, 1.5 mcg/kg
800–1200 24–48 by genotype* A: 66
B: 62
Kamal et al, 2011, Egypt25
Fair
A: 109
B: 108
Not reported 100 100 genotype 4 A: α-2a, 180 mcg
B: α-2b, 1.5 mcg/kg
1000–1200 48 A: 71
B: 55
Khan et al, 2007, Pakistan26
Quality not assessed
A: 33
B: 33
Not reported Not reported 100 genotype 3 A: α-2a, 180 mcg
B: α-2b, 1.0 mcg/kg
800 24 A: 79
B: 82
Mach et al, 2011, Poland27
Fair
A: 138
B: 122
Not reported Not reported 100 genotype 1b A: α-2a, 180 mcg
B: α-2b, 1.5 mg/kg
1000–1200 48 A: 49
B: 44
Magni et al, 2009, Italy6
Quality not assessed
A: 100
B: 118
Not reported Not reported ~55 genotype 1 or 4 A: α-2a, 180 mcg
B: α-2b, 1.5 mcg/kg
10.5/kg 24–48 by genotype* A: 68
B: 67
McHutchison and Sulkowski, 2008 (IDEAL), USA21, 32
Fair
A: 1035
B: 1019
C: 1016
A: 10‡
B: 11
C: 11
A: 80
B: 81
C: 81
100 genotype 1 A: α-2a, 180 mcg
B: α-2b, 1.5 mcg/kg
C: α-2b, 1.0 mcg/kg
A: 1000–1200
B: 800–1400
C: 800–1400
48 A: 41
B: 40
C. 38
Miyase et al, 2012, Japan28
Fair
A: 101
B: 100
A: 20
B: 17
Not reported 100 genotype 1 A: α-2a, 180 mcg
B: α-2b, 60-150 mcg/kg (weight-based)
600–1000 48 A: 65
B: 51
Rumi et al, 2010, Italy29
Fair
A: 212
B: 219
A: 20
B: 18
A: 59§
B: 59§
~50 genotype 1 or 4 A: α-2a, 180 mcg
B: α-2b, 1.5 mcg/kg
A: 1000–1200 (genotypes 1 or 4) and 800 mg (genotypes 2 or 3)
B: 800–1200
24–48 by genotype* A: 66
B: 54
Yenice et al, 2006, Turkey30
Poor
A: 37
B: 37
Not reported (all had at least minimal fibrosis) A: 70
B: 76
100 genotype 1 A: α-2a, 180 mcg
B: α-2b, 1.5 mcg/kg
800–1200 48 A: 49
B: 35
Duration effects||
48 wk vs. 24 wk
Hadziyannis et al, 2004 (PEGASYS), worldwide35
Fair
A: 99
B: 153
C: 96
D: 144
A: 7
B: 8
C: 5
D: 7
100 38 genotype 2 or 3 α-2a, 180 mcg A: 800
B: 1200
C: 800
D: 1200
A/B: 48
C/D: 24
A/B: 75
C/D: 82
Zeuzem et al, 2004 (PEGASYS), Australia, Europe, New Zealand, North and South America43
Fair
A: 59
B: 58
A: 1
B: 0
0 28 genotype 2 or 3 α-2a, 180 mcg 800 A: 48
B: 24
A: 78
B: 72
24 wk vs. 12–16 wk
Lagging et al, 2008, Denmark and Finland35
Fair
A: 188
B: 194
A: 13
B: 13
Not reported 100 genotype 2 or 3 α-2a, 180 mcg 800 A: 24
B: 12
A: 78
B: 59
Manns et al, 2011, international53
Poor
A: 230
B: 228
Not reported 100 100 genotype 2 or 3 α-2b, 1.5 mcg 800–1400 A: 24
B: 16
A: 67
B: 57
Shiffman et al, 2007, 132 centers worldwide40
Good
A: 732
B: 733
A: 23
B: 25
100 100 genotype 2 or 3 α-2a, 180 mcg 800 A: 24
B: 16
A: 70
B: 62
Yu et al, 2007, Taiwan42
Fair
A: 100
B: 50
A: 20
B: 22
100 100 genotype 2 or 3 α-2a, 180 mcg 1000–1200 A: 24
