Safety of New HCV Direct-Acting Antivirals Called into Question

A report from the Institute of Safe Medication Practices (ISMP), “New Safety Issues for Hepatitis C Antivirals,” was published in QuarterWatch, on January 25.

The report warns that liver failure might be associated with nine new direct-acting antivirals (DAA), including sofosbuvir, ledipasvir-sofosbuvir, and simeprevir. According to the report, these drugs may have suppressed hepatitis C in many patients, however, it appears that the drugs also reactivated hepatitis B in 24 patients, and even caused “severe health consequences.”

The ISMP initiated its investigation of liver failure in patients receiving DAAs after noting that three of the cases involved in the October 2016 advisory on the reactivation of hepatitis B had experienced liver failure. Of those three patients, two had died, while the last received a liver transplant.

The report acknowledged that the new agents represent the kind of therapeutic advance that the US Food and Drug Adminstration (FDA) characterizes as "breakthrough". However, the report also pointed out that in reducing the required clinical testing from 24 to 12 weeks, the agency could have missed cases of deterioration occurring after the primary efficacy end-point of sustained virologic response (SVR).

"The FDA and pharmaceutical companies were also overoptimistic in labeling as a "cure" the results of a laboratory assay at 12 weeks indicating undetectable levels of the hepatitis C virus genotype," the report stated.

In searching the FDA Adverse Event Reporting System (FAERS) for reports filed in the 12 months ending June 30, 2016, the ISMP found 524 cases of liver failure in which one of the nine DAAs was a primary or secondary suspect drug. It also identified 1,058 cases of severe liver damage that had not progressed to liver failure.

Since the adverse event reports didn’t include medical history, the ISMP was not able to discern whether cases of liver failure reflected adverse drug reaction or progression of the underlying disease.

However, according to the ISMP, healthcare professionals reported that 90% of these cases were, in fact, not related to consequences of hepatitis C infection, but rather adverse effects of the antivirals.

In addition, the ISMP noted that while liver failure in patients receiving a DAA could reflect an advanced or aggressive disease state, it also marked that "the drugs failed to work”. The ISMP discovered 761 cases in the DAA clinical trials in which the outcome was described as "Drug Ineffective". Seventeen of these were included in the 524 cases that progressed to liver failure.

"This form of treatment failure is consequential, given that the patient is exposed to the risk and expense of treatment, and the drugs are sometimes used in patients starting to suffer clinical complications of hepatitis C with limited options available," the ISMP reported.

Although the report did not contain a response from the FDA, the agency has described its rationale for reducing the duration of clinical testing of the DAAs within a draft guidance for industry issued in May.

"In brief, there was a high rate of concordance between SVR12 and SVR24 in more than 13,0000 patients pooled from multiple clinical trials of peg-IFN-based regimens," the draft guidance explained.

The ISMP report concluded that further investigation is needed. "While direct-acting antivirals should be classified as a major advance, important questions remain unanswered about their long-term effects and appropriate patient population."

"A better understanding of what is occurring in hundreds of additional liver failure cases should be a priority for further investigation," the report declared.