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  • IDSA, AASLD Express Concerns About Cochrane Review of DAAs for Hep C


    IDSA and AASLD submitted the following letter to the editors of the Cochrane Review regarding a recent review of the benefits of direct acting antivirals in the treatment of hepatitis C.

    We are writing to express our serious concerns regarding the recent Cochrane Group Review concluding that there is a lack of valid evidence supporting the benefit of direct acting antiviral (DAA) therapy for chronic infection with hepatitis C virus (HCV), and its supposition: “the possibility of potentially harming people with chronic hepatitis ought to be considered before treating people with hepatitis C with DAAs.” Our review of this Cochrane publication suggests significant flaws in this analysis, yielding a misleading and a harmful conclusion.

    The objective as stated is to assess the benefits and the harms of DAAs in people with chronic HCV. The selection criteria used only randomized clinical trials comparing DAA versus no intervention or placebo in patients with chronic HCV. Randomized trials in chronic HCV have only focused on the FDA recommended virologic endpoint of sustained virologic response (SVR), which is limited to a short follow-up period meant only to confirm permanent eradication of the virus from the blood stream. The Review’s conclusion stating a lack of evidence that SVR impacts long term clinical outcomes (morbidity) and mortality ignores both fundamental mechanisms and mounting published literature supporting the clear clinical benefit of SVR obtained with DAAs.

    First, experience from earlier HCV therapies (based on interferon), for which long term follow-up data are now available, clearly demonstrate numerous health benefits including a decrease in liver inflammation as reflected by improved aminotransferase levels and a reduction in the rate of progression of liver fibrosis as reflected in paired liver biopsy studies (Poynard, 2002). Of 3010 treatment-naive HCV-infected patients with pretreatment and posttreatment biopsies from four randomized trials of 10 different interferon-based regimens, 39 percent to 73 percent of patients who achieved an SVR had improvement in liver fibrosis and necrosis in liver biopsies separated by a mean of 20 months (Poynard, 2002). Cirrhosis resolved in half of the cases. Portal hypertension, splenomegaly and other clinical manifestations of advanced liver disease also improved. Among HCV-infected persons with advanced fibrosis, SVR is associated with a more than 70 percent reduction in the risk of hepatocellular carcinoma (HCC) and a 90 percent reduction in the risk of liver-related mortality and liver transplantation (Morgan, 2013); (van der Meer, 2012); (Veldt, 2007). It is precisely for these reasons that the FDA recommended SVR as the primary endpoint for all contemporary HCV trials. SVR is a validated surrogate for long-term benefits. Based on these data, there is every reason to expect that analogous clinical benefits will be observed with cure of HCV infection obtained via DAAs after a sufficient follow-up period.

    Second, even early data from the DAA experience support clear improvements in clinical outcomes that can be measured in the short term. Cure of HCV infection immediately reduces symptoms and organ dysfunction from severe extrahepatic manifestations including cryoglobulinemic vasculitis, a complication affecting up to 10 percent of HCV-infected patients (Saadoun, 2017); (Sise, 2016). Historically, HCV-infected persons with non-Hodgkin lymphoma (NHL) and other B-cell lymphoproliferative disorders achieved complete or partial remission in up to 75 percent of cases following successful IFN-based therapy for HCV infection (Gisbert, 2005); (Takahashi, 2012); (Svoboda, 2005); (Mazzaro, 2002); (Hermine, 2002). Recent data show that DAA regimens produce similar remission rates in NHL and even higher rates of SVR (Arcaini, 2016). Perhaps the most striking evidence of direct clinical improvement comes from data demonstrating the success of DAAs in patients with decompensated liver disease for whom SVR was associated with improved MELD scores and albumin levels in the majority of patients with Child B and C cirrhosis (Charlton, 2015). Indeed, success in this group in many cases obviates the need for liver transplantation, meaning that more donor organs could become available to other patients on the waitlist (Belli, 2016). Thus, even without long term follow-up to prove a survival benefit, there are already clear indications of the clinical benefit of SVR offered by use of DAAs to reduce disease complications.

    We are troubled by the implications of this review for the ongoing international efforts to halt the HCV epidemic, and to give patients back their futures. In the face of the National Academies of Science, Engineering, and Medicine statement 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. We 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. In light of the evidence that we have cited, we urge the Cochrane Review authors to retract or to revise their conclusions.


    Anna Lok, MD, FAASLD, President, AASLD

    William Powderly, MD, FIDSA, President, IDSA

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