IDSA, AASLD critical of Cochrane review of HCV drugs

WIlliam Powderly
William G. Powderly

Members of the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases have issued a strongly worded rebuke of a recent Cochrane review of drugs for the treatment of hepatitis C virus infection.

The IDSA and AASLD wrote a joint response, which was published in Clinical Infectious Diseases, to the Cochrane review that concluded that direct-acting antiviral (DAA) drugs have not been shown to reduce risks for HCV-related morbidity or all-cause mortality. The review also claimed that prior trials have underestimated DAA adverse effects.

In the IDSA/AASLD response, the authors cited what they considered to be flaws in the review and bluntly suggested that it could undermine efforts to eliminate HCV.

“In the face of the National Academies of Sciences, Engineering and Medicine reports that elimination of HCV is possible by 2030 with optimal implementation of high-efficacy therapy, we believe that the Cochrane review does a grave disservice to these efforts and to patients living with chronic HCV infection, a disease responsible for tens of thousands of deaths around the world each year,” IDSA President William G. Powderly, MD, director of the Washington University, St. Louis Institute for Public Health, and colleagues wrote.

The review included 138 trials of 51 total DAAs. Its authors conceded that DAAs may affect SVR but added that SVR does not necessarily translate to better outcomes.

“There was not enough information to confirm or reject if DAAs have clinically relevant effects on other clinically relevant outcomes,” they wrote. “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.”

They added that neither the benefits nor the adverse effects of the drugs were sufficiently measured.

“All trials and outcome results were at high risk of bias, so our results presumably overestimate benefit and underestimate harm,” they wrote. “The quality of the evidence was very low.”

Powderly and colleagues retorted in part by citing studies showing links between SVR and desirable outcomes.

“Recognizing the natural history of HCV infection, during which clinical outcomes may take years to become apparent, that late relapse after achieving SVR is rare, and the mounting evidence that SVR decreases HCV-related morbidity and mortality, the FDA accepted SVR as a valid surrogate and a practical endpoint for clinical trials of DAAs,” they wrote.

They also cited data showing DAAs were associated with alleviation of various liver diseases and remission of non-Hodgkin lymphoma. The IDSA and AASLD authors insisted they will not be deterred in forging ahead with HCV treatment.

“We therefore stand behind our associations’ recommendations that all patients with HCV should be treated to prevent complications of this curable disease and we will continue to fight for the global elimination of this viral infection,” they wrote. “In light of the evidence that we have cited, we urge the Cochrane review authors and/or editors to retract or to revise their conclusions.”

Board members for the European Association for the Study of the Liver responded to the Cochrane review similarly.

“The review examines the intervention in a clinical vacuum that fails to accept that DAA treatment to attain [a sustained virological 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 HCV,” the EASL board members wrote in Journal of Hepatology.

They, too, feared a chilling effect on HCV treatment.

“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 HCV. It will create dangerous confusion in the minds of patients treated or about to be treated and their families.” – by Joe Green

Disclosure: Powderly reports that he has received research grants at his institution from Merck and has worked as a consultant to Merck and Gilead Sciences. Please see the article for all other authors’ relevant financial disclosures.

References:

EASL. Response to the Cochrane Systematic Review on DAA-Based Treatment of Chronic Hepatitis C. http://www.journal-of-hepatology.eu/pb/assets/raw/Health%20Advance/journals/jhepat/CochraneEASLJMP003.pdf. Accessed July 20, 2017.

Cochrane. Direct-acting antivirals for chronic hepatitis C. http://www.cochrane.org/CD012143/LIVER_direct-acting-antivirals-chronic-hepatitis-c. Accessed July 20, 2017.

ISMP. QuarterWatch. New data from 2016 Q2. 2017. http://www.ismp.org/quarterwatch/pdfs/2016Q2.pdf. Accessed January 25, 2017.

Powderly WG, et al. Clin Infect Dis. 2017;doi:10.1093/cid/cix620.

