Low Risk for Adverse Events With DAAs Cause for Reassurance, Experts Say

Diana Phillips

June 07, 2019

Direct-acting antiviral (DAA) drugs do not appear to increase the risk for treatment-related adverse events in patients with chronic hepatitis C virus (HCV) infection and may even decrease the risk, new data suggest.

A review of outcomes from a retrospective cohort of 33,808 patients with chronic HCV from three healthcare systems showed that patients who were treated with DAAs did not experience higher rates of adverse events across any of the categories considered, including hepatic, renal, cardiovascular, or oncologic events.

Treatment with DAAs also did not appear to increase use of urgent, emergent, or inpatient healthcare services, nor was it linked to hepatitis B virus (HBV) reactivation, write Elizabeth A. McGlynn, PhD, of Kaiser Permanente Research in Pasadena, California, and colleagues. The researchers report their findings in an article published online today in JAMA Network Open.

The authors note that patients who received DAAs had consistently lower rates of adverse events compared with individuals who did not receive treatment. However, they warn against presuming a protective effect, because of the possibility of selection bias in the study.

To estimate adverse event risks, McGlynn and colleagues reviewed claims and clinical data from January 1, 2012, to December 31, 2017, from three healthcare systems to identify patients aged 18 years to 88 years for whom there was any indication of their having had an HCV infection and for whom HCV RNA or genotyping results indicated active infection.

They then compared rates and types of adverse clinical events and healthcare service utilization over a 6-month period among those patients who had been prescribed a DAA and those patients who had not been prescribed a DAA. The specific outcomes of interest included death, multiple organ failure, liver cancer, hepatic decompensation, an acute-on-chronic liver event, acute myocardial infarction (AMI), ischemic or hemorrhagic stroke, arrhythmia, acute kidney failure, nonliver cancer, and HBV reactivation, as well as hospitalizations and emergency department visits.

In addition to time-to-event analysis, the investigators used marginal structural modeling to control for confounding by indication. This is an important consideration, according to the author of an accompanying commentary, because some of the adverse outcomes that were measured may not have been related to treatment but could have been caused by the HCV infection itself.

"Patients who receive DAAs inevitably differ from patients who do not receive DAAs in ways that could potentially affect their risk of experiencing an adverse outcome during the treatment period," writes Lauren A. Beste, MD, of the VA Puget Sound Health Care System in Seattle, Washington, in the commentary. "The study methods help to overcome biases inherent in large observational studies of drug safety by minimizing the issue of confounding by indication to the extent statistically feasible," she states.

With follow-up of 7207.2 person-years in the DAA group and 64,823.5 person-years in the non-DAA group, unadjusted and adjusted analyses across outcomes favored the DAA group.

The adjusted odds ratios (aORs) in the DAA vs non-DAA group were 0.42 (95% confidence interval [CI], 0.30 – 0.59) for death, 0.67 (95% CI, 0.49 – 0.90) for multiple organ failure, 0.61 (95% CI, 0.49 – 0.76) for hepatic decompression, 0.71 (95% CI, 0.56 – 0.91) for acute-on-chronic liver event, and 0.47 (95% CI, 0.25 – 0.88) for arrhythmia.

The aORs for liver cancer and AMI differed by healthcare system. In two healthcare systems, the adjusted odds were significantly lower in the DAA group vs the non-DAA group (0.51; 95% CI, 0.32 – 0.80 in system 1 and 0.44; 95% CI, 0.26 – 0.74 in system 2). In the third system, the analysis also suggested a lower risk with DAAs, but the difference did not reach statistical significance (aOR, 1.45; 95% CI, 0.65 – 3.22). For AMIs, the only statistical difference was observed in system 2 (aOR, 0.41; 95% CI, 0.20 – 0.83).

Health resource utilization was lower among patients treated with DAAs, for whom the adjusted rate ratios were significantly lower for hospitalizations (0.71; 95% CI, 0.60 – 0.84) and emergency department visits (0.82; 95% CI, 0.77 – 0.87).

The consistent patterns across different types of adverse events should help ease concerns about the safety of DAAs that have stemmed from clinical trials that had highly selected cohorts, the authors write.

"Because clinical trials are commonly conducted with participants who have different demographic and health profiles than patients who are subsequently offered medication therapy, the results of postmarketing studies, such as this one, that are based on real-world patients and their experiences can contribute a richer source of information for shared decision making," the authors explain.

The patient population of the current study was more racially and ethnically diverse than was the case in most of the clinical trials to date. The current study included patients with histories or comorbidities that typically preclude clinical trial enrollment. Such factors include a past history of liver cancer, liver transplant, or cirrhosis.

The lower risk for adverse events in the DAA group is particularly notable, Beste writes in her commentary, because "[p]atients treated for HCV likely receive more contact with the health care system and closer surveillance with laboratory results, imaging, and other diagnostic testing in the course of their treatment."

Clinicians should consider these findings in communicating the risks and benefits of DAAs in HCV treatment. "The long-term benefits of HCV treatment have been extensively reported and include lower mortality, lower risk of liver cancer, and improved health-related quality of life for patients," Beste writes. "While no retrospective study of adverse drug events can completely eliminate treatment selection bias, the results of McGlynn and colleagues may help support clinicians' confidence that DAA therapy is not associated with excess treatment-related risks to patients."

The study was supported by funding from the Patient-Centered Outcomes Research Institute (PCORI). McGlynn and coauthor Elizabeth Shenkman, MD, have received funding for other research from PCORI. One coauthor has received grants from Bristol-Myers Squibb, Allergan, Gilead, and AbbVie. Another coauthor received grants from AbbVie, Merck, and Gilead during the conduct of the study and owns stock in Target PharmaSolutions. Beste has disclosed no relevant financial relationships.

JAMA Netw Open. Published online June 7, 2019. Full text, Commentary

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