Objectives

The following Key Questions are the focus of our report:

Analytic Framework

The analytic framework that guided this report is shown in Figure A. The numbers in the analytic framework indicate the Key Questions listed above. The population was patients with chronic HCV infection who were receiving antiviral therapy. The interventions were dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin, or triple therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin plus a protease inhibitor approved by the FDA (either boceprevir or telaprevir). Comparisons were between different regimens, as well as between regimens including the same drugs administered at different doses or for different durations. Intermediate outcomes were sustained virologic response and hepatic histological improvement. Final outcomes were morbidity and mortality from HCV infection (including hepatic cirrhosis, HCC, and liver transplantation rates) and quality of life, as well as harms of antiviral therapies (including flulike symptoms, hematologic effects, rash, and psychiatric effects).

Figure A

Analytic framework for treatment of hepatitis C infection in adults. KQ = Key Question

Input From Stakeholders

The topic of treatment for HCV infection was nominated for a comparative effectiveness review (CER) in a public process. The Key Questions were proposed in the public nomination process and developed by investigators from the Evidence-based Practice Center (EPC) with contributions from expert Key Informants (KI), who helped refine Key Questions, identify important methodological and clinical issues, and define parameters for the review of evidence. The revised Key Questions were then posted to a public Web site for comment. The Agency for Healthcare Research and Quality (AHRQ) and the EPC agreed on the final Key Questions after reviewing the public comments and receiving additional advice from a Technical Expert Panel (TEP) convened for this report. We then drafted a protocol for this CER, which the TEP reviewed. Access it from the AHRQ Web site, where it was posted in November 2011: (www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=855).

A multidisciplinary group of clinicians, researchers, and patient advocates with expertise in hepatitis C treatment and research were selected to serve as the TEP members to provide high-level content and methodological expertise throughout the development of the review. Prior to participation in this report, the TEP members disclosed all financial or other conflicts of interest. The AHRQ Task Order Officer and the authors reviewed all of these disclosures and determined the panel members had no significant conflicts of interest that precluded participation. KIs and TEP members had expertise in hepatology, epidemiology, screening, and primary care. TEP members and other experts were invited to provide external peer review of the draft report.

Search Strategy and Study Selection

To identify articles relevant to each Key Question, a research librarian searched the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and Ovid MEDLINE^® from 1947 to April 2011 (see Appendix A for the search strategies), and a final updated search was conducted in August 2012. The search strategies were peer reviewed by another research librarian and revised prior to finalization. Unpublished trials were sought by searching clinical trial registries (ClinicalTrials.gov, Current Controlled Trials, Clinical Trial Results, WHO Trial Registries) and grants databases (NIHRePORTER, HSRProj, and AHRQ GOLD). Scientific Information Packets on unpublished and published trials were solicited from manufacturers of included antiviral drugs through the Scientific Resource Center. We also hand-searched the reference lists of relevant studies. Searches were updated before the report was finalized to identify relevant new publications.

Studies were selected according to criteria developed for inclusion and exclusion. The selection criteria were based on the Key Questions and the populations, interventions, comparators, outcomes, timing, and setting (PICOTS) approach. Papers were selected for full review if they were about chronic HCV infection, were relevant to Key Questions in the analytic framework, and met the predefined inclusion criteria. To evaluate the potential effects of publication bias, we included trials published only as conference abstracts of sensitivity analyses. We restricted inclusion to English language articles. Studies of nonhuman subjects were also excluded, and studies had to include original data.

Abstracts and full-text articles were dual reviewed for inclusion and exclusion for each Key Question. Full-text articles were obtained for all studies identified as potentially meeting inclusion criteria. Two investigators independently reviewed all full-text articles for final inclusion or exclusion, and discrepancies were resolved through discussion and consensus, with a third investigator making the final decision if necessary.

Data Extraction and Quality Assessment

We assessed the quality of each study based on predefined criteria (Appendix E). We adapted criteria from methods proposed by Downs and Black (observational studies),³⁰ the USPSTF,³¹ and the Quality Assessment of Diagnostic Accuracy Studies-2 Group.³² The criteria used are consistent with the approach recommended by AHRQ in the Methods Guide for Effectiveness and Comparative Effectiveness Reviews (Methods Guide).³³ We used the term “quality” rather than the alternate term “risk of bias.” Although both refer to internal validity, “quality” may be more familiar to most users and has potential advantages in terms of readability.

