Direct-Acting Antivirals Don't Increase Adverse Events in Hepatitis C Treatment

Despite previous reports raising concerns, direct-acting antiviral exposure does not increase the risk of serious adverse events, according to a new study.

In 2016, the US Food and Drug Administration (FDA) received reports through their Adverse Events Reporting System of liver failure (500) and severe liver injury (1000) among patients who had been taking direct-acting antivirals (DAAs) for the past year as treatment for the hepatitis C virus (HCV). This created concerns about the safety of DAAs for treatment of HCV, although investigators noted that the data’s accuracy was limited by the nature of voluntary reporting, lack of detailed patient medical history, and possibility of misclassification, since many of these adverse events could be a result of HCV itself rather than DAA treatment.

In response, investigators conducted a retrospective cohort study. The study used claims and clinical data from 3 health systems—Kaiser Permanente Southern California (serves 4.5 million), Kaiser Permanents Northern California (serves 4.3 million), and OneFlorida (serves 10 million)—between January 2012 and December 2017 to calculate unadjusted adverse event rates in exposed vs unexposed patients (33,808 total) over time.

Analyses were adjusted, time-to-event, to account for characteristics associated with outcomes and probability of treatment.

Adverse events considered included death, multiple organ failure, liver cancer, hepatic decompensation, acute-on-chronic liver event, acute myocardial infarction, ischemic or hemorrhagic stroke, arrhythmia, acute kidney failure, non-liver cancer, hepatitis B reactivation, hospitalizations, and emergency department visits.

Considered covariates included demographics (age, sex, race, and ethnicity), year, body mass index, smoking status, history of use (skilled nursing, home health, emergency department, inpatient), laboratory results, and a calculated aspartate aminotransferase level to platelet ratio index score.

Prior to adjustment, analyses associated DAA exposure with significantly lower rates of death (10.7 vs 33.7 events per 1000 person-years; rate ratio [RR], 0.32, 95% CI, .25-.40). Additionally, 7 other unadjusted adverse events were far more likely in the DAA group: multiple organ failure (RR, 0.56; 95% CI, 0.44-0.72), liver cancer (RR, 0.62; 95% CI, 0.48-0.80), hepatic decompensation (RR, 0.62; 95% CI, 0.52-0.73), acute-on-chronic liver event (RR, 0.68; 95% CI, 0.56-0.84), acute myocardial infarction (RR, 0.64; 95% CI, 0.42-0.97), ischemic stroke (RR, 0.63; 95% CI, 0.42-0.95), and hemorrhagic stroke (RR, 0.47; 95% CI, 0.25-0.89), while none were more likely in the non-DAA group.

After the adjustments were applied, however, the odds of adverse events for DAA-exposed patients plummeted, dropping even lower than the risk level of non-DAA patients for death (adjusted odds ratio [aOR], 0.42; 95% CI, 0.30-0.59), multiple organ failure (aOR, 0.67; 95% CI, 0.49-0.90), hepatic decompensation (aOR, 0.61; 95% CI, 0.49-0.76), acute-on-chronic liver event (aOR, 0.71; 95% CI, 0.56-0.91), and arrhythmia (aOR, 0.47; 95% CI, 0.25-0.88).

Investigators acknowledge that it is usually healthier patients who are assigned to DAA treatment, so it would be presumptuous to assume that DAAs actually lower the risk of adverse events. The data nevertheless indicates, at the very least, that DAAs do not increase the risk of adverse events, despite previous fears raised by the FDA report. Given the frequent reliance upon DAAs in HCV treatment, this is encouraging news for many patients.

The study, “Assessing the Safety of Direct-Acting Antiviral Agents for Hepatitis C,” was published by JAMA Network.