B: 16
A: 95
B: 94
24 wk vs. 12–16 wk among those with undetectable virus by wk 4
Dalgard et al, 2008, Denmark, Sweden, Norway34
Fair
A: 150
B: 148
Not reported 100 100 genotype 2 or 3 α-2b, 1.5 mcg/kg 800–1400 A: 24
B: 14
A: 91
B: 81
Mecenate et al, 2010 (CLEO), Italy39
Fair
A: 71
B: 72
10 (overall) 100 100 genotype 2 or 3 α-2a, 180 mcg 800–1200 A: 24
B: 12
A: 75
B: 83
von Wagner et al, 2005, Germany41
Fair
A: 71
B: 71
Not reported 100 100 genotype 2 or 3 α-2a, 180 mcg 800–1200 A: 24
B: 16
A: 80
B: 82
Other duration comparisons
Andriulli et al, 2009, Italy33
Fair
A: 61
B: 59
Not reported 100 100 genotype 2 or 3 α-2a, 180 mcg A: 1000–1200 for 12 wk
B: 1000–1200 for 6 wk
12 A: 82
B: 54
Mangia et al, 2005, Italy37
Fair
A: 70
B: 213
A: 23
B: 16
100 100 genotype 2 or 3 α-2b, 1.0 mcg/kg 1000–1200 A: 24
B: 12–24**
A: 76
B: 77
Dose effects: pegylated interferon||
Higher vs. lower doses of pegylated interferon α-2b
Abergel et al, 2006, France44
Fair
A: 37
B: 41
A: 46
B: 57
100 38 genotype 2 or 3 A: α-2b, 0.75 mcg/kg
B: α-2b, 1.5 mcg/kg
800 48 A: 73
B: 73
Kawaoka et al, 2009, Japan45
Fair
A: 26
B: 27
None Not reported 100 genotype 2 or 3 A: α-2b, 1.0 mcg/kg
B: α-2b, 1.5 mcg/kg
600–1000 24 A: 39
B: 74
Krawitt et al, 2006, USA46
Fair
A: 43
B: 43
A: 17
B: 10
A: 88††
B: 88††
29 genotype 2 or 3 A: α-2b, 50 mcg
B: α-2b, 100-150 mcg
1000 48 A: 56
B: 65
Meyer-Wyss, 2006, Switzerland47
Poor
A: 55
B: 36
None 100 42 genotype 2 or 3 A: α-2b, 1.0 mcg/kg
B: α-2b, 1.5 mcg/kg
800 24–48 by genotype* A: 71
B: 81
Sood et al, 2008, India48
Fair
A: 76
B: 27
Not reported 100 100 genotype 2 or 3 A: α-2b, 1.0 mcg/kg
B: α-2b, 1.5 mcg/kg
10–12/kg 24 A: 79
B: 93
Manns et al, 2011, international38
Poor
A: 224
B: 230
Not reported 100 100 genotype 2 or 3 A: α-2b, 1.0 mcg/kg
B: α-2b, 1.5 mcg/kg
800–1400 24 A: 64
B: 67
Dose effects: ribavirin||
Ferenci et al, 2008, Austria49
Poor
A: 141
B: 141
Not reported 100 100 genotype 2 or 3 α-2a, 180 mcg A: 400
B: 800
24 A: 64
B: 69
Hadziyannis et al, 2004 (PEGASYS), worldwide35
Fair
A: 96
B: 144
C: 99
D: 153
A: 5
B: 7
C: 7
D: 8
100 38 genotype 2 or 3 α-2a, 180 mcg A/C: 800
B/D: 1000–1200
A: 24
B: 24
C: 48
D: 48
A/C: 80
B/D: 77
Helbling et al, 2006, Switzerland50
Fair
A: 31
B: 29
A: 57
B: 52
100 48 genotype 2 or 3 α-2a, 180 mcg A: 600–800
B: 1000–1200
24–48 by genotype* A: 45
B: 72
Jacobson et al, 2007 (WIN-R), USA51
Fair
A: 911
B: 920
A: 10
B: 10
100 37 genotype 2 or 3 α-2b, 1.5 mcg A: 800
B: 800–1400
24–48 by genotype* A: 60
B: 62

