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Full Text Available @ Annals Of Internal Medicine
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
Discussion Only
Full Text Available @ Annals Of Internal Medicine
Antiviral therapy for chronic HCV infection continues to evolve. No study evaluated comparative effectiveness of current 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 SVRpegylated 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 trials ( 21,29) , 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 guidance ( 4,79 - 80) . 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 approaching the 70% to 80% rates observed in trials of dual therapy for genotype 2 or 3 infection ( 20,22,31,55 - 59) . This has important implications for treatment, as well as for screening, because screening benefits depend in part on the effectiveness of available treatments ( 81) .
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 with boceprevir (neutropenia, anemia, and thrombocytopenia) and anemia and rash with telaprevir (including severe rash in less than 10% of patients), 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 confounders ( 61) . 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 methodological 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 cautiously ( 82) . 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 companies ( 83 - 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 adherence ( 85) . 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 years ( 86) .
Full Text Available @ Annals Of Internal Medicine
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