The Cochrane reviewers highlight a major limitation of their review: most trials had short follow-up periods, so “our results can neither confirm nor reject that DAAs have clinical long-term effects”. In fact, the average follow-up period was just 34 weeks, far too short to detect any effect on mortality except in people with decompensated cirrhosis and end-stage liver disease.
In a letter to The Guardian, Professor Graham Foster of Queen Mary University of London and senior colleagues from the United Kingdom said: “The trials were neither designed, nor powered, to assess mortality, so it is not at all surprising that the Cochrane review was unable to identify any impact on mortality.“
In contrast, a systematic review of 31 studies of the effect of pegylated interferon and ribavirin on the survival of people after being cured of hepatitis C was able to draw on studies that followed people for a median of 5.4 years, allowing researchers from Imperial College, London, to conclude that a sustained virological response to treatment reduced the risk of death by 50-80% over five years.
Another weakness of the Cochrane review was the lack of deaths during the follow-up period: 16, compared to 2210 in the studies of pegylated interferon and ribavirin-treated people reviewed by the researchers from Imperial College.
The authors of the review also described the well-accepted relationship between sustained virologic response and long-term outcomes of liver disease as a “non-validated surrogate outcome”.
“I'm not sure how the Cochrane Collaboration could claim that curing Hepatitis C with new direct-acting antiviral drugs does not improve survival,” commented Dr Andrew Hill, one of the authors of the Imperial College review.
“They could claim that being cured of hepatitis C from the new drugs is somehow different in terms of survival, compared to being cured on the old interferon-based treatments. But this would be hard to understand – for most experts, curing Hepatitis C should have the same clinical consequences, no matter what treatment is used to achieve this.”
The review does identify the lack of independent, long-term follow-up of people treated with DAAs as a problem. Almost all studies were classified as low-quality evidence, mainly due to pharmaceutical company sponsorship and design, and because of technical problems in the way that procedures such as randomisation were carried out.
“As a patient-led and patient-driven organisation, we have seen, heard and experienced the real evidence of being treated with DAAs. The true story is one of remarkable, if surprising, success over just a decade, transforming an unpleasant and sometimes fatal disease into one that is readily cured,” said Charles Gore, President of the World Hepatitis Alliance. “What is absolutely imperative is that this Review should not be used as another excuse not to treat when currently only 1.5% of people living with hepatitis C are accessing treatment worldwide.”