We rated the quality of each randomized trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to followup; the use of intent-to-treat analysis; and ascertainment of outcomes.³¹

We rated the quality of each cohort study based on whether it used nonbiased selection methods to create an inception cohort; whether it evaluated comparable groups; whether rates of loss to followup were reported and acceptable; whether it used accurate methods for ascertaining exposures, potential confounders, and outcomes; and whether it performed appropriate statistical analyses of potential confounders.³¹

Following assessment of individual quality criteria, individual studies were rated good, fair, or poor quality, as defined below.³³

Good-quality studies are considered likely to be valid. Good-quality studies clearly describe the population, setting, interventions, and comparison groups; use a valid method for allocation of patients to interventions; clearly report dropouts and have low dropout rates; use appropriate methods for preventing bias; and appropriately measure outcomes and fully report results.

Fair-quality studies have some methodological deficiencies but no flaw or combination of flaws judged likely to cause major bias. The study may be missing information, making it difficult to assess its methods or assess limitations and potential problems. The fair-quality category is broad, and studies with this rating vary in their strengths and weaknesses—the results of some fair-quality studies are likely to be valid, while others are only probably valid.

Poor-quality studies have significant flaws that may invalidate the results. They have a serious or fatal flaw in design, analysis, or reporting; large amounts of missing information; or discrepancies in reporting. The results of these studies are judged to be at least as likely to reflect flaws in the study design as true effects of the interventions under investigation. We did not exclude studies rated poor quality a priori, but they were considered to be the least reliable studies when synthesizing the evidence, particularly when discrepancies between studies were present.

We recorded factors important for understanding the applicability of studies, such as whether the publication adequately described the study population, how similar patients were to populations likely to be targeted by screening, whether differences in outcomes were clinically (as well as statistically) significant, and whether the interventions and tests evaluated were reasonably representative of standard practice.³⁴ We also recorded the funding source and role of the sponsor. We did not assign a rating of applicability (such as high or low) because applicability may differ based on the user of this report.

Data Synthesis and Rating the Strength of the Body of Evidence

We performed meta-analysis of trials that evaluated similar populations, interventions, comparisons, and outcomes to estimate pooled relative risks.³⁵ When present, statistical heterogeneity was explored through subgroup and sensitivity analyses, as well as qualitatively. Subgroup analyses were performed in groups stratified by HCV genotype as well as by race, age, body weight, viral load, stage/severity of disease, and IL-28b status when these data were available. We performed sensitivity analysis by excluding poor-quality studies and outlier trials, and by including results from studies published only as abstracts to evaluate the stability of estimates and conclusions. We did not perform meta-analyses for Key Question 4 because all studies were observational and had important methodologic shortcomings. These studies were synthesized qualitatively.

We rated the strength of evidence for each Key Question using the four categories recommended in the AHRQ Methods Guide.³³ We synthesized the overall quality of each body of evidence based on the type and quality of studies (graded good, fair, or poor); the precision of the estimate of effect based on the number and size of studies and confidence intervals for the estimates (graded high, moderate, or low); the consistency of results between studies (graded high, moderate, or low); and the directness of the evidence linking the intervention and health outcomes (graded direct or indirect). We did not downgrade a body of evidence for directness that evaluated an intermediate outcome if the intermediate outcome was the specific focus of the Key Question. We were not able to formally assess for publication bias due to small numbers of studies, methodological shortcomings, or differences across studies in designs, measured outcomes, and other factors.

We graded the strength of evidence for each comparison and outcome by using the four categories recommended in the AHRQ Methods Guide:³³ A “high” grade indicates high confidence that the evidence reflects the true effect and that further research is very unlikely to change our confidence in the estimate of effect and will not change the estimate. A “moderate” grade indicates moderate confidence that the evidence reflects the true effect and that further research may change our confidence in the estimate of effect and may change the estimate. A “low” grade indicates low confidence that the evidence reflects the true effect and that further research is likely to change the confidence in the estimate of effect and is likely to change the estimate. An “insufficient” grade indicates evidence either is unavailable or is too limited to permit any conclusion.

