Direct-Acting Antiviral Agents Safe for Hepatitis C


Direct-acting antiviral (DAA) exposure may not be associated with higher rates of any serious adverse events when used for hepatitis C virus (HCV) treatment, according to a study published in JAMA Network Open.

At this time, there are approximately 2.4 million individuals living in the United States who are infected with HCV. Further, 28% of those infected individuals have chronic HCV liver cirrhosis and 1% to 4% of those individuals will develop liver cancer annually. Previously, antiviral treatments for HCV required a combination of agents taken over 24 to 48 weeks and were associated with significant adverse events while only being effective in 54% to 63% of patients who completed the program. The advent of DAAs were considered a breakthrough in treating HCV because they could be administered from 8 to 12 weeks with fewer significant adverse events while sustaining virologic response in 93% to 99% across various treatment regimens and target populations.

However, in 2016, the US Food and Drug Administration issued a boxed warning for DAAs about the potential for reactivation of hepatitis B virus among coinfected individuals. This finding prompted the US Food and Drug Administration’s voluntary Adverse Events Reporting System to be analyzed, which reported 500 cases of liver failure and 1000 cases of severe livery injury among patients receiving DAAs during a 12-month period. Although the Adverse Events Reporting System has limitations that include the voluntary nature of reporting, possible misclassifications because some adverse events of interest are also significant complications of the disease, and a lack of detailed patient medical history data, approximately 90% of reports were from health professionals. Therefore, this retrospective cohort study assessed the rates of adverse events in patients with HCV infection exposed to DAAs compared with those who were not exposed.

In total, 33,808 adults who had a quantitative HCV RNA result or genotype in 2012 or later and who were naive to DAA treatment were enrolled between 2012 and 2017. Of the cohort, 61.8% were male and the mean age was 57.2 years. Using claims and clinical data from 3 health systems, unadjusted adverse event rates for exposed vs unexposed time were calculated. To adjust time-to-event analyses for characteristics that were associated with both outcomes and probability of treatment, marginal structural modeling methods were used. The main outcomes and measures included death, liver cancer, hepatic decompensation, multiple organ failure, acute-on-chronic liver event, acute kidney failure, nonliver cancer, hepatitis B reactivation, hospitalizations, and emergency department visits.

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In unadjusted analyses, DAA exposure was associated with significantly lower death rates (10.7 vs 33.7 events per 1000 person-years). The DAA group was also favored in 7 other unadjusted adverse clinical events ratios that were below 70% and statistically significant, including hemorrhagic stroke (risk ratio [RR], 0.47), ischemic stroke (RR, 0.63), acute myocardial infarction (RR, 0.64), liver cancer (RR, 0.62), hepatic decompensation (RR, 0.62), acute-on-chronic liver event (RR, 0.68), and multiple organ failure (RR, 0.56). None of these favored the non-DAA group. In the marginal structural modeling-adjusted analysis, when compared with non-DAA exposure, DAA exposure was associated with statistically significant lower odds of adverse events for arrhythmia (adjusted odds ratio [aOR], 0.42), hepatic decompensation (aOR, 0.61), acute-on-chronic liver event (aOR, 0.71), multiple organ failure (aOR, 0.67), and death (aOR, 0.42).

Overall, the study authors concluded that, “Concerns about safety risks based on analyses of the US Food and Drug Administration’s Adverse Events Reporting System did not appear to be confirmed, suggesting that dispensed direct-acting antivirals may be safe for patients with hepatitis C.”


McGlynn EA, Adams JL, Kramer J, et al. Assessing the safety of direct-acting antiviral agents for hepatitis C. JAMA Network Open. 2019;2(6):e194765