Cirrhosis = METAVIR (Meta-analysis of Histologic Data in Viral Hepatitis) F4, Ishak 5–6, or equivalent; Minimal or no fibrosis = METAVIR F0–F1, Ishak 0–2, or equivalent; CLEO = Club Epatologi Ospedalieri; HCV = hepatitis C virus; IDEAL = Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy; WIN-R = Weight-based dosing of pegINterferon α-2b and Ribavirin.
* Treatment duration varied according to genotype: typically 48 wk for genotype 1 or 4 and 24 wk for genotype 2 or 3.
† Published as abstract only; only included in sensitivity analysis.
‡ Severe fibrosis or cirrhosis.
§ More than 2 times the upper limit of normal.
|| Sample sizes and results are restricted to patients with genotype 2 or 3 infection.
¶ Patients who had undetectable virus by wk 4 were randomly assigned to 12 or 6 wk of ribavirin.
** Treatment for 12 wk if HCV RNA undetectable at 4 wk and for 24 wk if detectable.
†† Alanine aminotransferase level >40 IU/L.

Appendix Table 3. Trials of Triple Therapy With Boceprevir or Telaprevir, Pegylated Interferon, and Ribavirin

Study, Year, Country (Reference)
Quality
Sample Sizes, n Cirrhosis, % Elevated
Aminotransferase
Levels, %
Boceprevir or Telaprevir
Dose/Duration
Weekly Pegylated
Interferon Dose
Daily Ribavirin
Dose, mg
Duration, wk Sustained
Virologic
Response
Rate, %
Trials of triple therapy with pegylated interferon α-2b, ribavirin, and boceprevir versus dual therapy with pegylated interferon α-2b plus ribavirin
Kwo et al, 2010, SPRINT-1, USA, Canada, Europe55
Fair
A: 103
B: 107
C: 103
D: 103
E: 104  
7 overall Not reported A: 800 mg tid wk 1–48
B: 800 mg tid wk 1–28
C: 800 mg tid wk 5–48*
D: 800 mg tid wk 5–28
E: placebo
α-2b, 1.5 mcg/kg 800–1400 A: 48
B: 28
C: 48
D: 28
E: 48
A: 67
B: 54
C: 75*
D: 56
E: 38  
Poordad et al, 2011, SPRINT-2, USA and Europe22
Fair
A: 366
B: 368
C: 363
A: 11
B: 9
C: 7
A: 74
B: 80
C: 77
A: 800 mg tid wk 5–48
B: 800 mg tid wk 5–28
C: placebo
α-2b, 1.5 mcg/kg A: 600–1400 wk 5–48
B: 600–1400 wk 5–28
C: 600–1400
A: 48
B: 28/48
C: 48
A: 66*
B: 63
C: 38
Trials of triple therapy with pegylated interferon α-2b, ribavirin, and telaprevir
Hézode et al, 2009, Europe56
Fair
A: 82
B: 81
C: 78
D: 82
A: 0
B: 0
C: 1
D: 0
Not reported A: 750 mg tid wk 1–12
B: 750 mg tid wk 1–12
C: 750 mg tid wk 1–12
D: placebo
α-2a, 180 mcg A: 1000–1200
B: 1000–1200
C: placebo
D: 1000–1200
A: 12
B: 24
C: 12
D: 48
A: 60
B: 69
C: 36
D: 46
Jacobson et al, 2011, worldwide20
Good
A: 364
B: 363
C: 361
6 overall Not reported A: 750 mg tid wk 1–8
B: 750 mg tid wk 1–12
C: placebo
α-2a, 180 mcg 1000–1200 A: 24/48§
B: 24/48§
C: 48
A: 69
B: 75
C: 44
Kumada et al, 2012, Japan57
Fair
A: 126
B: 63
Not reported
(decompensated cirrhosis excluded)
Not reported A: 750 mg tid wk 1–12
B: placebo
α-2b, 1.5 mcg/kg 600–1000 A: 24
B: 48
A: 73
B: 49
Marcellin et al, 2011, Europe31
Fair
A: 40
B: 42
C: 40
D: 39
A: 2.5
B: 2.4
C: 0
D: 5.1
Not reported A: 750 mg tid wk 1–12
B: 750 mg tid wk 1–12
C: 1125 mg bid wk 1–12
D: 1125 mg bid wk 1–12
A: α-2a, 180 mcg
B: α-2b, 1.5 mcg/kg
C: α-2a, 180 mcg
D: α-2a, 1.5 mcg/kg
A: 1000–1200
B: 800–1200
C: 1000–1200
D: 800–1200
24/48 A: 85
B: 81
C: 83
D: 82
McHutchison et al, 2009, PROVE1, USA58
Fair
A: 17
B: 79
C: 79
D: 75
None Not reported A: 750 mg tid wk 1–12
B: 750 mg tid wk 1–12
C: 750 mg tid wk 1–12
D: placebo
α-2a, 180 mcg 1000–1200 A: 12
B: 24
C: 48
D: 48
A: 35
B: 61
C: 67
D: 41
Sherman et al, 2011, ILLUMINATE, USA59**
Fair
A: 162
B: 160
A: 11
B: 8
Not reported A: 750 mg tid wk 1–12
B: 750 mg tid wk 1–12
α-2a, 180 mcg 1000–1200 A: 24
B: 48
A: 92
B: 88

