This complex well-conducted review assessed the benefits and harms of anti-viral drug treatments for patients with previously untreated hepatitis C. The authors’ main conclusion was that for genotype 1 viral infection, a new three-drug treatment increased likelihood of sustained virological response compared with standard dual therapy. This conclusion appears reliable but is based on relatively few trials.

To compare the benefits and harms of anti-viral regimens for chronic hepatitis C virus infection in treatment-naive adults. A further objective (not covered in this abstract) was to examine the association between intermediate outcomes and final clinical outcomes.

MEDLINE, The Cochrane Library (including DARE), EMBASE and PsycINFO were searched from inception up to August 2012. Search strategies were reported. Four clinical trial registries and three grant databases were searched. Manufacturers were contacted for published and unpublished trial information. References of relevant studies were checked. Only English language papers were considered for inclusion.

Eligible for inclusion were randomised trials that compared: dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin; or triple therapy with pegylated interferon (alfa-2a or alfa-2b), ribavirin, and either boceprevir or telaprevir (protease inhibitors). The population of interest was previously untreated adults with chronic hepatitis C virus infection. In addition to harms of antiviral therapies, trials were required to report at least one of the following clinical outcomes: sustained virological response; hepatic histological improvement; morbidity and mortality from hepatitis C virus infection (including hepatic cirrhosis, hepatocellular carcinoma, and liver transplantation rates); and quality of life.

Included studies compared dual therapy interferon alfa-2a plus ribavirin versus dual therapy interferon alfa-2b plus ribavirin (with some studies looking at different dosages of the interferon or ribavirin duration of treatment, or only patients with genotype 1, 2 or 3 infection). A further set of trials compared triple therapy (boceprevir or telaprevir, interferon alfa-2a or alfa-2b plus ribavirin) with dual therapy in patients with genotype 1 infection. Baseline prevalence of cirrhosis ranged from 0 to 20% across all trials. One trial primarily enrolled patients with advanced fibrosis or cirrhosis. Full details were presented in the appendices to the main report.

Two reviewers independently selected studies for inclusion; disagreements were resolved by discussion and recourse to a third reviewer where necessary.

An adaptation of a validated tool was used to assess study quality covering 11 key criteria for controlled trials. Based on these individual criteria, each study was rated overall as good, fair or poor quality (defined in detail in the full report).

Two reviewers independently assessed study quality; disagreements were resolved by discussion and recourse to a third reviewer where necessary.

One reviewer extracted the data to derive risk ratios (RR) with associated 95% confidence intervals (CI). A second reviewer checked the data extraction for accuracy.

A random-effects DerSimonian-Laird model was used to estimate pooled relative risks. Heterogeneity was assessed using the Q-statistic and Ι²; it was also explored using subgroup and sensitivity analyses, as well as narratively.

Pre-specified groupings of interest included: hepatitis C genotype, age, race, body weight, viral load and severity of the disease.

The overall strength of evidence for each comparison was assessed using AHRQ guidance based on type and quality of studies, consistency of results, directness of the evidence, and precision of the estimate of effect. This resulted in an overall grading of high, moderate, low or insufficient for the evidence around each conclusion (definitions provided in the full report).

Publication bias was considered but not formally assessed due to the small number of studies included.

More than 90 studies were included in the review; the total number of participants was unclear.

Longer term health outcomes

No trials were identified that evaluated long-term clinical outcomes (mortality, complications of chronic hepatitis C infection or quality of life). Three trials compared current antiviral regimes and found no differences in risk of short-term mortality, although very few events were reported (low strength of evidence). One RCT measured short-term quality of life and found small, statistically significant improvements for patients who receiving dual therapy with pegylated interferon alfa-2a plus ribavirin compared with pegylated interferon alfa-2b plus ribavirin (strength of evidence was low).

Dual therapy with interferon alfa-2a or alfa-2b plus ribavirin

Seven trials found that interferon alfa-2b dual therapy reduced the likelihood of achieving a sustained virological response (RR 0.87, 95% CI 0.80 to 0.95; Ι²=27%; moderate strength of evidence) compared with interferon alfa-2a dual therapy. Further results were reported exploring differences in population, duration and dosage of treatments.

Triple therapy with interferon, ribavirin plus protease inhibitor (boceprevir) versus dual therapy with interferon plus ribavirin

Two trials in patients with genotype 1 infection found triple therapy with boceprevir more effective in achieving a sustained virologic response than dual therapy with interferon alfa-2b plus ribavirin (RR 1.81, 95% CI 1.58 to 2.06; Ι²=0%; moderate strength of evidence).

Three trials in patients with genotype 1 infection found triple therapy with telaprevir (interferon alfa-2a) followed by dual therapy more effective than dual therapy (interferon alfa-2a) in producing a sustained virologic response (RR 1.48, 95% CI 1.26 to 1.75; Ι²=0%; moderate strength of evidence). Further results were reported exploring differences in combination, duration and dosage of treatments.

Harms of antiviral treatments

Dual therapy with interferon alfa-2b was associated with slightly (but statistically significantly) greater risk of headache (three trials), lower risk of serious adverse events (2 trials), lower risk of neutropenia (5 trials) and lower risk of rash (2 trials) compared with interferon alfa-2a dual therapy. There were no significant differences in withdrawals from trials due to adverse events.

Triple therapy with boceprevir (interferon alfa-2b) was associated with increased risk of neutropenia (two trials), dysgeusia (taste sense distortion; two trials), anaemia (two trials) and thrombocytopenia (two trials) compared with interferon alfa-2b dual therapy. The strength of evidence was moderate.

Triple therapy with protease inhibitor telaprevir (interferon alfa-2a) was not associated with any increased risks compared with interferon alfa-2a dual therapy (two trials). The strength of evidence was moderate.

Triple therapy with telaprevir (interferon alfa-2a or 2b) followed by dual therapy was associated with increased risk of anaemia (three trials) and rash (three trials) compared with interferon alfa-2a dual therapy. The strength of evidence was moderate.

Further results were given in the full report.

Sustained virological response rates in patients with genotype 1 infection were higher with an interferon triple therapy that included a protease inhibitor (boceprevir or telaprevir) than for standard interferon dual therapy (plus ribavirin).

This complex review addressed several clear clinical questions with appropriate inclusion and exclusion criteria. The search was fairly comprehensive, but only English language papers were included; it was not clear how many papers were excluded based on language (whether bias was introduced). The review processes were rigorous and reduced the chances of reviewer error/bias.

The included studies were described and quality assessed was according to standard criteria. The analysis appears to have been appropriate, exploring relevant patient characteristics, trial level variables and quality of the studies. Some of the subgroup analyses (a large number were performed) were based on small numbers of trials and patients, so the results may not be considered as conclusive.

This was a well-conducted review that drew a number of cautious conclusions that appear to be consistent with the evidence presented. The main conclusion (about the benefits of triple therapy for genotype 1 viral infections) appears reliable but is based on relatively few trials.

Practice: The authors stated that triple therapy was a valid alternative to dual therapy; the choice of protease inhibitor should be guided by factors such as cost and concern over specific adverse events.

Research: The authors suggested that studies were needed to explore the long-term clinical outcomes associated with different anti-viral treatments, long-term harms of telaprevir and boceprevir, comparative effectiveness of triple therapy with telaprevir versus boceprevir, and to determine effective strategies to improve adherence.

Agency for Healthcare Research and Quality (AHRQ) Contract, UK.

Chou R, Hartung D, Rahman B, Wasson N, Cottrell E, Fu R. Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: a systematic review. Annals of Internal Medicine 2012:November 27.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.