An open letter to the Cochrane Collaboration

26 Jun 2017 Bridie Taylor

The members of the Executive Board of the World Hepatitis Alliance are elected to represent the more than 300 million people who have the experience of living with viral hepatitis—for many, a progressive and frightening disease— and the civil-society groups who have worked tirelessly to increase access to life-saving medicines for them.

We take strong exception to the recent Cochrane review of direct-acting antivirals (DAAs) for the treatment of hepatitis C.1 We believe its methodology is flawed and its conclusions are unwarranted and dangerous.

The review looked at trials designed and powered to assess one endpoint— sustained virological response (SVR)— and judged them against other endpoints—morbidity and mortality— for which they were not designed or powered, since these endpoints require far longer follow-up than was available for the trials. Just as methodologically unsound is the inclusion of any trial since 2004 that included DAAs, as if all DAAs are the same or indeed relevant to decision-making today on their use. Furthermore, drugs were included that were withdrawn. Even though they were analysed separately, they should not have been included, since these drugs were withdrawn generally because of safety concerns or poor efficacy.

Despite their obvious and admitted lack of evidence on morbidity and mortality, the authors conclude that “DAAs do not seem to have any effects on the risk of hepatitis C-related morbidity or all-cause mortality.” Equally, based on an assessment of the risk of bias, the authors conclude that the trials “presumably [……] underestimate harm”, and state that “the lack of valid evidence and the possibility of potentially harming people with chronic hepatitis ought to be considered before treating people with hepatitis C with DAAs.”

There is plenty of evidence that an SVR leads to clinical benefits, which is why regulatory authorities and health technology assessment agencies accept SVR as a valid endpoint. This may not be from randomised clinical trials but it cannot be simply dismissed for that reason, particularly as it would be wholly unethical to carry out such a trial over the required time period based on the evidence we have. Nevertheless, the authors of the review call for just such trials.

Why does this matter? It matters because the world has signed up to a WHO Global Health Sector Strategy on viral hepatitis, the goal of which is the elimination of hepatitis B and C as public health concerns by 2030 and yet, despite large, rapid and continuing falls in the prices of hepatitis C drugs, many governments have still not committed to providing treatment. In the absence of a vaccine for hepatitis C, treatment is an essential element of the Global Strategy. The concern is that governments will believe that something emanating from the Cochrane Collaboration must be true based on its reputation. If governments now believe that DAAs have no beneficial effect, the whole global strategy will be undermined.

Just as important is the possible effect on individuals living with hepatitis C. Because symptoms are not readily apparent for many individuals living with the virus, there is often already a significant lack of urgency in addressing their disease. The findings of the review could deter them further from seeking treatment.

The authors of the review and the Cochrane Collaboration have a responsibility. That responsibility is to the people the review concerns and also, because of the nature of hepatitis C, to global public health. We therefore call upon them to review the conclusions that they have drawn from their findings and present them in such a way that reflects those findings properly. They must not unjustifiably put people at risk. One must not forget that 400 000 people die each year from hepatitis C.

Charles Gore, on behalf of the Executive Board of the World Hepatitis Alliance

1 Jakobsen JC, Nielsen EE, Feinberg J, et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017 6: CD012143.

This open letter was submitted to The Lancet Gastroenterology & Hepatology and featured alongside an editorial from the journal.