ABSTRACT
Current therapies for chronic hepatitis B (CHB) have a number of limitations, and better treatment options are needed. Peginterferon alpha-2a (40 kDa) is superior to conventional interferon alpha-2a in the treatment of chronic hepatitis C. This is the first report on peginterferon alpha-2a (40 kDa) in the treatment of CHB. In this phase II study, 194 patients with CHB not previously treated with conventional interferon-alpha were randomized to receive weekly subcutaneous doses of peginterferon alpha-2a (40 kDa) 90, 180 or 270 microg, or conventional interferon alpha-2a 4.5 MIU three times weekly. Twenty-four weeks of therapy were followed by 24 weeks of treatment-free follow-up. All subjects were assessed for loss of hepatitis B e antigen (HBeAg), presence of hepatitis B antibody (anti-HBe), suppression of hepatitis B virus (HBV) DNA, and normalization of serum alanine transaminase (ALT) after follow-up. At the end of follow-up, HBeAg was cleared in 37, 35 and 29% of patients receiving peginterferon alpha-2a (40 kDa) 90, 180 and 270 microg, respectively, compared with 25% of patients on conventional interferon alpha-2a. The combined response (HBeAg loss, HBV DNA suppression, and ALT normalization) of all peginterferon alpha-2a (40 kDa) doses combined was twice that achieved with conventional interferon alpha-2a (24%vs 12%; P = 0.036). All treatment groups were similar with respect to frequency and severity of adverse events. These results indicate that peginterferon alpha-2a (40 kDa) is superior in efficacy to conventional interferon alpha-2a in chronic hepatitis B based on clearance of HBeAg, suppression of HBV DNA, and normalization of ALT.
Subject(s)
Hepatitis B e Antigens/immunology , Hepatitis B, Chronic/drug therapy , Interferon-alpha/administration & dosage , Polyethylene Glycols/administration & dosage , Adolescent , Adult , Aged , Confidence Intervals , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Hepatitis B, Chronic/immunology , Humans , Injections, Subcutaneous , Interferon alpha-2 , Interferon-alpha/adverse effects , Male , Middle Aged , Polyethylene Glycols/adverse effects , Recombinant Proteins , Reference Values , Risk Assessment , Serologic Tests , Treatment OutcomeABSTRACT
BACKGROUND & AIMS: Ganciclovir is a nucleoside analogue active against cytomegalovirus. The compound has also shown in vitro and in vivo activity against duck hepatitis B virus. We investigated the ability of ganciclovir to inhibit another Hepadnaviridae, the woodchuck hepatitis virus, which is the most closely related with hepatitis B virus. We compared two different quantification methods of woodchuck hepatitis virus DNA. METHODS: We treated seven chronic woodchuck hepatitis virus carriers by daily intravenous injections of 5 mg/kg body weight of ganciclovir for seven consecutive days, and followed the animals for 3 weeks post therapy. In addition to traditional X-ray autoradiography, which is a semi-quantitative method, we evaluated woodchuck hepatitis virus DNA levels with storage phosphor technology. RESULTS: A reduction in serum woodchuck hepatitis virus DNA was observed during treatment in all animals regardless of pre-treatment viraemia levels when using x-ray films and phosphor storage technology. The latter method allowed calculation of mean values of average phosphor imager signals. When comparing the mean values (+/- 95% confidence intervals) before and during therapy, a significant decrease in woodchuck hepatitis virus DNA (80 to 100%) could be shown. After stopping therapy, virus DNA rebounded in all animals. CONCLUSIONS: Our results show that ganciclovir inhibits viral replication in woodchucks chronically infected with woodchuck hepatitis virus. No signs of toxicity were observed. After dot-blot hybridization, storage phosphor imaging was proven superior to X-ray autoradiography for measuring viral DNA. Storage phosphor technology is highly sensitive, quantitative and easy to handle. By comparing mean values and confidence intervals before and during therapy, treatment effects can be distinguished from natural fluctuations.
Subject(s)
Antiviral Agents/pharmacology , DNA, Viral/drug effects , Ganciclovir/pharmacology , Hepatitis B Virus, Woodchuck/drug effects , Hepatitis B/drug therapy , Animals , Antiviral Agents/therapeutic use , Autoradiography/methods , Carrier State/virology , DNA, Viral/analysis , Disease Models, Animal , Ganciclovir/therapeutic use , Hepatitis, Animal/drug therapy , Injections, Intravenous , Marmota , Radiographic Image Enhancement , Reference Values , Virus Replication/drug effectsABSTRACT
Dideoxycytidine (ddC) is a nucleoside analogue active against human immunodeficiency virus and with in vitro activity against human hepatitis B virus. We investigated the ability of ddC to inhibit one of the Hepadnaviridae, the woodchuck hepatitis virus and compared the results with the effect obtained by a conjugate of lactosaminated human serum albumin 2',-3'-dideoxycytidine monophosphate (L-HSA ddCMP). This compound specifically enters the hepatocyte via the asialoglycoprotein receptor. We treated five chronic woodchuck hepatitis virus carriers with intravenous injections of 0.5 mg/kg body weight of ddC for 5 consecutive days, and under the same protocol five woodchucks with 10.4 mg/ kg L-HSA ddCMP, a dose equivalent to 0.25 mg/kg of free ddC. A reduction of serum woodchuck hepatitis virus DNA (5-125 fold) was observed during therapy in three out of five animals receiving ddC and in two of the five animals treated with L-HSA ddCMP. In responding woodchucks, virus DNA levels rebounded immediately after stopping therapy. No signs of toxicity were observed during or after the course of therapy. These preliminary results of short-term treatment indicate that ddC has anti-viral activity against woodchuck hepatitis virus. When the dose was reduced by 50%, L-HSA ddCMP showed anti-viral activity to an even lesser degree.