The Institute for Safe Medication Practices (ISMP), a nonprofit group based in Horsham, Pennsylvania, has examined the emerging risks of new hepatitis C drugs for triggering liver failure, a catastrophic medical event that often leads to death or a liver transplant. The group reviewed nine direct-acting antiviral medications for hepatitis C virus (HCV) infection, including the blockbusters Sovaldi (sofosbuvir, Gilead), approved in 2013, and Harvoni (ledipasvir/sofosbuvir, Gilead), approved in 2014. Both are priced at $1,000 per pill.
In the United States, an estimated 2.7 million to 3.9 million people have HCV infection and at least 20,000 a year die from it, according to the Centers for Disease Control and Prevention. There is no vaccine to prevent the infection.
In October 2016, the FDA identified the first new major safety problem linked to nine direct-acting antiviral HCV drugs. While these medications appeared to suppress HCV to undetectable levels in most patients, treatment also made some patients susceptible to reactivation of the hepatitis B virus, with severe health consequences, including liver transplant and death.
Reviewing the most-recent 12 months’ data from the FDA Adverse Event Reporting System (FAERS), the ISMP identified 524 reported cases of liver failure associated with HCV drugs, and 1,058 reports of severe liver injury. In an additional 761 cases, the adverse event was antiviral failure against the targeted virus. “Our data show the need for further investigation into the negative consequences of these expensive and important new drugs,” the authors wrote.
Direct-acting antivirals, first approved in November 2013, represent a major advance in the treatment of HCV infection, according to the ISMP report: They often suppress the virus to undetectable levels more quickly than other antivirals (12 weeks instead of 26 weeks); are more effective, eliminating detectable virus in 89% to 100% of selected patients enrolled in clinical studies; and are better-tolerated, reducing withdrawal rates by nearly half.
The new HCV medications are also notable for their high costs: $55,000 to $125,000 per patient, the report adds. Despite only an estimated 250,000 patients treated in 2015, the list-price spending for HCV treatments exceeded similar spending for cholesterol-lowering drugs, antibiotics, or blood pressure drugs, each with patient populations measured in tens of millions.
The 524 reported cases of liver failure in the ISMP report included all of the approved direct-acting antivirals as either primary or secondary suspect drugs, often in combination with each other or with ribavirin. Almost half of the cases also included the hallmark symptom of liver failure, encephalopathy––a form of brain injury resulting in delirium, personality changes, suicidal behavior, sleep–wake reversal, and coma. Overall, 165 patients (32%) had died at the time of the report.
“While it was challenging to separate cases to which complications of hepatitis C may have contributed, 90% of the cases were submitted by health care professionals, who would be likely to understand the natural progression of the disease,” the ISMP noted.
The suspect drugs include:
Dr. Thomas J. Moore, a senior scientist at the ISMP and a coauthor of the report, said the study reflected a larger question about the drug approval process. Approval of the new HCV drugs was expedited because better treatments were so badly needed. But did the rush to market come at a price?
“Here is something that really qualifies as a breakthrough, and we have policies to get it into use as quickly as possible, which means we know less about it,” Moore told the New York Times. “Benefits and side effects evolve over the long term, not over 12 weeks.”