Direct-acting antivirals for chronic hepatitis C

Area of Science:

• Hepatology and Viral Gastroenterology
• Clinical Pharmacology and Therapeutics
• Evidence-Based Medicine and Systematic Reviews

Background:

• Chronic hepatitis C (HCV) affects millions globally, posing risks of severe liver disease, liver cancer, and mortality.
• Direct-acting antivirals (DAAs) are emerging, expensive treatments for HCV, with preliminary data suggesting potential for viral eradication (sustained virological response, SVR).
• SVR is currently used as a surrogate for morbidity and mortality outcomes, but this lacks validation from randomized trials.

Purpose of the Study:

• To systematically assess the benefits and harms of direct-acting antivirals (DAAs) in adult patients with chronic hepatitis C (HCV).
• To evaluate the impact of DAAs on primary outcomes including hepatitis C-related morbidity, serious adverse events, and health-related quality of life.
• To investigate secondary outcomes such as all-cause mortality and specific liver-related complications.

Main Methods:

• Conducted a comprehensive search for randomized clinical trials (RCTs) of DAAs versus placebo or no intervention in adults with chronic HCV, including unpublished and ongoing trials.
• Included 138 RCTs with 25,232 participants, evaluating 51 different DAAs, with a focus on trials assessing SVR, morbidity, mortality, and adverse events.
• Employed rigorous systematic review methodology, including risk of bias assessment, Trial Sequential Analysis, and GRADE evaluation for evidence quality.

Main Results:

• DAAs on the market or in development showed a low-quality evidence of reducing the risk of no SVR (from 54.1% to 23.8%).
• Very low-quality evidence suggests DAAs do not significantly influence serious adverse events, though simeprevir showed a potential reduction.
• Insufficient evidence exists to determine the effects of DAAs on hepatitis C-related morbidity, all-cause mortality, and other clinical outcomes due to short trial durations and high risk of bias.

Conclusions:

• Current evidence from short-term trials is insufficient to determine the long-term clinical benefits or harms of DAAs for chronic HCV.
• While DAAs may increase SVR rates, their impact on long-term clinical outcomes like morbidity and mortality remains uncertain and requires validation.
• Further high-quality, long-term randomized trials are essential to validate SVR as a surrogate outcome and fully understand the clinical utility of DAAs.