On March 18, 2016, the European Medicines Agency (EMA) released a statement concerning a review the agency is currently conducting on direct-acting antiviral drugs (DAAs) used for treating chronic hepatitis C viral (HCV) infection. The agency’s Pharmacovigilance Risk Assessment Committee recently expanded the scope of that review of DAAs to include the potential risk for early liver cancer recurrence. DAAs are molecules that directly target and disrupt hepatitis C’s ability to replicate, the primary mode by which the virus remains a viable driver of infection.
The London-based EMA, an agency of the European Union (EU), is responsible for the scientific evaluation, supervision and safety monitoring of medicines developed by pharmaceutical companies for use in the EU. The impetus for the EMA review is now twofold: A handful of reported cases of hepatitis B virus (HBV) reactivation in patients who have been infected with the hepatitis B and C viruses, and reports of two European follow-up studies on the recurrence of previous hepatocellular carcinoma after patients were treated with DAAs for HCV.
In the case of HBV reactivation, the EMA’s decision comes on the heels of a few case reports wherein patients with inactive HBV infection experienced a reactivation of the virus during the course of their DAA-based HCV treatment. The five cases reported to date occurred in individuals with different genotypes and involved different DAA combination therapies. While a correlation remains unclear, there seem to be slight risks in activating dormant HBV among a few individuals taking these new HCV DAAs.
Meanwhile, the results of a study from Spain published in the Journal of Hepatology (AJH) showed somewhat surprisingly high rates of liver cancer recurrence in patients who were treated with DAAs for HCV. In all, 27.6% of the 58 HCV-infected/DAA-administered patients included in the study experienced a return of a type of liver cancer called hepatocellular carcinoma (HCC). The report, “Unexpected Early Tumor Recurrence in Patients with Hepatitis C Virus-Related Hepatocellular Carcinoma Undergoing Interferon-Free Therapy: A Note of Caution,” was published online in AJH on April 12th.
In a second preliminary study from Italy, 26 of 344 patients (7.6%) with HCV and cirrhosis who were treated with one or two DAAs were diagnosed with HCC during a six- month, post-treatment evaluation period. This number included 17 of 59 patients previously treated for HCC and 9 of 285 patients with no history of carcinoma. An abstract based on these findings was presented on April 13th at the International Liver Congress in Barcelona, Spain.
To date, the HCC-related reports do not show a clear association between HCC recurrence by hepatitis C genotype nor regimen, although patients with advanced cirrhosis seem to be among those more affected. While these studies are preliminary and warrant further study, they nonetheless highlight the need for patients on DAAs to be routinely monitored by their hepatologist and/or hematologist on a six-month (or at least annual) basis. In particular, patients with previous hepatitis B infection, any cirrhosis and/or previous hepatocellular carcinoma need to receive follow-up after their treatment with DAAs.
The National Hemophilia Foundation’s (NHF's) Medical and Scientific Advisory Council (MASAC) has been reviewing published reports relevant to these issues. MASAC members are also consulting with the leading hepatitis specialists and the US Food and Drug Administration (FDA) to determine how this may specifically affect individuals with hemophilia taking DAAs to treat HCV. While this review is ongoing, patients should speak to their physician if they have any questions or concerns. NHF will continue to report on any relevant developments as they arise. Clearly, there exists a need for additional research to better understand these developments and determine whether certain patients may be at greater risk.
EMA’s announcement of the review came via a statement released on March 18, 2016.
EMA’s follow-up announcement of the expanded review was released on April 15, 2016.