Dual Therapy Regimens with Pegylated Interferon Plus Ribavirin

In trials of treatment-naïve patients, dual therapy with pegylated interferon alfa-2b plus ribavirin was associated with a slightly lower likelihood of achieving an SVR than dual therapy with pegylated interferon alfa-2a plus ribavirin, with a difference in absolute SVR rates of about 8 percentage points.^{16–19, 36–38} In patients with genotype 2 or 3 infection, dual therapy for 12 to 16 weeks appears to be associated with a lower likelihood of SVR, compared with dual therapy for 24 weeks, with no differences between 24 weeks and longer courses of therapy.^39–44 In trials comparing different doses of dual therapy with pegylated interferon plus ribavirin, lower doses of pegylated interferon alfa-2b were less effective than standard doses,^{41, 45–49} and limited evidence found no clear differential effects of ribavirin dosing.^{39, 50}

There were no clear differences in estimates of relative effectiveness between dual therapy with pegylated interferon alfa-2a plus ribavirin versus dual therapy with pegylated interferon alfa-2b plus ribavirin in patient subgroups defined by demographic or clinical characteristics, although absolute response rates were lower in older patients, Black patients, patients with high viral load, patients with more advanced fibrosis or cirrhosis, and patients with genotype 1 infection.^{16, 17, 19, 51}

Differences in harms between dual therapy with pegylated interferon alfa-2a plus ribavirin versus pegylated interferon alfa-2b plus ribavirin were relatively small, with no differences in withdrawals due to adverse events, although dual therapy with pegylated interferon alfa-2b was associated with a lower risk of serious adverse events.^{16–19, 38, 52}

Triple Therapy Regimens With Pegylated Interferon, Ribavirin, and Either Boceprevir or Telaprevir

Trials of antiviral regimens including either boceprevir or telaprevir have been primarily conducted in patients with genotype 1 infection. Triple antiviral regimens (pegylated interferon alfa-2a or alfa-2b, ribavirin, and boceprevir or telaprevir) were associated with a substantially increased likelihood of achieving an SVR than dual therapy with pegylated interferon alfa-2a or alfa-2b plus ribavirin).^{26–28, 53–57}

Two trials found triple therapy with boceprevir for 48 weeks (dual therapy with pegylated interferon alfa-2b plus ribavirin for 4 weeks followed by 44 weeks of triple therapy with the addition of boceprevir) was associated with a higher likelihood of SVR than dual therapy with pegylated interferon alfa-2b plus ribavirin for 48 weeks (pooled relative risk [RR] 1.81, 95% confidence interval [CI] 1.58 to 2.06, I²=0.0%) with an absolute increase in SVR rate of 31 percentage points (95% CI 23 to 39).^{26, 28}

Three trials found triple therapy with telaprevir for 24 weeks (pegylated interferon alfa-2a, ribavirin, and telaprevir triple therapy for 12 weeks followed by 12 weeks of pegylated interferon alfa-2a plus ribavirin without telaprevir) was associated with a higher likelihood of SVR than dual therapy with pegylated interferon alfa-2a plus ribavirin for 48 weeks (pooled RR 1.48, 95% CI 1.26 to 1.75, I²=0.0%), with an absolute increase in SVR rate of 22 percentage points (95% CI 13 to 31).^{27, 53, 55} One trial found response-guided telaprevir triple therapy (8 or 12 weeks of pegylated interferon alfa-2a, ribavirin, and telaprevir followed by 12 or 36 weeks of response-guided dual therapy with pegylated interferon alfa-2a plus ribavirin) was associated with a higher likelihood of SVR than dual therapy with pegylated interferon alfa-2a plus ribavirin for 48 weeks (RR 1.6, 95% CI 1.4 to 1.9), with an absolute increase in SVR rate of 25–31 percentage points.⁵⁴

Relative estimates of the effects of triple therapy with either boceprevir or telaprevir, compared with dual therapy, were similar across subgroups, except in patients with low viral load, in whom triple therapy was no more effective than dual therapy in achieving an SVR. Triple therapy with boceprevir was associated with increased risk of hematological adverse events and triple therapy with telaprevir with increased risk of anemia and rash (including severe rash) than dual therapy; adverse events were generally self-limited with discontinuation of therapy.^{26, 28} All antiviral regimens were associated with a high incidence of flulike symptoms, with small or no clear differences in risk.

Sustained Virologic Response After Antiviral Therapy and Clinical Outcomes

A large cohort study that was well controlled for confounders found that patients with an SVR after antiviral therapy had a lower risk of all-cause mortality than patients with no SVR (adjusted hazard ratio estimates 0.51 to 0.71).⁸ Eighteen other cohort studies also found SVR associated with reduced risk of all-cause mortality, liver-related mortality, and other hepatic complications rather than no SVR, but had more methodological shortcomings.^{9, 58–74} Ten of the studies were conducted in Asian countries and might not be directly applicable to U.S. populations.

