Editorial: Direct-acting Antiviral Treatment for Hepatitis C Significantly Reduces Long-Term Complications

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In patients with chronic hepatitis C virus (HCV) infection, complications such as cirrhosis, end-stage liver disease, hepatocellular carcinoma and death have tripled over the past 15 years. Meanwhile, a new generation of HCV therapy has come along: oral, direct-acting antivirals—which can achieve sustained virologic responses or cure in >95% of patients.

It has seemed highly plausible to gastroenterologists that direct-acting antivirals would also lead to reductions in HCV-related complications. In an editorial in The Lancet, Jacinta A. Holmes, MBBS, research fellow in medicine, Stephanie M. Rutledge, MBBCh, clinical fellow in medicine, and Raymond T. Chung, MD, vice chief of the Division of Gastroenterology and director of Hepatology and the Liver Center at Massachusetts General Hospital, comment on a large prospective study in France that demonstrated exactly that.

Highlights of the ANRS Study

The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) enrolled more than 10,000 adults with chronic HCV infection in a large, multicenter cohort. Approximately three-quarters of the cohort received direct-acting antivirals; the others served as an untreated control group.

The median follow-up period was 33.4 months (interquartile range, 24.0–40.7 months), which was considered adequate for the development of HCV-related complications. In the accompanying report in The Lancet, the researchers state that direct-acting antiviral therapy significantly reduced:

• All-cause mortality (hazard ratio [HR], 0.48; 95% CI, 0.33–0.70; P = 0.0001)
• Liver-related mortality (HR, 0.39; 95% CI, 0.21–0.71; P = 0.002)
• Hepatocellular carcinoma (HR, 0.66; 95% CI, 0.46–0.93; P = 0.02)

Limitations of the Study

Dr. Chung and his colleagues discuss some potential limitations of the study, but they explain that none of them would change the overall conclusions:

• Not all patients underwent a liver biopsy to confirm cirrhosis; platelet count or prothrombin time was used to classify cirrhosis in 44% of patients. However, in a validation substudy, noninvasive markers of fibrosis correctly classified cirrhosis in all patients
• Patients who received more than one course of direct-acting antivirals were considered to have continuous exposure from the first course to the last course. There could have been a lag time between courses, but that scenario would have underestimated rather than overestimated the benefit of antivirals
• Patients with a history of decompensated cirrhosis and liver transplantation were excluded. However, because these patients are at highest risk of complications, the effect of excluding them would have been to underestimate the potential benefits of direct-acting antivirals

Hope for the Future

The editorialists conclude that the findings of the French study:

• Strongly contradict a 2017 Cochrane review of direct-acting antiviral treatment trials, which neither confirmed nor rejected the proposition that direct-acting antivirals affect long-term HCV-related morbidity and mortality
• Provide the best support to date for practice guidelines that recommend direct-acting antiviral therapy for all patients with chronic HCV infection
• Lend credence to the World Health Organization's goals of substantially reducing the complications of HCV and completely eliminating it by 2030 

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