Since the first direct-acting antiviral agents (DAAs) were approved by the US Food and Drug Administration (FDA) in 2013, 9 such agents have become available for treatment of hepatitis C virus (HCV) infection. While DAAs undoubtedly represent a significant advance in the treatment of this common condition, serious safety issues have been reported since their introduction. The current issue of QuarterWatch, an independent publication that monitors FDA data on adverse drug events, includes a review of such reports pertaining to DAAs.1
The Centers for Disease Control and Prevention (CDC) estimates that 75% to 85% of individuals who become infected with HCV develop the chronic form of the disease, which affects 2.7 to 3.9 million people in the United States.2 Approximately 5% to 20% of patients infected eventually develop cirrhosis, and liver cancer occurs in 1% to 3% of these cases each year.
Before the availability of DAAs, treatment of HCV typically involved a 24- to 48-week course of a combination of antivirals, including ribavirin and interferon.3 These regimens led to a wide range of serious adverse effects, such as hemolytic anemia, psychiatric symptoms, and suicide. In addition, they were effective in eliminating detectable levels of the virus in only 50% to 75% of cases. For these reasons, many patients remained untreated or terminated treatment prematurely.
In contrast, clinical trials showed that the newer regimens typically required a 12-week course and resulted in undetectable virus levels in 89% to 100% of patients, and discontinuations were reduced by at least one-half.4 However, a Drug Safety Communication issued by the FDA in October 2016 warned about “a potentially catastrophic side effect that had not been clearly identified in pre-approval drug testing….that in 24 known cases, attempting to suppress the hepatitis C infection with direct-acting antivirals had permitted reactivation of hepatitis B,” wrote the investigators in the QuarterWatch report.5 Liver failure occurred in 3 of these patients; 2 died and 1 received a liver transplant.
For the current paper, the investigators searched 12 months of data from the FDA Adverse Event Reporting System (FAERS). They identified 524 global cases of reported liver failure in which a DAA was the suspected cause. Encephalopathy was present in nearly 50% of cases, and 31.5% of patients had died at the time the cases of liver failure were reported. There were 1058 additional incidents of severe liver injury, as well as 761 reports of antiviral failure.
“While direct-acting antivirals should be classed as a major advance, important questions remain unanswered about their long-term effects and appropriate patient population,” the researchers wrote. Further research is needed into the mechanisms involved in such cases of liver failure, as well as the reasons for the antiviral failures observed in this review.
- Institute for Safe Medication Practices. Perspectives from new adverse event reports: New safety issues for hepatitis C antivirals. Quarter Watch. 2017;2016(Q2):11-15.
- Centers for Disease Control and Prevention. Hepatitis C FAQs for the public. https://www.cdc.gov/hepatitis/hcv/cfaq.htm. Updated October 17, 2016. Accessed February 13, 2017.
- Mishra P. Clinical review new drug application (NDA) 204671: Sofosbuvir (GS-7977). Silver Spring, MD: Food and Drug Administration, Center for Drug Evaluation and Research; 2013.
- Bidell MR, McLaughlin M, Faragon J, Morse C, Patel N. Desirable characteristics of hepatitis C treatment regimens: a review of what we have and what we need. Infect Dis Ther. 2016; 5:299-312. doi:10.1007/s40121-016-0118-x
- US Food and Drug Administration. FDA drug safety communication: FDA warns about the risk of hepatitis B reactivating in some patients treated with direct-acting antivirals for hepatitis C. http://www.fda.gov/Drugs/DrugSafety/ucm522932.htm. Updated October 12, 2016. Accessed February 13, 2017.