Treatment with direct-acting antivirals (DAAs) appears to reduce the risk of death and liver cancer among patients with chronic hepatitis C virus (HCV) infection, including those with cirrhosis, new research shows. In a prospective cohort study of more than 10,000 adult patients with HCV, risk of all-cause mortality, liver-related mortality, non-liver-related mortality, and hepatocellular carcinoma (HCC) was significantly reduced among those who received direct-acting antiviral (DAA) medications compared with those who did not, Fabrice Carrat, PhD, Sorbonne University, French National Institute of Health and Medical Research (INSERM), Paris, and colleagues report. The study was published online February 11 in The Lancet. And while decompensated cirrhosis was not significantly influenced by DAA treatment, patients with cirrhosis who achieved sustained virologic response with DAA treatment experienced similarly decreased mortality and cancer risk, the authors write. Reports in the literature of a possible increase in the occurrence and recurrence of HCC related to DAA treatment in chronic HCV have spurred some controversy, the authors write. Although previous observational studies have linked DAA treatment with reduced risk of mortality and liver cancer in chronic HCV patients, the heterogeneity of the study populations, variations in inclusion and exclusion criteria, follow-up time, and other considerations have lead researchers to seek more definitive answers, they note. The current investigation, which the authors say is the first prospective longitudinal study addressing clinical outcomes in DAA-treated HCV, was designed to do just that. The French ANRS CO22 Hepather study compared outcomes among patients treated with DAAs with an untreated control group, independent of their sustained viral response status. The study enrolled 14,389 patients with antibodies against HCV between August 6, 2012, and December 31, 2015, including 11,870 with chronic HCV infection at entry. After excluding patients with active hepatitis B virus co-infection at entry; a history of hepatocellular carcinoma; decompensated cirrhosis; a history of liver transplantation; or a history of receiving peginterferon and ribavirin with or without a first-generation protease inhibitor, along with patients for whom follow-up information was not available, 9895 patients were included in the final analysis. Of these, 7344 patients were treated with DAAs and 2551 were not. Compared with the untreated control group, patients in the DAA group were older, had more comorbidities, and more severe liver disease. In adjusted multivariable analyses of outcomes over a median 33.4 months, exposure to DAAs significantly reduced all-cause mortality by 52% (hazard ratio [HR] 0.48, 95% confidence interval [CI], 0.33–0.70; P = .0001), liver-related mortality by 61% (HR, 0.39; 95% CI, 0.21–0.71; P = .0020), non-liver-related mortality by 40% (HR, 0.60, 95% CI, 0.36–1.00; P = .048), and hepatocellular carcinoma by 34% (HR, 0.66; 95% CI, 0.46–0.93; P =.018). However, DAA treatment was not associated with a reduction in risk for decompensated cirrhosis (HR, 1.14; 95% CI, 0.57–2.27; P = .72). When the authors stratified patients based on whether they achieved a sustained virologic response, they found that those who did had significantly reduced risk of all-cause mortality, liver-related mortality, non-liver-related mortality, and hepatocellular carcinoma, compared with untreated patients. There was also a trend toward reduced risk of decompensated cirrhosis, but it did not reach statistical significance. However, those treated with DAAs who did not achieve a sustained virologic response had an increased risk of hepatocellular carcinoma compared with their untreated peers (HR, 2.23; 95% CI, 1.37–3.64; P = .0012). A similar pattern was seen in a subgroup analysis of patients with cirrhosis. Those who achieved sustained virologic response showed a reduced risk for all-cause mortality, liver-related mortality, non-liver-related mortality, and hepatocellular carcinoma. However, the patients with cirrhosis who failed to achieve sustained virologic response were at increased risk for hepatocellular carcinoma. Strongest Evidence Yet to Support Treatment With DAAs The reduced risk of non-liver-related mortality in patients treated with DAA compared to untreated controls was a "striking finding," the authors write. "Although a decrease in long-term, non-liver-related mortality has been reported in patients with sustained virological response compared with those without a sustained virological response after interferon-based therapy, reverse causality could be another possibility if patients with the most severe liver disease and the highest risk for death from any cause had a lower probability of starting direct-acting antiviral treatment," they note. In this case, however, patients with decompensated cirrhosis or a history of hepatocellular carcinoma were excluded at baseline. Further, the analyses were adjusted for markers of liver insufficiency and comorbidities, and the results were similar even after exclusion of the first 12 months of follow-up. Together, these considerations "seem to exclude reverse causality," the authors conclude. The observational study design prevents the investigators from reporting a cause-and-effect inverse relationship between DAA treatment and mortality and liver cancer risks, "[h]owever we can postulate about plausible mechanisms," they write. "Direct-acting antivirals induce a sustained virological response, reducing liver damage and inflammation. This effect causes liver regeneration, decreasing risk for progression to liver-related complications or hepatocellular carcinoma." Although several considerations potentially limit the study findings, including different methods of data collection for deriving fibrosis and cirrhosis information from patient records and a short follow-up duration, none of the reported limitations "would be expected to materially affect the overall findings and most likely biased the findings away from clinical benefit with direct-acting antivirals," according to the authors of an accompanying commentary, Jacinta A. Holmes, PhD, from the Liver Center, Gastrointestinal Division, at Massachusetts General Hospital in Boston, and colleagues state that the study "offers substantive evidence" that DAA-related HCV cure offers additional clinical benefits. The findings "provide the best evidence to date to support guidance documents that recommend direct-acting antiviral treatment for all patients with chronic HCV infection," the editorialists write. They add that the results also support the possibility of eliminating HCV and reducing its complications, consistent with the guidelines established by the World Health Organization. The study was funded by INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche. The authors and editorialists report multiple types of financial relationships with pharmaceutical and biomedical companies. For the full list of disclosures, please see the journal website. Source