WIlliam Powderly
William G. Powderly

Members of the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases have issued a strongly worded rebuke of a recent Cochrane review of drugs for the treatment of hepatitis C virus infection.

The IDSA and AASLD wrote a joint response, which was published in Clinical Infectious Diseases, to the Cochrane review that concluded that direct-acting antiviral (DAA) drugs have not been shown to reduce risks for HCV-related morbidity or all-cause mortality. The review also claimed that prior trials have underestimated DAA adverse effects.

In the IDSA/AASLD response, the authors cited what they considered to be flaws in the review and bluntly suggested that it could undermine efforts to eliminate HCV.

“In the face of the National Academies of Sciences, Engineering and Medicine reports that elimination of HCV is possible by 2030 with optimal implementation of high-efficacy therapy, we believe that the Cochrane review does a grave disservice to these efforts and to patients living with chronic HCV infection, a disease responsible for tens of thousands of deaths around the world each year,” IDSA President William G. Powderly, MD, director of the Washington University, St. Louis Institute for Public Health, and colleagues wrote.

The review included 138 trials of 51 total DAAs. Its authors conceded that DAAs may affect SVR but added that SVR does not necessarily translate to better outcomes.

“There was not enough information to confirm or reject if DAAs have clinically relevant effects on other clinically relevant outcomes,” they wrote. “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.”

They added that neither the benefits nor the adverse effects of the drugs were sufficiently measured.

“All trials and outcome results were at high risk of bias, so our results presumably overestimate benefit and underestimate harm,” they wrote. “The quality of the evidence was very low.”

Powderly and colleagues retorted in part by citing studies showing links between SVR and desirable outcomes.

“Recognizing the natural history of HCV infection, during which clinical outcomes may take years to become apparent, that late relapse after achieving SVR is rare, and the mounting evidence that SVR decreases HCV-related morbidity and mortality, the FDA accepted SVR as a valid surrogate and a practical endpoint for clinical trials of DAAs,” they wrote.

They also cited data showing DAAs were associated with alleviation of various liver diseases and remission of non-Hodgkin lymphoma. The IDSA and AASLD authors insisted they will not be deterred in forging ahead with HCV treatment.

PAGE BREAK

“We therefore stand behind our associations’ recommendations that all patients with HCV should be treated to prevent complications of this curable disease and we will continue to fight for the global elimination of this viral infection,” they wrote. “In light of the evidence that we have cited, we urge the Cochrane review authors and/or editors to retract or to revise their conclusions.”

Board members for the European Association for the Study of the Liver responded to the Cochrane review similarly.

“The review examines the intervention in a clinical vacuum that fails to accept that DAA treatment to attain [a sustained virological 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 HCV,” the EASL board members wrote in Journal of Hepatology.

They, too, feared a chilling effect on HCV treatment.

“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 HCV. It will create dangerous confusion in the minds of patients treated or about to be treated and their families.” – by Joe Green

Disclosure: Powderly reports that he has received research grants at his institution from Merck and has worked as a consultant to Merck and Gilead Sciences. Please see the article for all other authors’ relevant financial disclosures.

References:

EASL. Response to the Cochrane Systematic Review on DAA-Based Treatment of Chronic Hepatitis C. http://www.journal-of-hepatology.eu/pb/assets/raw/Health%20Advance/journals/jhepat/CochraneEASLJMP003.pdf. Accessed July 20, 2017.

Cochrane. Direct-acting antivirals for chronic hepatitis C. http://www.cochrane.org/CD012143/LIVER_direct-acting-antivirals-chronic-hepatitis-c. Accessed July 20, 2017.

ISMP. QuarterWatch. New data from 2016 Q2. 2017. http://www.ismp.org/quarterwatch/pdfs/2016Q2.pdf. Accessed January 25, 2017.

Powderly WG, et al. Clin Infect Dis. 2017;doi:10.1093/cid/cix620.