Key Findings and Strength of Evidence

The evidence reviewed in this study is summarized in Table A. The specific domain scores used to determine the overall strength of evidence for each body of evidence are shown in Appendix G. We identified no studies that evaluated comparative effectiveness of current antiviral regimens on long-term clinical outcomes such as mortality, complications of chronic HCV infection, or quality of life. Such trials would be difficult to design and carry out due to the long time required for complications of chronic HCV infection to develop in most patients.

Table A

Summary of evidence on comparative effectiveness of treatment for hepatitis C.

Dual Therapy Regimens With Pegylated Interferon and Ribavirin

In lieu of direct evidence on long-term clinical outcomes, SVR rates are the primary outcome to assess comparative benefits of different antiviral regimens. In trials of treatment-naïve patients, the likelihood of achieving an SVR was slightly lower with dual therapy with pegylated interferon alfa-2b plus ribavirin compared with dual therapy with pegylated interferon alfa-2a plus ribavirin (pooled RR 0.87, 95% CI 0.80 to 0.95; I²=27.4%), with a difference in absolute SVR rates of about 8 percentage points. Although the largest study, the Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) trial, found no difference in SVR rates for dual therapy with pegylated interferon alfa-2a plus ribavirin compared with dual therapy with pegylated interferon alfa-2b plus ribavirin, excluding the IDEAL trial from pooled analyses, resulted in similar effect estimates.¹⁸ Although there was no difference between types of dual therapy regimens in risk of withdrawals due to adverse events, dual therapy with pegylated interferon alfa-2b plus ribavirin was associated with a lower risk of serious adverse events than dual therapy with pegylated interferon alfa-2a plus ribavirin (pooled RR 0.76, 95% CI 0.71 to 0.88, I²=0.0%), suggesting a potential tradeoff between greater benefits and greater harms. However, serious adverse events were only reported in two trials,^{18, 19} and the rate of serious adverse events was relatively low (about 4 percent overall in IDEAL), with an absolute difference of about 1 percent, and adverse events with antiviral treatments generally resolve following discontinuation of therapy. Trials found no clear difference in estimates of relative effectiveness of dual therapy with pegylated interferon alfa-2a plus ribavirin compared with dual therapy with pegylated interferon alfa-2b plus ribavirin in patient subgroups stratified by age, sex, race, viral load, fibrosis stage, and genotype, although absolute response rates were lower in older patients, Black patients, patients with high viral load, patients with more advanced fibrosis or cirrhosis, and patients with genotype 1 infection.^{16–19, 51} SVR rates ranged from 24 to 42 percent lower in patients with genotype 1 infection compared with patients with genotype 2 or 3.

In patients with genotype 2 or 3 infection, dual therapy for 12 to 16 weeks appears to be associated with a lower likelihood of SVR compared with dual therapy for 24 weeks, with no differences between 24 weeks and longer courses of therapy.^39–44 Standard doses of pegylated interferon alfa-2b were more effective than lower doses (no trials compared different doses of pegylated interferon alfa-2a).^{41, 45–49} Although trials comparing different ribavirin doses found no clear differences, they evaluated different dose comparisons, precluding firm conclusions.^{39, 50, 75, 76}

Triple Therapy Regimens With Pegylated Interferon, Ribavirin, and Either Boceprevir or Telaprevir

Trials of triple therapy regimens with the protease inhibitors boceprevir or telaprevir (both approved by the FDA in 2011) in treatment-naïve patients with genotype 1 infection found each associated with substantially higher SVR rates than standard dual therapy without a protease inhibitor. SVR rates with triple therapy were similar to the 70–80 percent observed with dual therapy in patients with genotype 2 or 3 infection.^{23, 26–28, 53–57, 77} Trials that evaluated the telaprevir regimen recommended by the FDA (12 weeks of triple therapy with telaprevir followed by response-guided duration of 12 or 36 weeks of dual therapy) reported SVR rates of 75–80 percent.^{54, 56} Trials that evaluated the boceprevir regimen recommended by the FDA for antiviral-naïve patients with cirrhosis (4 weeks of dual therapy lead-in followed by 44 weeks of triple therapy with boceprevir) reported SVR rates of 66–75 percent.^{26, 28} Trials that evaluated other regimens in antiviral naïve patients, including fixed duration telaprevir regimens, shorter fixed duration triple therapy boceprevir therapy, and boceprevir without dual therapy lead-in, reported similar or lower SVR rates.

