Use of direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV) is not linked to higher rates of serious adverse events, and in fact is associated with reduced mortality and a lower risk of liver, kidney and heart problems, according to a recent study.
The advent of DAAs—starting with Sovaldi (sofosbuvir) in 2013—has led to shorter, more convenient and much more tolerable treatment with a substantially higher cure rate than the old interferon-based therapy.
In 2017, a review by the influential Cochrane Collaboration reached the shocking conclusion that treating and curing HCV with DAAs does not reduce rates of liver-related illness or death. Experts criticized the findings, arguing that randomized clinical trials of DAAs were designed to show that the new medications cure hepatitis C—generally defined as an undetectable HCV viral load after finishing treatment, known as sustained virological response—but did not last long enough to demonstrate improvements in long-term clinical outcomes or mortality.
Finally, a large prospective study published earlier this year firmly established an association between DAA treatment and a lower risk of liver cancer and death. The authors of an accompanying commentary concluded that the report “offers substantive evidence that cure of HCV delivered by all-oral direct-acting antiviral regimens is associated with clinical benefits.”
Now, a group of researchers with Kaiser Permanente have shown that use of DAAs does not appear to be associated with any notable harms.
As described in JAMA Network Open, Elizabeth McGlynn, PhD, of Kaiser Permanente Research in Pasadena, California, and colleagues compared rates of adverse events among people with HCV who were treated with DAAs and those who were not exposed to these drugs.
Recent reports based on the Food and Drug Administration’s voluntary Adverse Events Reporting System have raised some questions about the safety of DAAs, the study authors noted. One potential concern is hepatitis B virus (HBV) reactivation when HCV is cured, as the two viruses appear to keep each other in check.
This retrospective cohort study looked at data from three large health systems between January 2012 and December 2017. The Kaiser Permanente Southern California managed care system serves about 4.5 million members, Kaiser Permanente Northern California serves about 4.3 million members and OneFlorida provides care to more than 10 million people. The systems maintain extensive electronic health records including medical visits, diagnoses, laboratory results and pharmacy dispensing.
The analysis included 33,808 adults who had an HCV viral load or genotypic test result from 2012 or later and had not yet taken DAAs at the start of the study. Just over 60% were men, and the average age was 57. The authors noted that the study included a higher proportion of people from racial/ethnic minorities than most clinical trials (up to 32% Black, up to 7% Asian or Pacific Islander and up to 30% Hispanic or Latino in the three health systems). The study also included people who are typically excluded from clinical trials of new HCV therapies, such as those with liver cirrhosis, liver cancer or prior liver transplants.
The researchers compared outcomes including death, multiple organ failure, liver cancer, liver decompensation (advanced liver failure), acute-on-chronic liver events (sudden severe liver injury in people with a chronic liver disease), acute myocardial infarction (heart attack), stroke, heart arrhythmias (abnormal heart rhythms), acute kidney failure, other types of cancer, hepatitis B virus (HBV) reactivation, hospitalizations and emergency department visits.
This analysis only counted events that occurred within 180 days of receiving a DAA—the time frame in which a event might reasonably be attributable to drug exposure. The study was not intended to assess how DAAs influence long-term outcomes of HCV infection, which can itself include liver cancer and liver decompensation.
In an unadjusted analysis, DAA use was associated with a statistically significant lower rate of death: 10.7 versus 33.7 deaths per 1,000 person-years, or a 68% reduction. Seven clinical events were also significantly less likely in the DAA group, meaning the difference was probably not driven by chance alone. Liver cancer and decompensation risk were both 38% lower, acute-on-chronic liver events were 32% lower, heart attack risk was 36% lower, stroke risk was 37% to 53% lower (depending on the type of stroke) and the risk of multiple organ failure was 44% lower.
After adjusting for other factors that could have influenced the outcomes, DAA exposure was associated with a significant 58% lower risk of death, a 33% decline in multiple organ failure, a 39% lower risk of liver decompensation, a 29% decline in acute-on-chronic liver events and a 53% lower risk of heart arrhythmias. Hospitalizations and emergency department visits were also less likely in the DAA group.
None of the adverse outcomes analyzed were less frequent in the non-DAA group. Of note, the risk of HBV reactivation did not differ significantly in the DAA and non-DAA groups; in fact, the authors identified only one clinically meaningful reactivation event.
“Direct-acting antiviral exposure may not be associated with higher rates of any serious adverse events, including those related to liver, kidney, and cardiovascular systems,” the study authors wrote. “Safety concerns based on previous reports did not appear to be supported in this study with more comprehensive data and rigorous statistical methods.”
“Although it is tempting to conclude that DAAs are protective against many serious adverse outcomes, these outcomes may be a consequence of channeling healthier patients to DAA treatment. A more conservative conclusion is that DAA exposure may not be associated with higher rates of adverse events,” they cautioned.
“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,” Lauren Beste, MD, of the University of Washington School of Medicine in Seattle wrote in an accompanying commentary. “While no retrospective study of adverse drug events can completely eliminate treatment selection bias, [these results] ”may help support clinicians’ confidence that DAA therapy is not associated with excess treatment-related risks to patients."
Click here to read the full study (available for free).