AASLD Expresses Concern for Cochrane Review of DAAs

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In July Newsletters - Rebuttal over Cochrane Review of DAAs
View each rebuttal and all ongoing media coverage.
In June the HCV community was blindsided when an article with a somewhat "clickbait" headline was released by The Guardian. The Guardian reported on a systematic review published by the Cochrane Collaboration that suggested achieving SVR (cure) for patients using hepatitis C direct-acting antivirals (DAAs) doesn't correlate with any long term benefits.

Begin here....

AASLD and IDSA would like 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.

AASLD and IDSA 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 (www.hcvguidelines.org (link is external)) 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.

Sincerely,
Anna Lok, President, AASLD
William Powderly, President, IDSA

References

1. AASLD-IDSA. Recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org (link is external).
2. Arcaini L, Besson C, Frigeni M, et al. Interferon-free antiviral treatment in B-cell lymphoproliferative disorders associated with hepatitis C virus infection. Blood. 2016 Nov 24;128(21):2527-2532. Epub 2016 Sep 7
3. Belli, L.S., Berenguer, M., Cortesi, P.A., Strazzabosco, M., Rockenschaub, S.R., Martini, S. et al, Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study. J Hepatol. 2016; 65:524–531.
4. Charlton M, Everson GT, Flamm SL, et al. Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease. Gastroenterology. 2015 Sep;149(3):649-59. doi: 10.1053/j.gastro.2015.05.010. Epub 2015 May 15.
5. Gisbert JP, Garcia-Buey L, Pajares JM, Moreno-Otero R. Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection. Aliment Pharmacol Ther. 2005;21(6):653-662
6. Hermine O, Lefrere F, Bronowicki JP, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med. 2002;347(2):89-94.
7. Mazzaro C, Little D, Pozzato G. Regression of splenic lymphoma after treatment of hepatitis C virus infection. N Engl J Med. 2002;347(26):2168-2170.
8. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med. 2013;158(5 Pt 1):329-337.
9. Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology. 2002;122(5):1303-1313.
10. Saadoun D, Pol S, Ferfar Y, et al. Efficacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinemia Vasculitis. Gastroenterology. 2017 Mar 10. pii: S0016-5085(17)30269-X. doi: 10.1053/j.gastro.2017.03.006. [Epub ahead of print]
11. Sise ME, Bloom AK, Wisocky J, et al. Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology. 2016 Feb;63(2):408-17. Epub 2015 Dec 11.
12. Svoboda J, Andreadis C, Downs LH, Miller Jr WT, Tsai DE, Schuster SJ. Regression of advanced non-splenic marginal zone lymphoma after treatment of hepatitis C virus infection. Leuk Lymphoma. 2005;46(9):1365-1368.
13. Takahashi K, Nishida N, Kawabata H, Haga H, Chiba T. Regression of Hodgkin lymphoma in response to antiviral therapy for hepatitis C virus infection. Intern Med. 2012;51(19):2745-2747.
14. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584-2593.
15. Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147(10):677-684.

AASLD
https://www.aasld.org/about-aasld/press-room/aasld-expresses-concern-cochrane-review-daas

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