As with the head-to-head trials of dual therapy with pegylated interferon alfa-2a plus ribavirin compared with pegylated interferon alfa-2b plus ribavirin, RR estimates for triple, compared with dual, therapy were similar (or there were no clear differences) in patient subgroups based on age, sex, or race, although absolute SVR rates were lower in older patients and Black patients. In two trials, triple therapy with boceprevir was no more effective than dual therapy in the subgroup of patients with lower HCV-RNA viral load (<600,000 or <800,000 IU/mL),^{26, 28} but two trials of triple therapy with telaprevir were inconsistent in showing differential effects depending on baseline viral load.^{54, 55} There was insufficient evidence to evaluate relative effectiveness of triple, compared with dual, therapy based on fibrosis stage.

In addition to a higher likelihood of SVR, another advantage of triple therapy regimens in patients with genotype 1 infection is the potential for a shorter duration of treatment (24 or 28 weeks in patients with early virologic response, compared with the standard 48 weeks of dual therapy with pegylated interferon plus ribavirin). Shorter courses of treatment would probably be appealing to patients, given the frequency of bothersome flulike symptoms associated with interferon-based therapy. On the other hand, triple therapy regimens were associated with increased risk of certain harms, in particular hematological adverse events (neutropenia, anemia, and thrombocytopenia) with boceprevir, and anemia and rash (including severe rash in up to about 10 percent of patients, which could result in treatment discontinuation) with telaprevir. However, there was no clear increase in risk of serious adverse events or overall withdrawal due to adverse events with use of protease inhibitors, and the adverse events appear to be self-limited following drug discontinuation.

Sustained Virologic Response After Antiviral Therapy, and Clinical Outcomes

The strongest evidence on the association between an SVR after antiviral therapy and improved clinical outcomes is a large U.S. Department of Veterans Affairs (VA) cohort study (n=16,864) that adjusted for many confounders and found decreased risk of all-cause mortality compared with no SVR across patient groups stratified by genotype (adjusted hazard ratio [HR] 0.71 [0.60–0.86], 0.62 [0.44–0.87] and 0.51 [0.35–0.75] for genotypes 1, 2, and 3, respectively).⁸ Despite controlling for important confounders, the possibility of residual confounding is suggested by the very rapid separation of mortality curves for people with an SVR versus those without an SVR, which was observed at 3 months after assessment for SVR. This is more rapid than expected given the typically prolonged natural history of HCV infection. Therefore, estimates of effects of SVR on clinical outcomes from this study may be exaggerated, although it is not possible to determine to what degree. Eighteen other cohort studies also found an SVR after antiviral therapy associated with decreased risk of all-cause mortality and complications of chronic HCV infection, including studies specifically of patients with baseline cirrhosis, but had more methodological shortcomings. In addition, 10 of the 19 studies were conducted in Asia, where the incidence of HCC in patients with chronic HCV infection is higher than in the United States,⁷⁸ potentially limiting their generalizability. Other studies found an SVR after antiviral therapy associated with better scores on measures of quality of life than with no SVR, but those studies focused on short-term outcomes and typically did not adjust for confounders or blind patients to SVR status when assessing outcomes.

Findings in Relationship to What Is Already Known

Our findings regarding the comparative effectiveness of dual therapy with pegylated interferon alfa-2b plus ribavirin compared with dual therapy with pegylated interferon alfa-2a plus ribavirin are consistent with recent systematic reviews that also found the former associated with a lower likelihood of SVR.^{14, 79} Our findings of no clear difference in comparative effectiveness between 12 to 16 weeks compared with 24 weeks of response-guided dual therapy with pegylated interferon plus ribavirin in hepatitis C genotype 2 or 3 infection with rapid virologic response are discordant with a recent systematic review, which found a shorter duration of treatment associated with a lower likelihood of achieving an SVR.⁸⁰ The discrepancy may be explained by the inclusion in the other systematic review of a study that we excluded because it evaluated a nonstandard dose of pegylated interferon,⁸¹ as well as its inclusion of subgroup analyses from trials of patients randomized to different fixed durations of therapy prior to assessment of rapid virologic response,^{40, 42, 43} which we considered separately because they did not represent randomized comparisons of response-guided treatment.