Ibid = twice daily; HCV = hepatitis C virus; ILLUMINATE = Illustrating the Effects of Combination Therapy with Telaprevir; PROVE = Protease Inhibition for Viral Evaluation; SPRINT = Serine Protease Inhibitor Therapy; tid = thrice daily. Cirrhosis = METAVIR (Meta-analysis of Histologic Data in Viral Hepatitis) F4, Ishak 5–6, or equivalent. Minimal or no fibrosis = METAVIR F0–F1, Ishak 0–2, or equivalent.
* Dosing recommended by the U.S. Food and Drug Administration for boceprevir in antiviral-naive patients with cirrhosis at baseline.
† Severe fibrosis or cirrhosis.
‡ Response-guided duration: 28 wk of pegylated interferon/ribavirin if HCV RNA is negative from wk 8–24. Patients not meeting these criteria continued until wk 48.
§ Response-guided duration: 24 wk of pegylated interferon/ribavirin if HCV RNA negative from week 4 through week 12. Patients not meeting these criteria continued until week 48.
‖Dosing regimen recommended by the U.S. Food and Drug Administration for telaprevir.
¶ Response-guided duration: 24 weeks of treatment with pegylated interferon/ribavirin if HCV RNA is negative from wk 4–20. Patients not meeting these criteria continued until wk 48.
** Patients with undetectable HCV RNA at wk 4 and wk 12 randomly assigned to 24 or 48 wk of dual therapy.

Appendix Table 4. Harms: Triple Therapy With Boceprevir or Telaprevir With Pegylated Interferon, and Ribavirin Versus Dual Therapy With Pegylated Interferon Alfa-2b Plus Ribavirin

