Safety and efficacy of oral entecavir given for 28 days in patients with chronic hepatitis B virus infection

Abstract

Entecavir is an oral antiviral drug with selective activity against hepatitis B virus (HBV). We conducted a randomized, placebo-controlled, dose-escalating study in patients with chronic hepatitis B infection in which we evaluated the efficacy and safety of entecavir given for 28 days. Follow-up was 24 weeks. All doses of entecavir (0.05 mg, 0.1 mg, 0.5 mg, and 1.0 mg) showed a pronounced suppression of replication of the HBV with a 2.21, 2.29, 2.81, and 2.55 mean log 10 reduction of viral load, respectively. Approximately 25% of patients on entecavir showed a decline of HBV DNA below the limit of detection of the Chiron HBV-DNA assay (<0.7 MEq/mL). In the postdosing follow-up period patients who were treated with 0.5 and 1.0 mg of entecavir showed a considerably slower return in their HBV DNA levels to baseline compared with those patients treated with lower dosages (P < .05). All doses of entecavir were well tolerated with no significant difference between treated patients and those receiving placebo. No significant changes in alanine transaminase (ALT) levels within the dose groups and the placebo group between baseline and the end of treatment were observed. Three patients (9%) (1 each in the 0.05-, 0.1-, and 0.5-mg groups) experienced asymptomatic hepatitis flares 16 weeks (2 patients) and 24 weeks (1 patient) after withdrawal of entecavir. In conclusion, in this 28-day study of entecavir a pronounced decrease of HBV DNA was observed and there were no significant side effects in entecavir patients in comparison with placebo-treated patients. (HEPATOLOGY 2001;34:578-582.)Although the introduction of an effective vaccine against hepatitis B has drastically reduced the incidence of new infections, more than three hundred million people are affected by chronic hepatitis B infection worldwide. The infection may eventually lead to a substantial percentage of deaths caused by cirrhosis with complications of liver failure and hepatocellular carcinoma. 1 Interferon alfa has been the only registered therapy during recent years but it is effective in only one third of patients, 2 requires parenteral administration, and causes many side effects especially in cases of cirrhosis. 3 Lamivudine, a cytosine nucleoside analogue, is an orally administered antiviral agent with few side effects. It has recently been registered for the treatment of chronic hepatitis B infection. [4][5][6] However, the development of mutations with decreased sensitivity of the virus for lamivudine, 7-9 and the rebound of viral replication after withdrawal of the drug 10,11 leave room for further improvement of nucleoside analogue therapy. The increase in viral replication after withdrawal of the drug is based on residual covalently closed circular DNA (cccDNA) inside the nucleus of the hepatocyte, which is not affected by lamivudine. 12,13 Entecavir, a new deoxyguanine nucleoside analogue, is a selective inhibitor of the replication of the hepatitis B virus (HBV). 14-16 In HepG2.2.15 cell lines, this compound has proved to be 30 times more potent...

High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation

“…60 Hence, the use of more potent nucleoside analogues is desirable. Several new nucleoside analogues, including adefovir dipivoxil, 61 entecavir, 62 and emtricitabine, 63 have been found to be effective in suppressing HBV replication. Additional clinical trials of these nucleoside analogues are needed to determine their antiviral efficacy in patients.…”

Clinical Emergence of Entecavir-Resistant Hepatitis B Virus Requires Additional Substitutions in Virus Already Resistant to Lamivudine

“…Entecavir (ETV; BMS-200475) is a novel deoxyguanosine analog with potent activity against HBV in vitro, in animal studies, and in patients chronically infected with HBV (7,11,14,17,21,23,29). In enzymatic studies, 3TC r HBV polymerases were shown to have reduced susceptibility to ETV (20).…”

“…Treatment with ADV, recently approved by the U.S. Food and Drug Administration, can be associated with dose-limiting nephrotoxicity (6), although the reported frequency of resistance to ADV is considerably lower than that to 3TC (2, 28). Therefore, more potent and safer oral therapies, with less frequent development of viral resistance, are needed for the treatment of chronic HBV infections.Entecavir (ETV; BMS-200475) is a novel deoxyguanosine analog with potent activity against HBV in vitro, in animal studies, and in patients chronically infected with HBV (7,11,14,17,21,23,29). In enzymatic studies, 3TC r HBV polymerases were shown to have reduced susceptibility to ETV (20).…”

Monitoring Drug Resistance in Chronic Hepatitis B Virus (HBV)-Infected Patients during Lamivudine Therapy: Evaluation of Performance of INNO-LiPA HBV DR Assay

“…However, viral breakthrough is detected in approximately 16% to 32% of patients after 1 year of treatment (12). Newer oral nucleoside/nucleotide analogues in clinical trials, such as adefovir dipivoxil (4), entecavir (6), and emtricitabine (19,18), appear to be at least as potent as lamivudine. In vitro and in vivo studies showed that adefovir and entecavir are also effective in suppressing lamivudine-resistant HBV (8).…”