Treatment with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) was associated with a “rapid and significant” decrease in risk for all-cause mortality and hepatocellular carcinoma (HCC), a French prospective study found.
After adjustment for multiple variables, DAA treatment correlated to a hazard ratio of 0.48 (95% CI 0.33-0.70) for all-cause mortality and 0.66 (95% CI 0.46-0.93) for HCC, a team led by Fabrice Carrat, PhD, of Sorbonne University in Paris, reported in The Lancet.
But the study could not clarify the long-term effects of these agents on liver decompensation: DAA treatment was associated with an HR of 1.14 (95% CI 0.57-2.27) for decompensated cirrhosis.
The authors noted that this is the first prospective longitudinal study to compare outcomes in patients treated or not treated with DAAs, irrespective of sustained virological response (SVR) status, and with careful control of confounding and indication biases.
“Taking a large cohort like this provides the opportunity to evaluate the effect of direct-acting antiviral therapy on the long-term outcomes of patients with hepatitis C,” Carrat said in a news release. “We saw a reduction of risk for complications related to the disease, and to mortality, and believe this treatment should be considered for all patients with chronic hepatitis C infection.”
During 2012 to 2015, the multicenter study identified 10,166 eligible HCV patients in France’s ANRS CO22 Hepather cohort, of whom 97% had follow-up information for analysis. Median follow-up was 33.4 months. DAA treatment was started during follow-up in 7,344 patients, while 2,551 patients remained untreated at the final follow-up visit. Mean age in the DAA group was 57 and 54 in the non-DAA group, while 56% and 46%, respectively, were male in the two groups.
More than 60% of the patients were from France, but the cohort also included patients from Asia, Africa, and Eastern Europe. Almost 100% reported no excess alcohol consumption at entry.
During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported HCC (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated).
In unadjusted analysis, DAA exposure initially correlated with an increased risk of HCC, for an HR of 2.77 (95% CI 2.07-3.71) and of decompensated cirrhosis, for an HR of 3.83 (2.29-6.42). DAA treatment exerted an inverse effect, however, after adjustment for a range of variables, including age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naiveté, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score.
In a subgroup of 3,045 patients with baseline cirrhosis, the study found the same association for mortality and HCC cancer, provided the patients achieved SVR.
The prospective findings parallel those of the American Electronically Retrieved Cohort of HCV Infected Veterans retrospective cohort, in which a significant 57% decrease in all-cause mortality was noted in DAA recipients achieving SVR versus propensity score-matched untreated patients.
In terms of the mechanisms of action, the authors noted that DAAs induce SVR, which reduces liver damage and inflammation, triggers liver regeneration, and decreases the risk of progression to liver-related complications or HCC. “Our results showing strikingly different risks for these liver-related events in patients with and without a sustained virological response support these mechanisms,” the team wrote.
The researchers added that while failure to achieve SVR has been suggested as a sign of underlying HCC, the current findings counter that suggestion because the median time between SVR assessment and HCC diagnosis did not differ between patients with and without SVR.
Findings Counter Those of a Cochrane Review
In an accompanying commentary, Raymond T. Chung, MD, of Massachusetts General Hospital in Boston, and colleagues, wrote that the study “offers substantive evidence that cure of HCV delivered by all-oral direct-acting antiviral regimens is associated with clinical benefits.” In addition, Chung and co-authors said, the findings counter those of a 2017 Cochrane Systematic Review that neither confirmed nor rejected findings that DAAs affect long-term HCV-related morbidity and mortality.
The findings also lay to rest the suggestion from some single-center reports that DAAs are associated with an increased HCC incidence, a suggestion also refuted by other studies, the commentary continued. The current study’s results “also provide the best evidence to date to support guidance documents that recommend direct-acting antiviral treatment for all patients with chronic HCV infection,” and support the World Health Organization’s stated goals to eliminate HCV and substantially reduce its complications.
Study limitations, the researchers noted, include its observational nature, which cannot determine causality; that some patients might have had less regular HCC screening, leading to missed diagnoses; that fibrosis and cirrhosis were assessed at entry by different criteria in patients’ records and were not updated; and the relatively short follow-up, which precluded having data on long-term outcomes. In addition, no association emerged between DAAs and risk of decompensated cirrhosis, and although the analysis according to SVR revealed a non-significant inverse association in patients with cirrhosis at baseline, the study likely did not have enough statistical power to clarify this outcome.
Finally, Carrat and co-authors said, despite many multivariable analyses, the study could not exclude either a residual risk of bias from confounding due to unmeasured prognostic factors or a complex time-dependent selection bias.
The editorial by Chung and colleagues noted, however, that it is unlikely that any of the limitations materially affected the overall findings.
The study received funding from France’s Institut National de la Santé et de la Recherche Médicale and the Agence Nationale de la Recherche, and Direction Générale de la Santé, as well as from Janssen, MSD, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.
Several authors reported financial ties to commercial entities, including Janssen, Gilead, AbbVie, Bristol-Myers Squibb, Roche, Genfit, Merck, LFB, Novartis, Astellas. Biotest, Echosens, Abbott, Bayer, Boehringer Ingelheim, and Intercept.