The Cochrane Review Conclusion for Hepatitis C DAA Therapies is Wrong
by Paul Y. Kwo, MD, FACG; Mitchell L. Shiffman, MD, FACG; and David E. Bernstein, MD, FACG
There are few diseases that cause such morbidity and mortality as chronic hepatitis C that can be treated successfully with a finite duration of well-tolerated oral medicines and see a change in the natural history of the disease. Thus, it is surprising and disappointing that the recent Cochrane database review on direct-acting antivirals for chronic hepatitis C concluded that DAA administration has little or no clinical relevance to patients with hepatitis C, stating it was questionable if sustained virologic response has any clinical relevance to the person with chronic hepatitis C. We hope the Cochrane database review is not misinterpreted to suggest there are no benefits to achieving sustained virologic response.
Gastroenterologists and hepatologists have been privileged to be part of the identification and subsequent successful treatment of multiple diseases that have caused significant morbidity and mortality in the United States and abroad. The seminal observations that Helicobacter pylori caused gastritis, ulcer disease and gastric cancer have led to large screening programs to diagnose and treat this infection, and due to these efforts, in part, the incidence of ulcer disease and gastric cancer has been on the decline. Universal access to colon cancer screening has led to a decrease in the incidence of and mortality from colon cancer. The significant findings of decreased cancer rates and mortality did not occur within the first two years of these treatments entering the mainstream, but rather were noted years or decades later.
To this list, we are now adding chronic hepatitis C. In 2014, we entered the era of direct-acting antiviral agents (DAAs) for hepatitis C with sustained response rates above 95% (cure) across all genotypes being achieved routinely. Moreover, these direct-acting antiviral agents are well-tolerated, a marked departure from the previous interferon era, in which therapies were far more difficult to tolerate, lasting up to 48 weeks with cure rates of 50% or less. From the interferon era, we learned that sustained virologic response was associated with meaningful endpoints including regression of fibrosis, reduction of liver-related deaths, and a reduction in the risk of liver cancer. However, it took many years before these positive effects were noted.
Already, there has been an immediate effect of DAAs, with extremely high cure rates and a marked reduction in the number of new hepatitis C-related cirrhosis registrations for orthotopic liver transplant. In addition, there are improvements in extrahepatic manifestations of hepatitis C with SVR, including resolution of cryoglobulinemia and HCV-related lymphomas. Indeed, when a patient infected with hepatitis C presents to us for evaluation, we can now tell them that a cure is to be expected and that improvement of underlying fibrosis will improve in the years to come following SVR.
There are few diseases that cause such morbidity and mortality as chronic hepatitis C that can be treated successfully with a finite duration of well-tolerated oral medicines and see a change in the natural history of the disease.
Surprised and Disappointed
Thus, it is surprising and disappointing that the recent Cochrane database review on direct-acting antivirals for chronic hepatitis C concluded that DAA administration has little or no clinical relevance to patients with hepatitis C, stating it was questionable if sustained virologic response has any clinical relevance to the person with chronic hepatitis C. These conclusions were drawn from analysis of 138 trials in hepatitis C patients with an average treatment duration of 14 weeks and average total follow-up duration of 34 weeks, during which SVR was the primary outcome and other clinical endpoints, including decompensation events such as ascites, encephalopathy, varices, etc., were not assessed.
However, this Cochrane database report tried to extrapolate clinical outcomes including survival and other liver-related outcomes from trials that were not designed with these outcomes in mind. Indeed, there have been three long-term studies that have assessed outcomes such as survival, decompensation and hepatocellular cancer development in patients with hepatitis C that were done in the interferon era, and these studies were years in duration and enrolled predominantly those with advanced fibrosis.
Endpoints for direct-acting antiviral therapy trials are limited to sustained virologic response, which is required for the registration of new therapies across the world. Certainly, one would not expect improvement in mortality or morbidity to occur in a six-month period, which is now typical for most DAA trials, as even untreated cirrhotic patients with hepatitis C can live for many years without decompensation. Even so, there are a limited number of DAA trials that examined clinical outcomes in decompensated cirrhosis patients and were able to demonstrate improvements in MELD scores and CPT scores within 12 weeks of completing therapy, though these trials were powered for sustained virologic response, not clinical improvement.
We hope the Cochrane database review is not misinterpreted to suggest there are no benefits to achieving sustained virologic response.
Across the world, there have been multiple groups advocating for universal access to these highly effective, direct-acting antiviral agents, and many organizations, both governmental and non-governmental, have set a goal to eliminate hepatitis C worldwide by 2030. We hope the Cochrane database review is not misinterpreted to suggest there are no benefits to achieving sustained virologic response. The ample data from the interferon era, coupled with the short-term improvements in DAA-treated individuals not captured in the trials examined by the Cochrane review group and other data, suggests that the strategy of eliminating hepatitis C will provide multiple benefits by reducing the number of individuals requiring transplant for hepatitis C, reducing the rates of hepatitis C-related cirrhosis and its complications, including liver cancer, as well as reducing the many extrahepatic manifestations of hepatitis C.
As gastroenterologists and hepatologists, we are on the right track with our current treatment strategies and goals for hepatitis C, and we should not turn back. It is our hope that the Cochrane conclusion is revised or retracted, but this will not deter our efforts to eradicate this and other diseases.
ACG Note
The College endorses the concerns expressed by our colleagues at AASLD and IDSA about the Cochrane Group Review of DAAs in this recent statement: “AASLD Expresses Concern for Cochrane Review of DAAs.”