An article published in The Guardian on June 8, 2017, led with the startling headline that “‘Miracle’ hepatitis C drugs costing £30k per patient ‘may have no clinical effect’”. The article was reporting on a Cochrane review of randomised clinical trials of direct-acting antivirals (DAAs) for individuals with chronic hepatitis C virus (HCV) infection, which concluded that “DAAs on the market or under development do not seem to have any effects on risk of serious adverse events [but] we could neither confirm nor reject that DAAs had any clinical effects”. Given the excitement surrounding the development of DAAs, which form the bedrock on which efforts to eliminate HCV by 2030 are based, what is the basis for these surprising conclusions?
The primary outcomes of the Cochrane review were hepatitis C-related morbidity, serious adverse events, and quality of life; secondary outcomes included all-cause mortality, various common sequelae of advanced liver disease (eg, ascites, variceal bleeding, etc), and sustained virological response (SVR; defined as achieving undetectable HCV RNA over a certain period of time after treatment). However, a close look at the review reveals that no data were available for hepatitis C-related morbidity and only 16 deaths from any cause were reported among nearly 3000 patients included in that analysis, rendering interpretation of these endpoints essentially meaningless. Likewise, only one study among the 138 identified by the review reported on the effect of DAAs on quality of life, making assessment impossible. Meta-analysis showed no difference between those treated with DAAs compared with controls in terms of the risk of serious adverse events (odds ratio 0·93, 95% CI 0·75–1·15), whereas treatment with DAAs significantly reduced the odds of not achieving an SVR (relative risk 0·44, 95% CI 0·37–0·52).
The scarcity of data for hepatitis C-related morbidity and all-cause mortality is unsurprising, given the short follow-up available for many of the trials of DAAs—it takes many years for these outcomes to become apparent. Furthermore, the aim of many of these trials was to demonstrate virological efficacy; they are neither designed nor adequately powered to assess mortality. That only one study investigating the effect of DAAs on quality of life was included in the Cochrane review might be explained by the review’s cut-off date for inclusion (October, 2016). Several trials have reported quality-of-life data in recent months, and suggest that the use of DAAs is associated with improvements in quality of life—outcomes that are just as important to patients as hard clinical endpoints, if not more so.