Direct-acting antivirals for chronic hepatitis C

Area of Science:

• Hepatology
• Virology
• Clinical Trials

Background:

• Chronic hepatitis C affects millions globally, potentially leading to severe liver disease and cancer.
• Direct-acting antivirals (DAAs) are emerging treatments for hepatitis C virus (HCV), with preliminary data suggesting potential for viral eradication.
• Uncertainty remains regarding the long-term benefits, survival improvements, and complication reduction associated with DAA treatment.

Purpose of the Study:

• To evaluate the benefits and harms of direct-acting antivirals (DAAs) in individuals with chronic hepatitis C virus (HCV) infection.
• To assess the impact of DAAs on hepatitis C-related morbidity, mortality, and serious adverse events.
• To determine the effect of DAAs on quality of life and specific clinical outcomes like hepatocellular carcinoma.

Main Methods:

• Systematic review and meta-analysis of 138 randomized clinical trials involving 25,232 participants.
• Inclusion of trials comparing DAAs against placebo or no intervention, irrespective of publication status or language.
• Assessment of primary outcomes including hepatitis C-related morbidity, serious adverse events, and quality of life, alongside secondary outcomes like mortality and sustained virological response.

Main Results:

• Meta-analysis of DAAs on the market or in development showed no significant difference in hepatitis C-related morbidity or all-cause mortality compared to placebo (very low-quality evidence).
• No overall difference in serious adverse events was observed with DAAs, although simeprevir showed a potential benefit. Trial Sequential Analysis indicated futility for detecting a 20% reduction in serious adverse events.
• DAAs appeared to reduce the risk of no sustained virological response (RR 0.44, 95% CI 0.37 to 0.52), a finding confirmed by Trial Sequential Analysis, though its clinical relevance is questionable.
• Withdrawn or discontinued DAAs showed no difference in morbidity or mortality but were associated with an increased risk of serious adverse events.

Conclusions:

• Current evidence suggests DAAs on the market or in development do not significantly impact serious adverse events, with simeprevir being a potential exception.
• The clinical relevance of DAAs reducing the risk of no sustained virological response is uncertain due to its status as a non-validated surrogate outcome.
• All included trials exhibited a high risk of bias, suggesting potential overestimation of benefits and underestimation of harms. The overall quality of evidence was deemed very low.