Outcome Relative Risk (95% CI);
I2, %
Pooled Event Rates (95% CI), % Risk Difference (95% CI),
Percentage Points
Trials, n (References)
Intervention 1 Intervention 2
Dual therapy with pegylated interferon α-2b plus ribavirin vs. dual therapy with pegylated interferon α-2a plus ribavirin*
Serious adverse events 0.76 (0.61 to 0.95); 0 4.7 (0 to 1.3) 6.6 (1.7 to 12) −1.0 (−3.8 to 1.8) 221, 29
Withdrawal due to adverse events 1.1 (0.73 to 1.7); 42 7.7 (2.9 to 13) 6.6 (1.7 to 12) 0.8 (−2.0 to 3.6) 621, 23, 25, 28-30
Neutropenia 0.61 (0.46 to 0.83); 38 9.9 (4.5 to 15) 15 (7.4 to 22) −3.0 (−6.1 to 0.0) 521, 23, 24, 28, 29
Anemia 0.97 (0.72 to 1.3); 64 26 (5.7 to 47) 24 (7.0 to 42) 0.9 (−3.9 to 5.7) 421, 23, 28, 29
Thrombocytopenia 0.87 (0.59 to 1.3); 0 8.8 (1.1 to 16) 10 (1.7 to 19) −0.9 (−3.1 to 1.2) 323, 28, 29
Depression 1.1 (0.92 to 1.2); 0 12 (0 to 25) 12 (2.2 to 23) 0.6 (−1.9 to 3.1) 321, 23, 28
Fatigue 1.0 (0.96 to 1.1); 7 55 (40 to 69) 57 (48 to 66) 0.9 (−3.7 to 5.6) 321, 23, 28
Influenza-like symptoms 0.98 (0.85 to 1.1) 62 (56 to 68) 63 (57 to 70) −1.1 (−10 to 8.0) 229, 57
Headache 1.1 (1.1 to 1.2); 0 30 (7.2 to 53) 29 (10 to 47) 3.7 (−1.6 to 9.0) 321, 23, 28
Myalgia 1.1 (0.86 to 1.5); 33 18 (7.2 to 30) 18 (12 to 24) 1.9 (−3.8 to 7.5) 321, 23, 28
Rash 0.79 (0.71 to 0.88); 0 39 (5.4 to 72) 49 (7.5 to 90) −7.6 (−14 to −1.2) 221, 28
Triple therapy with boceprevir vs. dual therapy for 48 wk
Serious adverse events 1.4 (0.93 to 2.2) 12 (8.9 to 16) 8.5 (5.7 to 11) 3.8 (−0.7 to 8.2) 122
Withdrawal due to adverse events 1.1 (0.77 to 1.4); 0 13 (5.3 to 20) 12 (4.1 to 20) 0.8 (−3.5 to 5.2) 222, 55
Neutropenia 1.8 (1.5 to 2.3); 0 33 (29 to 38) 18 (14 to 22) 15 (9.8 to 21) 222, 55
Anemia 2.0 (1.4 to 2.8); 0 25 (0 to 67) 12 (0 to 34) 12 (−18 to 41) 222, 55
Thrombocytopenia 3.2 (1.2 to 8.2); 0 3.8 (2.1 to 5.6) 1.4 (0.2 to 2.6) 2.8 (0.8 to 4.8) 222, 55
Depression 0.87 (0.65 to 1.2) 19 (15 to 23) 22 (18 to 26) −2.9 (−8.7 to 2.9) 122
Fatigue 1.1 (0.82 to 1.5); 83 64 (50 to 77) 59 (54 to 63) 5.9 (−12 to 2.4) 222-55
Influenza-like symptoms 0.80 (0.58 to 1.1); 27 19 (11 to 27) 25 (21 to 29) −4.7 (−10 to 1.0) 222, 55
Headache 1.1 (0.96 to 1.3); 0 48 (42 to 54) 42 (38 to 47) 4.7 (−1.6 to 11) 222, 55
Myalgia 0.97 (0.76 to 1.2) 25 (21 to 30) 26 (21 to 30) −0.8 (−7.1 to 5.6) 122
Rash 1.1 (0.81 to 1.4) 24 (20 to 28) 23 (18 to 27) 1.2 (−5.0 to 7.3) 122
Dysgeusia 2.5 (2.0 to 3.2); 0 35 (20 to 50) 13 (4.6 to 22) 23 (17 to 29) 222, 55
Triple therapy with telaprevir for 24 weeks vs. dual therapy for 48 wk
Serious adverse events 1.0 (0.50 to 2.0) 16 (8.1 to 24) 16 (7.9 to 24) 0.2 (−11 to 11) 156
Withdrawal due to adverse events 1.1 (0.45 to 2.6); 60 15 (10 to 20) 14 (0 to 29) 1.0 (−11 to 13) 256, 57
Neutropenia 0.81 (0.51 to 1.3); 53 41 (0 to 94) 48 (0.4 to 96) −7.7 (−17 to 1.5) 257, 58
Anemia 1.3 (1.1 to 1.5); 0 52 (6.4 to 97) 39 (6.5 to 71) 13 (5.8 to 21) 356-58
Thrombocytopenia 1.8 (1.2 to 2.5) 64 (56 to 73) 36 (25 to 48) 28 (13 to 42) 157
Depression 1.0 (0.66 to 1.6); 0 21 (14 to 27) 20 (14 to 26) 0.4 (−8.4 to 9.3) 256, 58
Fatigue 0.96 (0.74 to 1.2); 53 51 (26 to 76) 54 (29 to 78) −2.5 (−15 to 9.8) 356, 58
Influenza-like symptoms 0.87 (0.63 to 1.2); 50 35 (15 to 55) 40 (24 to 56) −5.1 (−16 to 5.7) 356-58
Headache 0.83 (0.69 to 1.0); 0 42 (36 to 48) 52 (43 to 61) −8.8 (−18 to −0.01) 356-58
Myalgia 0.76 (0.43 to 1.3); 57 18 (7.4 to 28) 23 (17 to 28) −5.4 (−15 to 4.4) 356-58
Rash 1.4 (1.1 to 1.7); 0 49 (36 to 61) 35 (28 to 42) 14 (5.0 to 22) 356-58

RR, relative risk
* Intervention 1: interferon α-2b; intervention 2: interferon α-2a.
† Intervention 1: triple therapy with pegylated interferon and ribavirin for 48 wk with boceprevir from weeks 5 to 24; intervention 2: dual therapy for 48 wk.
‡ Intervention 1: triple therapy with telaprevir, pegylated interferon α-2, and ribavirin for 12 wk followed by dual therapy for 12 wk; intervention 2: dual therapy for 48 wk.

