FDA warns about the risk of HBV reactivation in patients treated with DAA for HCV-infection

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October 05, 2016 – Here, we make available to our readers a Drug Safety Communication by the American Food & Drug Administration (FDA), where FDA warns about the risk of hepatitis B virus (HBV) reactivation in some patients treated with direct-acting antivirals (DAA) for hepatitis hepatitis-c-iC virus (HCV)-infection. Apparently, this reactivation of HBV infection under direct acting antivirals (DAA)-therapy for HCV-infection is considered a very serious and urgent matter in that the FDA is requiring a “Boxed Warning” for this serious adverse drug event. A “Boxed Warning” is the highest level of alerting patients and  health care providers, including treating physicians, about selected dangers of a drug in its associated FDA-issued drug label.

In this context, it will be interesting to see how quickly other regulatory agencies around the world will act upon this finding and also modify drug labels and/or patient informations accordingly. In the sake of the individual patients safety, this would have to happen immediately and without administrative delay. Because one can expect that worldwide, a large number of patients are actually co-infected with HBV and HCV, a considerably significant number of patients worldwide are going to be affected by this HBV-infection reactivation problem under HCV-infection therapy with DAA’s.

In the meantime, please read the Drug Safety Communication by the FDA, unedited and uncommented, just as it was issued on October 04, 2016:

 by the FDA

The U.S. Food and Drug Administration (FDA) is warning about the risk of hepatitis B virus (HBV) becoming an active infection again in any patient who has a current or previous infection with HBV and is treated with certain direct-acting antiviral (DAA) medicines for hepatitis C virus. In a few cases, HBV reactivation in patients treated with DAA medicines resulted in serious liver problems or death.

As a result, we are requiring a Boxed Warning, our most prominent warning, about the risk of HBV reactivation to be added to the drug labels of these DAAs directing health care professionals to screen and monitor for HBV in all patients receiving DAA treatment. This warning will also be included in the patient information leaflet or Medication Guides for these medicines.

Direct-acting antiviral medicines are used to treat chronic hepatitis C virus (HCV) infection, an infection that can last a lifetime. These medicines reduce the amount of HCV in the body by preventing HCV from multiplying, and in most cases, they cure HCV. Without treatment, HCV can lead to serious liver problems including cirrhosis, liver cancer, and death (see List of Direct-Acting Antivirals).

Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with DAAs, and monitor patients using blood tests for HBV flare-ups or reactivation during treatment and post-treatment follow-up. It is currently unknown why the reactivation occurs.

Patients should tell your health care professional if you have a history of hepatitis B infection or other liver problems before being treated for hepatitis C. Do not stop taking your DAA medicine without first talking to your health care professional. Stopping treatment early could result in your virus becoming less responsive to certain hepatitis C medicines. Read the patient information leaflet or Medication Guide that comes with each new prescription because the information may have changed. Contact your health care professional immediately if you develop fatigue, weakness, loss of appetite, nausea and vomiting, yellow eyes or skin, or light-colored stools, as these may be signs of serious liver problems.

We identified 24 cases of HBV reactivation reported to FDA1 and from the published literature in HCV/HBV co-infected patients treated with DAAs during the 31 months from November 22, 2013 to July 18, 2016. This number includes only cases submitted to FDA, so there are likely additional cases about which we are unaware. Of the cases reported, two patients died and one required a liver transplant. HBV reactivation was not reported as an adverse event in the clinical trials submitted for the DAA approvals because patients with HBV co-infection were excluded from the trials. The trials excluded these patients in order to specifically evaluate the safety of DAAs, including their effects on the liver, in patients infected with only HCV and without the presence of another virus which affects the liver (see Data Summary).

We urge health care professionals and patients to report side effects involving DAAs and other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.

List of Direct-Acting Antivirals (DAAs)*

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 elbasvir and grazoprevir Merck Sharp Dohme

*DAA regimens not requiring use in combination with interferon. The DAA medicines, Victrelis (boceprevir) and Incivek (telaprevir), are not included in the list as they are used in combination with interferon and are no longer available in the United States.

 Related Information

Drug Safety Communication (PDF – 97KB)

The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective

Think It Through: Managing the Benefits and Risks of Medicines

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About the Author
thassodotcom Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.
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