EASL Responds to Unfavorable DAA Review

The European Association for the Study of the Liver responded with serious concern to a systematic review published by the Cochrane Group Review that stated, direct acting antivirals “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.”

“The review examines the intervention in a clinical vacuum that fails to accept that DAA treatment to attain [a sustained virologic response] is a pivotal outcome of treatment, and does not accept the likelihood that an SVR will reduce the risks of long-term outcomes of hepatitis C,” EASL governing board members and board directors wrote in a recent editorial published online in Journal of Hepatology. “With this deduction comes responsibility. The uncertainty created by the ill-conceived Cochrane group’s conclusions and the attendant press publicity could grievously affect policy making, and constrain the gathering momentum for diagnosis, testing and linkage to care of individuals with hepatitis C. It will create dangerous confusion in the mind of patients treated or about to be treated and their families.”

According to the editorial, as the primary endpoint in DAA investigational drug development is SVR, the Cochrane review’s conclusions were flawed for several reasons.

1. There was a seemingly contradictory outcome stated as most patients had “no SVR” but a meta-analysis confirmed that DAAs appeared to reduce the risk for no SVR by a risk ratio of 0.44 (P < .00001).

2. The pooled data included 57 trials that used drugs that have since been withdrawn or discontinued.

3. The authors failed to indicate in their measurements of serious adverse events the difference between drug-related adverse events and clinical adverse events.

4. The study’s health-related quality of life analysis did not include several recent reviews that show significant improvement in quality of life using DAAs over interferon- and ribavirin-based therapy.

5. The trials included in the study only assessed outcomes to “maximum follow-up.”

To the last point, EASL stated, “A meta-analysis should only evaluate the primary endpoint selected by the clinical studies. The trials were not designed or powered to capture long-term outcomes such as hepatitis C-related morbidity or all-cause mortality, but to establish whether infection, reflected by persistent viremia, could be safely and effectively terminated.”

“It is a triumph of evidenced base medicine carried to its illogical extreme! It is also extremely damaging to patients and seems to be ignorant of all the survival advantages that have been clearly shown in the literature for DAA treatment,” Douglas T. Dieterich, MD, director of the Institute for Liver Medicine and professor of medicine in the division of liver disease at Icann School of Medicine at Mount Sinai, told Healio.com/Hepatology.

EASL reached out to Rajiv Jalan, MBBS, MD, FRCP, FRCPE, PhD, professor of hepatology at the Royal Free Hospital and editor-in-chief of Journal of Hepatology for comment.

“Development of safe and effective treatments for hepatitis C virus has revolutionized the lives of millions of patients who live with this liver disease. Thousands of investigators around the world have confirmed their effectiveness,” Jalan said in a press release on EASL’s website. “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.”

EASL wrote in its conclusion that the premise of the Cochrane review will be seen as “egregiously mistaken” and “will rightly be disregarded.” According to EASL, the findings will not assist or advance the treatment of HCV patients. EASL has committed itself to the fight against HCV and the international efforts for HCV elimination by 2030, as supported and advocated by the World Health Organization.

“There is no precedent for a disease to be eliminated only 40 years after the discovery of its causal agent thus far. This chance cannot, and will not be missed.” – by Talitha Bennett

References:

EASL. J Hepatol. 2017. http://www.journal-of-hepatology.eu/pb/assets/raw/Health%20Advance/journals/jhepat/CochraneEASLJMP003.pdf. Accessed June 28, 2017.

Jakobsen JC, et al. Cochrane Database of Systematic Reviews. 2017;doi:10.1002/14651858.CD012143.pub2.

The European Association for the Study of the Liver responded with serious concern to a systematic review published by the Cochrane Group Review that stated, direct acting antivirals “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.”

“The review examines the intervention in a clinical vacuum that fails to accept that DAA treatment to attain [a sustained virologic response] is a pivotal outcome of treatment, and does not accept the likelihood that an SVR will reduce the risks of long-term outcomes of hepatitis C,” EASL governing board members and board directors wrote in a recent editorial published online in Journal of Hepatology. “With this deduction comes responsibility. The uncertainty created by the ill-conceived Cochrane group’s conclusions and the attendant press publicity could grievously affect policy making, and constrain the gathering momentum for diagnosis, testing and linkage to care of individuals with hepatitis C. It will create dangerous confusion in the mind of patients treated or about to be treated and their families.”

According to the editorial, as the primary endpoint in DAA investigational drug development is SVR, the Cochrane review’s conclusions were flawed for several reasons.

1. There was a seemingly contradictory outcome stated as most patients had “no SVR” but a meta-analysis confirmed that DAAs appeared to reduce the risk for no SVR by a risk ratio of 0.44 (P < .00001).

2. The pooled data included 57 trials that used drugs that have since been withdrawn or discontinued.

3. The authors failed to indicate in their measurements of serious adverse events the difference between drug-related adverse events and clinical adverse events.

4. The study’s health-related quality of life analysis did not include several recent reviews that show significant improvement in quality of life using DAAs over interferon- and ribavirin-based therapy.

5. The trials included in the study only assessed outcomes to “maximum follow-up.”

To the last point, EASL stated, “A meta-analysis should only evaluate the primary endpoint selected by the clinical studies. The trials were not designed or powered to capture long-term outcomes such as hepatitis C-related morbidity or all-cause mortality, but to establish whether infection, reflected by persistent viremia, could be safely and effectively terminated.”

“It is a triumph of evidenced base medicine carried to its illogical extreme! It is also extremely damaging to patients and seems to be ignorant of all the survival advantages that have been clearly shown in the literature for DAA treatment,” Douglas T. Dieterich, MD, director of the Institute for Liver Medicine and professor of medicine in the division of liver disease at Icann School of Medicine at Mount Sinai, told Healio.com/Hepatology.

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EASL reached out to Rajiv Jalan, MBBS, MD, FRCP, FRCPE, PhD, professor of hepatology at the Royal Free Hospital and editor-in-chief of Journal of Hepatology for comment.

“Development of safe and effective treatments for hepatitis C virus has revolutionized the lives of millions of patients who live with this liver disease. Thousands of investigators around the world have confirmed their effectiveness,” Jalan said in a press release on EASL’s website. “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.”

EASL wrote in its conclusion that the premise of the Cochrane review will be seen as “egregiously mistaken” and “will rightly be disregarded.” According to EASL, the findings will not assist or advance the treatment of HCV patients. EASL has committed itself to the fight against HCV and the international efforts for HCV elimination by 2030, as supported and advocated by the World Health Organization.

“There is no precedent for a disease to be eliminated only 40 years after the discovery of its causal agent thus far. This chance cannot, and will not be missed.” – by Talitha Bennett

References:

EASL. J Hepatol. 2017. http://www.journal-of-hepatology.eu/pb/assets/raw/Health%20Advance/journals/jhepat/CochraneEASLJMP003.pdf. Accessed June 28, 2017.

Jakobsen JC, et al. Cochrane Database of Systematic Reviews. 2017;doi:10.1002/14651858.CD012143.pub2.