Appendix Table 5. Sustained Virologic Response and Clinical Outcomes Summary Results*

Study, Year, Country (Reference) Quality Study Type
Patients Analyzed, n
Duration of Follow–up Proportion with Cirrhosis: SVR vs. no SVR, %
Adjusted Hazard Ratio (95% CI) Results Adjusted for at Least Age, Sex, Viral Load, Genotype, and Fibrosis Stage, or No Association Found in Univariate Analyses
Hepatocellular Carcinoma Liver-Related Mortality All-Cause Mortality Other Clinical Outcomes
Studies of general populations of treated patients with HCV infection
Arase et al, 2007, Japan60
Fair
Retrospective cohort
500
Mean, 7.4 y
Cirrhosis: 9 vs. 16
SVR vs. no SVR: 0.19 (0.08–0.45) SVR vs. no SVR: 0.13 (0.03-0.59) SVR vs. no SVR: 0.39 (0.16-0.93) NR Yes
Backus et al, 2011, USA61
Fair
Retrospective cohort
16,864
Median, 3.8 y
Cirrhosis: 9-12 vs. 12-20
NR NR SVR vs. no SVR (genotypes 1, 2, and 3, respectively): 0.71 (0.60-0.86), 0.62 (0.44-0.87), and 0.51 (0.35-0.75) NR NR
Coverdale et al, 2004, Australia64
Poor
Prospective cohort (some patients originally enrolled in randomized trials)
343
Median, 9 y
Cirrhosis: Not reported,
Median, fibrosis score F2 (Scheuer)
SVR vs. response–relapse vs. nonresponse
Adjusted HR not reported (P > 0.05)
SVR vs. response–relapse vs. nonresponse
Liver transplant or liver-related death: Adjusted HR not reported (P = 0.20)
NR SVR vs. response–relapse vs. nonresponse
Liver-related complications:§
Adjusted HR not reported (P = 0.06)
Unclear
Imazeki et al, 2003, Japan69
Fair
Retrospective cohort
459
Mean, 8.2 y
Cirrhosis: 13 overall
NR SVR vs. no SVR: 0.11 (0.01-0.96)|| SVR vs. no SVR: 0.12 (0.01-1.3)|| NR Yes
Innes et al, 2011, UK70
Fair
Retrospective cohort
1215
Mean, 5.3 y
Cirrhosis: 10 vs. 18
NR SVR vs. no SVR: 0.22 (0.09-0.58) NR SVR vs. no SVR
Liver-related hospital episode: 0.22 (0.15-0.34)
Yes
Izumi et al, 2005, Japan71
Fair
Cohort study, appears retrospective
495
Follow-up NR
Cirrhosis: 5.1 overall
SVR vs. no SVR: 0.36 (0.04–0.83) NR NR NR Unclear
Kasahara et al, 2004, Japan 72
Poor
Retrospective cohort
2698
Mean, 6 y
Cirrhosis: 3.0 vs. 5.4
NR SVR vs. no SVR: 0.04 (0.005-0.30) SVR vs. no SVR: 0.14 (0.06-0.35) NR NR
Maruoka et al, 2012, Japan 73
Fair
Retrospective cohort
577
Mean, 9.9 y
Cirrhosis: 10 overall
SVR vs. no SVR: 0.12 (0.04–0.40)|| NR SVR vs. no SVR: 0.20 (0.08-0.54)|| NR Yes
Yoshida et al, 2002, Japan 77
Poor
Retrospective cohort
2889
Mean, 5.4 y
Cirrhosis: 6.5 vs. 11
NR SVR vs. no SVR: 0.13 (0.02-0.66)|| SVR vs. no SVR: 0.32 (0.12-0.86)|| NR No
Yu et al, 2006, Taiwan78
Poor
Retrospective cohort
1057
Mean, 5.2 y
Cirrhosis: 16 overall
SVR vs. no SVR: 0.25 (0.13–0.50)|| NR SVR vs. no SVR: 0.28 (0.08-1.0)|| NR No
Studies of populations with advanced fibrosis and cirrhosis
Bruno et al, 2007, Italy62
Fair
Retrospective cohort study
883
Mean, 8 y
Cirrhosis: All
SVR vs. no SVR: 0.39 (0.17–0.88) SVR vs. no SVR: 0.14 (0.04-0.59) NR SVR vs. no SVR
Ascites, encephalopathy, or gastrointestinal bleeding:
Not calculated, 0 events/1061 person–years vs. 107 events/5703 person–years (1.88 events/100 person-years)
No
Cardoso et al, 2010, France63
Fair
Retrospective cohort study (of patients originally enrolled in clinical trials)
307
Median, 3.5 y
Cirrhosis: 53 vs. 61
SVR vs. no SVR: 0.33 (0.23–0.89) SVR vs. no SVR: 0.27 (0.08-0.95) NR SVR vs. no SVR
Ascites or variceal bleeding: 0.21 (0.05-0.92)
Yes
Braks et al, 2007, France65
Poor
Retrospective cohort study
113
Mean, 7.7 y
Cirrhosis: All
NR NR NR SVR vs. no SVR
Clinical events (hepatocellular cancer, ascites, hepatic encephalopathy, or death): 0.14 (0.04-0.45)
No
Fernández-Rodríaguez, 2010, Spain66
Poor
Retrospective cohort study
509
Median, 35 mo
Cirrhosis: All
NR NR NR SVR vs. no SVR
Combined clinical endpoint: 0.38 (0.18-0.76)
Unclear
Hasegawa et al, 2007, Japan67 **
Fair
Retrospective cohort study
105
Median, 4.6 y
Cirrhosis: All
SVR vs. no SVR: 0.18 (0.04–0.81) NR NR NR Yes
Hung et al, 2006, Taiwan68fair Cohort study (unclear if retrospective or prospective)
132
Median, 37 mo
Cirrhosis: All
SVR vs. no SVR: 0.28 (0.09–0.92) NR NR NR Yes
Morgan et al, 2010, USA74       nsplantation: 0.17 (0.06-0.46) SVR vs. no SVR
Any liver-related outcome:†† 0.15 (0.06-0.38)
Decompensated liver disease: 0.13 (0.03-0.53)
Unclear
Shiratori et al, 2005, Japan75
Poor
Prospective cohort study of patients enrolled in randomized trials
271
Median, 6.8 y
Cirrhosis: All
SVR vs. no SVR: 0.40 (0.18–0.89)|| NR SVR vs. no SVR: 0.07 (0.01-0.56)|| NR No
Veldt et al, 2007, Europe and Canada76
Fair
Retrospective cohort
479
Median, 2.1 y
Cirrhosis: 71 vs. 77
SVR vs. no SVR: 0.46 (0.12–1.7) SVR vs. no SVR: 0.19 (0.02-1.4) SVR vs. no SVR: 0.31 (0.07-1.4) SVR vs. no SVR
Any event (death, liver failure, and hepatocellular cancer): 0.20 (0.07-0.58)
No