Because telaprevir and boceprevir are so new, we are unaware of other published systematic reviews on the comparative benefits and harms of regimens including these drugs, compared with standard dual therapy. Our findings on the association between achieving an SVR and reduced risk of mortality or complications associated with chronic HCV infection are consistent with a recent review that used some systematic methods.⁸²

Applicability

The trials included in this review generally met criteria for efficacy studies based on the exclusion of patients with common comorbidities (such as serious psychiatric conditions or recent or ongoing substance abuse). In addition, the trials may have overestimated efficacy compared with what would be seen in typical practice due to improved adherence as a result of closer followup, effects of trial participation, selection of patients, or other factors. A separate review funded by AHRQ will be focusing on issues related to the screening for HCV infection in adults. ²⁹

The severity of baseline liver disease in the patients enrolled in the trials suggests a broad range of patients were enrolled. In trials of triple therapy with boceprevir or telaprevir, the proportion of patients with cirrhosis at enrollment ranged from <1 to 11 percent.^{26–28, 53, 54, 56, 57} Trials that reported the proportion of patients with minimal or no fibrosis reported rates of 27–39 percent.^{27, 53, 54, 56, 57}

Evidence to evaluate potential differences in comparative benefits or harms in patient subgroups based on age, sex, race, and other clinical factors was relatively limited, precluding strong conclusions in these specific subgroups. The strongest evidence on the association between an SVR versus no SVR after antiviral therapy and reduced mortality comes from a study performed in a VA population, which might limit generalizability to other settings.⁸ As described above, studies conducted in Asia on the association between an SVR after antiviral therapy and risk of clinical outcomes may be of limited applicability to U.S. populations because of a higher incidence of HCC in Asian patients with chronic HCV infection.⁷⁸ However, the incidence of HCC is increasing in the United States in HCV-infected people,⁸³ which may attenuate such concerns regarding applicability.⁷⁸

The results of this CER are not applicable to populations excluded from the review, including patients previously treated with antiviral therapies and excluded populations such as patients with Human immunodeficiency virus (HIV) coinfection, post-transplant patients, or hemodialysis patients. Antiviral therapy is not recommended in patients following kidney transplant, and ribavirin is not recommended in those with more severe (stage 3 to 5) kidney disease since it is cleared via renal function and associated with increased risk of hemolytic anemia in this setting.⁸⁴ Such patients were typically excluded from randomized trials of antiviral treatment.

Implications for Clinical and Policy Decisionmaking

Our review has potential implications for clinical and policy decisionmaking. For patients with genotype 1 infection, triple therapy regimens with pegylated interferon alfa-2a or alfa-2b, ribavirin, and telaprevir or boceprevir may be considered an alternative to dual therapy with pegylated interferon alfa-2a or alfa-2b plus ribavirin as standard treatment due to substantially superior efficacy for achieving SVR compared with dual therapy with pegylated interferon alfa-2a or alfa-2b, as well as a shorter duration of treatment. Factors that may affect decisions to use regimens with boceprevir or telaprevir include cost and specific harms associated with use of these drugs (such as hematologic adverse events with boceprevir and anemia and rash with telaprevir). Dual therapy with pegylated interferon alfa-2a plus ribavirin appears to be associated with a higher likelihood of achieving SVR compared with dual therapy with pegylated interferon alfa-2b plus ribavirin, but absolute differences were relatively small. Therefore, decisions about which pegylated interferon to use may be affected by other considerations, such as cost, patient preferences, or other factors. For genotype 2 or 3 infection, standard doses and duration (24 weeks) of pegylated interferon as part of dual therapy are more effective than shorter regimens or lower doses, lending support to dosing guidance from the FDA and clinical practice guidelines.^{11, 85, 86} Evidence on differential effects of ribavirin dose are too limited to draw strong conclusions about optimal dosing of this component of antiviral regimens, although differences appeared relatively small.

The findings that absolute SVR rates are lower in certain subgroups (such as older patients, Black patients, patients with worse baseline fibrosis, and patients with high viral load) can be used to guide individualized decisionmaking. Patients who are less likely to achieve an SVR may make different informed decisions about therapy compared with those more likely to achieve an SVR, given the adverse effects associated with treatment.

