EASL releases editorial response to Cochrane Review of DAAs in HCV

GENEVA, Switzerland 28 June 2017 - The European Association for the Study of the Liver (EASL) expresses its serious concerns with the recent publication by the Cochrane Group Review entitled "Direct acting antivirals for chronic hepatitis C" by Jakobsen et al. in which the authors conclude 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."

EASL Governing Board Members and Board of Editors at The Journal of Hepatology, state in an editorial response published online today that the Cochrane review could grievously affect policy making and could potentially constrain gathering momentum for an appropriate response to the Global Hepatitis Report from the World Health Organization (WHO). In their report, WHO expresses an alarm at the burden of viral hepatitis, and has promulgated critical targets for global elimination by 2030.

Hepatitis C is found worldwide, and according to WHO, approximately 399 000 people die each year from hepatitis C, mostly from cirrhosis and hepatocellular carcinoma. The negligent and flawed conclusions of the Cochrane review, which could potentially generate unnecessary confusion, serves as a potential barrier, amongst many existing challenges, to HCV elimination.

In the editorial, EASL experts explain that, because the complications of chronic hepatitis C take years to occur, depending on the stage of liver disease, and clinical trials with new DAAs with SVR as main endpoint last only a few months, the benefits in terms of clinical outcomes of achieving an SVR cannot be measured in these trials. The primary endpoint in DAA investigational drug development trials has been the SVR, e.g. undetectable HCV RNA 12 or 24 weeks after completion of treatment, reflecting permanent elimination of the viral infection. Once the infection is eliminated (i.e. SVR is achieved), the progression of liver disease is halted or at least considerably slowed down. The trials mentioned in the Cochrane review were not designed or powered to capture long-term outcomes, but to establish whether infection, reflected by a persistent presence of virus in the bloodstream, could be safely and effectively terminated. The Cochrane review displays a serious lack of understanding of hepatitis C and drug development in the context of a transmissible infectious disease with a long natural history.

As a result of their cursory analysis, the EASL editorial found that the Cochrane review overlooked a number of recent studies that showed improvement of quality of life with DAA therapy, demonstrating improved patient-reported outcomes. Subsequently, of grave concern is the Cochrane review authors' conclusion that "randomised clinical trials assessing direct effects of DAA are needed." The editorial goes on to illustrate that such a conclusion suggests an 'ethical anathema' where patients would be left untreated to accumulate increasing hepatic fibrosis, when there are treatments that would likely arrest viral infection, in the overwhelming majority.

"Development of safe and effective treatments for Hepatitis C virus has revolutionised the lives of millions of patients who live with this liver disease. Thousands of investigators around the world have confirmed their effectiveness," said Prof. Rajiv Jalan, Professor of Hepatology at the Royal Free Hospital and Editor-in-Chief of The Journal of Hepatology.

The review, as well as the publicity surrounding it, is drawing a growing body of criticism from experts in the field of hepatology who have respectively outlined the Cochrane review's errors and flawed analysis.

Pointing out the slipshod nature of the review, Prof. Jalan added, "The patients and health systems should be reassured that experts consider the recent suggestion that these drugs are ineffective as irresponsible and based on poor interpretation of the available data. With combined, ongoing, world-wide efforts, the deadly Hepatitis C virus can be eradicated and deaths from liver disease reduced."

Prof. Tom Hemming Karlsen, expert hepatologist and Secretary General of EASL echoed this criticism and commented: "The Cochrane analysis is an example of statistics which have gone astray without an expert guide. I quote Sir Austin Bradford Hill from his classic 1965 President's Address to the Royal Society of Medicine: 'Like fire, the chi-squared test is an excellent servant and a bad master.'"

"I am deeply worried that the ill-founded conclusions of the flawed Cochrane analysis might be used to withhold a potentially life-saving antiviral treatment to our patients affected by Hepatitis C," said Prof. Frank Tacke, Vice-Secretary of EASL.

EASL will continue to fight for the global elimination of this viral infection and urges the Cochrane Review authors to issue a corresponding statement to resolve the misconceptions.

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To read EASL editorial "Response to the Cochrane Systematic Review on DAA-Based Treatment of Chronic Hepatitis C", visit: http://www.journal-of-hepatology.eu/content/pressreleases