HCV = hepatitis C virus; HR = hazard ratio; NR = not reported; SVR = sustained virologic response; UK = United Kingdom.
* SVR defined in all studies as undetectable HCV RNA in serum 6 mo after the end of antiviral therapy, except as noted.
Study primarily evaluated patients who received pegylated interferon plus ribavirin.
SVR defined as undetectable HCV RNA on at least 2 occasions at least 2 years after completion of therapy.
§ Hepatic decompensation, complications of portal hypertension, hepatocellular carcinoma, liver transplantation, and liver-related mortality.
|| Calculated from estimates for SVR vs. untreated and no SVR vs. untreated.
Hepatic decompensation, upper gastrointestinal bleeding secondary to rupture of esophageal or gastric varices, hepatocellular carcinoma, liver transplantation, and liver-related or liver-unrelated mortality.
** Duration of undetectability to meet criteria for SVR not reported.
†† Decompensated liver disease (ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis), hepatocellular carcinoma, liver transplantation, and liver-related mortality.

Current as of: November 2012

Internet Citation: Comparative Effectiveness of Antiviral Treatment for Hepatitis C Virus Infection in Adults: A Systematic Review: Hepatitis C: Screening. U.S. Preventive Services Task Force. November 2012.
https://www.uspreventiveservicestaskforce.org/Page/Document/comparative-effectiveness-of-antiviral-treatment-for-hepatitis-c-virus-infection-in-adults-a-systematic-review/hepatitis-c-screening

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