Report Cites Liver Failure Risk With New Hepatitis C Drugs

Marcia Frellick

January 26, 2017

A new report questions the safety of some of the new drugs found to cure hepatitis C, in light of findings of liver failure and injury.

But hepatitis C virus (HCV) experts say the findings are inconclusive, should be interpreted with great caution, and should not influence prescribing.

Researchers at the Institute for Safe Medication Practices (ISMP) found 524 cases of liver failure associated with the drugs, and an additional 1058 reports of patients with severe liver injury. Of the 524 who had liver failure, 165 died.

In 761 additional cases, there was antiviral failure against the targeted virus, according to the report.

The 524 cases "included all the approved direct-acting antivirals as either primary or secondary suspect drugs, often in combination with each other or with ribavirin," according to the report, which mentions the blockbusters sofosbuvir (Sovaldi) and ledipasvir/sofosbuvir (Harvoni), both made by Gilead Sciences.

ISMP released the findings in its quarterly report QuarterWatch on January 25. QuarterWatch is an independent publication of ISMP, a nonprofit in Horsham, Pennsylvania, that monitors reports of all adverse drug events submitted to the US Food and Drug Administration (FDA).

"Our data show the need for further investigation into the negative consequences of these expensive and important new drugs," the researchers write.

The report comes after the first findings of major safety problems by the FDA in October of 2016 linked to the nine new direct-acting antiviral drugs for HCV.

That report found that the drugs that suppressed HCV to undetectable levels also could trigger reactivation of hepatitis B. The FDA report described 24 cases of such reactivation, "including 3 cases of acute liver failure."

The new HCV drugs are considered revolutionary, as HCV affects 2 million to 3 million people in the United States and millions more globally and the drugs can cure 99% of patients in 12 weeks. Their cost (some priced at $1,000 per pill) has sparked much controversy and debate over who should get them.

Experts: Report Inconclusive and Insignificant

Douglas Dieterich, MD, director of the Institute for Liver Medicine at the Mount Sinai Health System in New York City, downplayed the significance of the report and said the findings should not change physician practice.

"The data in this report do not conclusively prove the hepatitis C medications Sovaldi and Harvoni cause liver failure. Without clear evidence of cause and effect, we cannot risk this information deterring patients from seeking the care they need," he said in a prepared statement.

"This is data from all over the world and we know the standards of medical care are not equivalent," Dr Dieterich told Medscape Medical News.

He pointed out that the 165 deaths among 250,000 patients comes to a rate of .00066. Even if the drugs caused the liver failure — and this report doesn't prove that — the rate "is likely much lower than that of the liver disease itself," he said. "We don't know how many of these patients were cirrhotics but even healthy cirrhotics have a 10% per year mortality rate. For decompensated, it's more like 30%."

"We have a new Hepatitis C epidemic of under-30-year-olds," Dr Dieterich said. "We shouldn't be scaring them away with a report like this that has no relevance for 99.9% of the population."

Ype P. de Jong, MD, PhD, acting director for the Center for the Study of Hepatitis C at Weill Cornell Medicine in New York City, agrees that the results should not change prescribing behavior.

He told Medscape Medical News that the report's mention of potential Hepatitis B reactivation is important and the subject of a boxed warning from the FDA regarding the new HCV drugs.

But he also said that the number of people actively infected with both hepatitis B and C is tiny. "Those people should be monitored very closely for the hepatitis B getting worse," he says. "And clinicians should check for hepatitis B status before they give these hepatitis C drugs."

He pointed out that the ISMP report doesn't describe the patients and therefore the numbers of deaths may not be related to the drugs. There's also no control group. People with a Child -Pugh cirrhosis score of B or C generally have life expectancies of less than 6 months, he explains.

"If you give those people the new hepatitis drugs, they may cure the hepatitis C…but they will still die," Dr de Jong said.

Response From Gilead

Mark Snyder, spokesperson for Gilead Sciences, included these comments in his emailed response to Medscape Medical News, and said that information in the report should be taken with this context:

"To date, more than 1.2 million HCV-infected patients have been prescribed sofosbuvir-containing regimens worldwide, with the United States accounting for the largest number of patients treated from any country (>500,000 patients).

"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."

"Sofosbuvir-based regimens (Harvoni + ribavirin, Epclusa + ribavirin, Sovaldi+Daklinza+ribavirin) are approved for treating patients with decompensated liver disease. Prior to the availability of interferon-free HCV treatments in 2013, patients with advanced liver disease had limited treatment options. They have been prioritized for treatment due to the severity of their disease and the unmet medical need. Improvement in liver function is not observed in all patients who undergo HCV treatment, and furthermore, this improvement, if it does occur, may take months to fully manifest. Thus, some patients remain at risk for the progression of advanced liver disease, including liver failure and hepatic decompensation, despite oral DAA [direct-acting antivirals] therapy."

"We have worked closely with the FDA and other regulatory agencies to share our data and analyses on cases of liver failure, and no product updates have been deemed necessary by Gilead," Snyder said.

Dr Dietrich is a consultant for Gilead, AbbVie, and Janssen. Dr de Jong reports no financial relationships.

QuarterWatch. Published online January 25, 2017. Full text

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