By: Gerard Gallagher
January 25, 2017
Researchers raised questions about the long-term safety of direct-acting antivirals for hepatitis C virus infection after an analysis of FDA data uncovered more than 500 reports of liver failure and more than 1,000 reports of severe liver injury related to the drugs over one recent 12-month period.
According to the authors of QuarterWatch, an independent publication of the nonprofit Institute for Safe Medication Practices (ISMP), the FDA also received more than 700 reports of antiviral failure related to the drugs during the same time span.
Last October, the FDA announced that it would require certain DAAs to carry a box warning — its most prominent warning — after identifying 24 patients who experienced a recurrence of hepatitis B virus infection while being treated for HCV. Recurring HBV infection can potentially cause serious liver problems and death.
Thomas J. Moore, senior scientist for drug safety and policy at ISMP, and colleagues said they looked beyond the cases cited by the FDA to review the most recent data in the FDA’s Adverse Event Reporting System, also known as MedWatch reports.
Moore and colleagues uncovered 524 cases of liver failure linked to DAAs for HCV infection reported in the 12-month period ending June 30, 2016, including 165 related deaths. Of the total cases, 138 occurred in the United States. Additionally, they said the FDA data included 1,058 reports of severe liver injury related to the drugs and 761 cases of antiviral failure.
Less than 3 years since DAAs were first approved, 250,000 patients took them for HCV infection in 2015 at a cost of approximately $50,000 to $125,000 per patient, depending on the estimate, Moore and colleagues said. Overall spending on the drugs has far outstripped what is spent by the NIH to study all other infectious diseases, they said.
Moore and colleagues noted the FDA’s decision to speed the approval of DAAs by reducing the duration of clinical testing from 26 weeks to 12 weeks for some genotypes.
“This is an example of the price we pay for faster drug approval with reduced clinical testing,” Moore told Infectious Disease News. “Don’t we really want to know more than this about a new drug treatment on which we spent more than $10-20 billion in 2015 alone? We spent more than twice as much on these direct-acting antivirals for about 250,000 patients as the NIH did on all research into all infectious diseases.”
Moore and colleagues said the FDA received around 270,000 overall reports of adverse drug events in the second quarter of 2016, a decline of about 20% compared with the previous quarter. Approximately 90% of the 524 reports linking liver failure to DAAs were submitted to the FDA by health professionals, Moore and colleagues noted. They said the FDA data raised more questions than they resolved about DAAs.
“While direct-acting antivirals should be classified as a major advance, important questions remain unanswered about their long-term effects and appropriate patient population,” Moore and colleagues concluded.
The FDA reports mentioned a number of drugs, including two manufactured by Gilead Sciences, Sovaldi (sofosbuvir) and Harvoni (ledipasvir/sofosbuvir).
According to Gilead spokesman Mark Snyder, more than 1.2 million HCV-infected patients around the world have been prescribed regimens containing sofosbuvir, including over 500,000 in the U.S. This might explain reports of some patients experiencing treatment failure, Snyder said.
He also said it would not be unexpected to see a small subset of patients experience liver failure because sofosbuvir-based regimens are the only regimens approved for patients with advanced liver disease.
“Gilead closely assesses both post-marketing safety reports as well as safety data from our clinical trials on an ongoing basis and has found no suggestion of a causal relationship between Sovaldi or Harvoni and liver failure,” Snyder told Infectious Disease News.
Janssen Pharmaceuticals said the adverse event profile of its DAA Olysio (simeprevir) “was consistent with those seen in clinical trials and reflected in the prescribing information,” Moore and colleagues wrote.
ISMP. QuarterWatch. New data from 2016 Q2. 2017. http://www.ismp.org/quarterwatch/pdfs/2016Q2.pdf. Accessed January 25, 2017.