Patients with a past or current hepatitis B virus (HBV) infection can experience sometimes fatal HBV reactivation if they take any of nine direct-acting antivirals for hepatitis virus C (HCV) infection, the US Food and Drug Administration (FDA) announced today.

The agency will require a boxed warning for the drugs advising clinicians to screen patients for evidence of a past or current HBV infection before ordering antiviral treatment for HCV.

The nine direct-acting antivirals prevent HCV from multiplying, and usually cure it.

Table. Direct-Acting Antivirals Linked to Hepatitis B Reactivation

Brand Name Active Ingredient(s) Drug Manufacturer Daklinza Daclatasvir Bristol-Myers Squibb Epclusa Sofosbuvir and velpatasvir Gilead Sciences Harvoni Ledipasvir and sofosbuvir Gilead Sciences Olysio Simeprevir Janssen Sovaldi Sofosbuvir Gilead Sciences Technivie Ombitasvir and paritaprevir and ritonavir AbbVie Viekira Pak Dasabuvir and ombitasvir and paritaprevir and ritonavir AbbVie Viekira Pak XR Dasabuvir and ombitasvir and paritaprevir and ritonavir AbbVie Zepatier eEbasvir and grazoprevir Merck Sharp Dohme Source: FDA

The FDA said in a news release that it had identified 24 cases of HBV reactivation in coinfected patients treated with these antivirals from November 22, 2013, to July 18, 2016, in reports to the agency and published literature. Two patients died, and one needed a liver transplant.

"The mechanism through which HBV reactivation occurs with (direct-acting antivirals) is currently unknown," the FDA stated. It noted that clinical trials for the HCV drugs in question did not report HBV reactivation because they excluded patients infected with HBV.

Flare-ups of inactive or once-resolved HBV with direct-acting antivirals have rung alarm bells before. In March, the European Medicines Agency announced that it had launched a review of six direct-acting antivirals for HCV on the basis of reports of HBV reactivation in individuals infected with both viruses. The study will evaluate how widespread HBV reactivation is in such patients and what can be done to optimize treatment.

And just last month, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of American issued updated guidelines that advise clinicians not to prescribe direct-acting antivirals to patients with HCV until the patients are screened for HBV, all because the societies were hearing about HBV reactivation in coinfected patients treated with the drugs. If patients who test positive for HBV warrant treatment, they should begin that treatment before or at the same time they start to receive direct-acting antivirals for HCV, according to the guidelines.

Raymond Chung, MD, co-chair of the panel that produced the guidelines and director of hepatology at Massachusetts General Hospital in Boston, said HBV reactivation may result from HCV clearance rather than a drug-specific toxicity.

More information about today's announcement is available on the FDA website.

To report any problems with direct-acting antiviral drugs for HCV, contact MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800-FDA-1088; by fax at 1-800-FDA-0178; online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm; with postage-paid FDA form 3500, available at http://www.fda.gov/MedWatch/getforms.htm; or by mail to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.

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