Pegylated interferon therapy of chronic hepatitis D: In need of revision

E fficacious therapies are available to control hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, but no valid therapy has been developed against the hepatitis D virus (HDV); interferon (IFN)-a remains the only licensed therapy 30 years after it was empirically introduced in clinical practice on the wake of its use as a panacea for all types of viral hepatitis. The overall results with standard IFN were poor. At a dose of 3-6 MU thrice-weekly for 6-12 months, treatment controlled liver enzymes in no more than 20%25% of the patients; rates of HDV-RNA clearance were lower. Results were worse in patients with cirrhosis. The studies were difficult to compare; they were heterogeneous, had different designs and protocols, each examined only a small number of patients, and testing for HDVRNA was performed with homemade nucleic acid hybridization assays of limited sensitivity and specificity. Long-acting pegylated IFNs (Peg-IFNs) have increased efficacy only marginally. In four studies, a virological response was observed in 18%-25% of the patients; only in a series of 14 patients the response rate was 43%. Increasing the dosage of IFN, prolonging therapy to 24 months, adding an antiviral against HBV or ribavirin to Peg-IFN was of no advantage. All studies considered as the therapeutic endpoint the virological response 6 months posttherapy, following the paradigm of the sustained virological response (SVR) derived from the experience with HCV disease, where SVR is a surrogate of cure. No study performed with the current standard of care (i.e., Peg-IFN) addressed systematically the long-term virological and clinical outcome of treated HDV patients. The issue of the therapy for chronic hepatitis D (CHD) has been reconsidered in a number of comprehensive studies performed by a German-Turkish-Greek consortium on behalf of the Hep-Net International Delta Hepatitis Intervention Trial (HIDIT-I). They have included the larger number of HDV patients treated thus far and have analyzed, in structured, well-designed investigations, all the factors influencing therapy that had emerged from previous studies. In a first study published in 2011, 90 patients were randomly assigned to receive either 180 lg of PegIFN-a each week plus 10 mg of adefovir (31 patients), 180 lg/kg of Peg-IFN-a2a plus placebo (29 patients), or adefovir alone (30 patients). By week 48 of therapy, the reduction of HDV RNA was higher and similar in the two groups using Peg-IFN, compared with adefovir alone; overall HDV RNA was negative in 28% of patients given Peg-IFN, compared with only 8% of the patients given adefovir alone. The SVR rate of 28% confirmed that Peg-IFN may be efficacious in approximately one fourth of treated patients. The study confirmed also that a potent HBV antiviral such as adefovir had no therapeutic role, either alone or in combination with IFN. Nevertheless, the impact of therapy on liver disease was not consistent; more patients in the Peg-IFN groups had a worsening of histological scores on biopsies performed at the end of treatment, and the levels of alanine aminotransferase (ALT) normalized also in patients who remained positive for HDV RNA during the follow-up. A second piece of the HIDIT-I mosaic has been published in the July issue of HEPATOLOGY, where Heidrich et al. report on the outcome over the long term of HDV patients treated in the first HIDIT-I study. This information is critical in order to assess the true efficacy of Peg-IFN therapy; although relapses of HD viremia and hepatitis D after apparently successful therapy were repeatedly noted using first-generation insensive assays for serum HDV RNA, the report by Heidrich et al. is the first to systematically determine the extent and impact of late posttherapy relapses of HDV using a polymerase chain reaction assay with a sensitivity as low as 15 cps HDV RNA/mL. Abbreviations: ALT, alanine aminotransferase; CHD, chronic hepatitis D; HbsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HIDIT-I, Hep-Net International Delta Hepatitis Intervention Trial; IFN, interferon; Peg-IFN, pegylated IFN; SVR, sustained virological response. Received July 3, 2014; accepted October 21, 2014. Address reprint requests to: Mario Rizzetto, M.D., Division of Gastroenterology, University of Torino, Corso Dogliotti, 14 Torino 10126, Italy. E-mail: mario.rizzetto@unito.it; fax: 139 011 633 5927. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27585 Potential conflict of interest: Dr. Rizzetto advises and is on the speakers’ bureau for Janssen and Bristol-Myers Squibb. He advises Merck and AbbVie.