The findings of the review are also relevant to screening recommendations, which are based in part on the effectiveness of treatments in people found through screening to have HCV infection. Important new evidence that may affect assessments regarding potential benefits of screening include stronger evidence on the link between achieving an SVR and improvement in clinical outcomes, as well as evidence showing substantially higher SVR rates with newer triple therapy regimens with boceprevir or telaprevir in patients with genotype 1 infection, the predominant type of HCV infection in the United States.

Limitations of the Comparative Effectiveness Review Process

Our review had some potential limitations. We excluded non–English-language articles, which could result in language bias, although a recent systematic review found little empirical evidence that exclusion of non–English-language articles leads to biased estimates for noncomplementary or alternative medicine interventions.⁸⁷

We did not formally assess for publication bias with funnel plots due to small numbers (<10) of studies for all comparisons. Small numbers of studies can make interpretation of funnel plots unreliable, and experts suggest 10 studies as the minimum number of studies to perform them.⁸⁸ We included some studies that were published only as abstracts and found their inclusion or exclusion from analyses did not change conclusions. In addition, we searched trial registries and solicited drug manufacturers for additional unpublished trials and identified none.

Another potential limitation is that we included cohort studies to evaluate the association between SVR and either mortality or hepatic complications associated with chronic HCV infection. Such studies are susceptible to confounding if factors associated with SVR (such as age, race, viral load, or fibrosis stage) are also associated with these outcomes. Therefore, we only included studies that reported adjusted risk estimates, and we evaluated how well studies addressed key potential confounders as part of our quality assessment. Nonetheless, residual confounding is a possibility, even in cohort studies that adjust for potential confounding.

Limitations of the Evidence Base

We identified several important limitations of the evidence base. First, studies assessing important long-term clinical outcomes associated with current antiviral treatments for chronic HCV infection are not available. In the case of antiviral regimens involving newly approved antiviral drugs, such studies are not possible yet because of the extended followup required to adequately evaluate effects on clinical outcomes. Second, no trials directly compared regimens with boceprevir with regimens with telaprevir. Given the increased efficacy of these regimens for genotype 1 infection, trials directly comparing their effects would be helpful for guiding health care providers’ treatment choices between these drugs. Third, few trials have evaluated the regimens approved specifically by the FDA for these drugs, limiting confidence in conclusions regarding estimates of benefits and harms for the regimens likely to be used in clinical practice. Fourth, few methodologically rigorous studies conducted in settings applicable to U.S. populations evaluated the association between achieving an SVR and improvements in clinical outcomes. Such studies would be very helpful for confirming the results of the recent large, well-conducted VA cohort study showing an association between achieving an SVR and reduced mortality risk.⁸

Future Research

Evaluating the comparative effectiveness of current antiviral regimens on clinical outcomes in randomized trials or cohort studies is a challenge due to the long lead time and large sample sizes necessary to adequately assess these outcomes. This might be more feasible if the studies were to focus on populations at higher risk for complications from chronic HCV infection (e.g., patients with baseline cirrhosis, high viral load, or other risk factors for progression).

For all trials of antiviral treatments, studies that enroll broader populations with medical and psychological comorbidities, as frequently encountered in clinical practice, are needed to better understand comparative effectiveness, rather than just comparative efficacy. Studies designed using an effectiveness paradigm would also be helpful for understanding real-world outcomes of antiviral regimens, including effects related to the poorer treatment adherence than expected from efficacy trials.

Trials directly comparing triple therapy with telaprevir compared with triple therapy with boceprevir would be very helpful for understanding comparative effectiveness of these two protease inhibitors. In addition, trials evaluating the boceprevir regimen recommended by the FDA in antiviral-naïve patients without baseline cirrhosis are needed to verify that results from studies of previously treated patients were appropriately generalized. Prolonged followup of patients exposed to telaprevir and boceprevir is needed to understand the long-term harms associated with these medications. A number of other protease inhibitors and other newer drugs for treatment of hepatitis C virus infection are currently in active development, and further studies with new drugs and drug regimens are expected, including regimens without interferon.⁸⁹

It is critical that future studies that evaluate clinical outcomes in patients with an SVR versus no SVR after antiviral therapy adequately control for other factors that influence clinical outcomes in chronic HCV infection. Studies on effects of achieving an SVR on long-term quality of life would be very helpful for understanding other potential clinical benefits of antiviral therapy, but a significant challenge is whether it is possible to ethically blind patients to virologic status, which may have an important effect on assessments of quality of life.