Safety Concerns Over Some Hepatitis C Drugs

Red flags have been waved about the safety of some drugs now commonly prescribed to treat hepatitis C.

The Institute for Safe Medication Practices (ISMP) has issued a report citing data that link certain drugs to serious adverse side effects, such as liver failure. In its report, ISMP cites FDA data that implicate several direct-acting antiviral agents, including sofosbuvir (Sovaldi), ledipasvir sofosbuvir (Harvoni), and simeprevir (Olysio).

According to the ISMP report, while the drugs suppressed the hepatitis C virus to undetectable levels, the treatment in some cases led to reactivation of hepatitis B in coinfected patients, with severe health consequences-- including liver transplant and death.

The FDA report described 24 cases of hepatitis B reactivation, including acute liver failure and catastrophic life-threatening adverse drug events.

ISMP also cited the FDA Adverse Event Reporting System (FAERS) data that identified 524 reported cases of liver failure associated with the drugs and 1,058 reports of severe liver injury. The 524 reported cases of liver failure included all of the approved, direct-acting antivirals as primary or secondary suspect drugs.

ISMP believes that the data call for further investigation into these drugs.

Michael Cohen, RPh, MS, President of ISMP, told Drug Topics that this warning should receive attention. "It shouldn’t be ignored because there will be patients out there who do have suppressed hepatitis B as well as hepatitis C and the hepatitis B may activate and cause liver damage, need for transplant, or even death,” Cohen said.

However, manufacturers of these drugs have taken issue with FDA’s data and the ISMP report.

“Patient safety is our highest priority,” Mark Snyder, Director, Public Affairs for Gilead Sciences, told Drug Topics. Gilead manufactures Sovaldi and Harvoni.

Snyder said that Gilead continuously monitors safety information about its medicines to inform their appropriate use. It’s important to consider the following factors when reviewing the contents of this [ISMP] report, he added.

“To date, more than 1.2 million HCV-infected patients have been prescribed sofosbuvir-containing regimens worldwide. The US accounts for the largest number of patients treated from any country (>500,000 patients),” Snyder said.

He added that Gilead closely assesses both post-marketing safety reports as well as safety data from its 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, 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 therapy,” Snyder said.

In addition, Snyder asserted that Gilead has worked closely with the FDA and other regulatory agencies to share data and analyses on cases of liver failure, and no product updates have been deemed necessary by Gilead.  

Drug Topics attempted to contact Janssen Therapeutics, the manufacturer of simeprevir (Olysio). At press time, the company had not responded.

The ISMP report indicates that direct-acting antivirals for hepatitis C are notable due to the fact that the infection afflicts 2 to 3 million patients in the US. It can persist for decades without symptoms and can lead to cirrhosis and liver cancer. These agents were approved in 2013 and were considered a major advance in treatment because they rapidly suppressed viral loads to undetectable levels. These drugs are also notable for their high-price tag of $55,000 -- to $125,000 per patient according to QuintilesIMS.

According to ISMP, despite only an estimated 250,000 patients treated in 2015, the list price spending for hepatitis treatments exceeded similar spending for cholesterol-lowering drugs, antibiotics, or blood pressure drugs, each with patient populations measured in tens of millions.

The hepatitis market saw rapid growth in 2015, and projections indicate even further expansion for the next several years, according to Jeremy Schafer, PharmD, MBA, Senior Vice President, Specialty Solutions at Precision for Value.

But data cited by Schafer show that due to the high-price of hepatitis C drugs, payers responded by implementing policies that limit access to all but a segment of the 270,000 patients who were treated for hepatitis C in 2015. Industry forecasts show that in the coming year, only 60,000 to 70,000 patients will be treated with these new drugs annually.

A new survey from Precision for Value highlights payers’ unmet needs in the changing hepatitis C space, and focuses on what can be done to encourage payers to ease coverage policies for these drugs in the next wave of therapies for this infection. Among the top concerns, according to survey results, is drug pricing.  

Anthony Vecchione is the Executive Editor of Drug Topics.