EPIVIR-HBV is indicated for the treatment of chronic hepatitis B associated with viral replication and active liver inflammation in adults and children 2-17 years.

Safety and effectiveness of treatment beyond 1 year have not been established, and the optimal duration of treatment is not known.

Lamivudine as Initial Treatment for Chronic Hepatitis B in the United States.

This multicenter, randomized, double-blind, placebo-controlled trial was conducted to assess the efficacy and safety of lamivudine in previously untreated U.S. patients with compensated chronic hepatitis B infection. One hundred and forty-three (143) patients from 34 centers were randomized to treatment with lamivudine (100 mg/day) or placebo for a period of 1 year (52 weeks) with posttreatment follow-up for 16 weeks. The primary efficacy measurement was histologic response, which was measured by a > 2-point improvement in Knodell histologic activity index (HAI) score. Liver biopsies were performed pretreatment and at week 52 and were scored under blinded conditions by an independent histopathologist. Secondary efficacy parameters included serological responses (hepatitis Be antigen [HBeAg] seroconversion, HBeAg loss, loss of hepatitis B virus deoxyribonucleic acid [HBV DNA], hepatitis B surface antigen [HBsAg] seroconversion, HBsAg loss), additional histologic parameters (ranked response, Knodell HAI score summary statistics, Knodell HAI necroinflammatory response, components of Knodell HAI score), and alanine aminotransferase (ALT) normalization.

In the Modified Intent-to-Treat Population (n=137), which was used for the efficacy analysis, 66 patients were randomized to lamivudine and 71 to placebo. The mean patient age was 41 (range 18-73) years; 114/137 (83%) patients were male. Ethnic background was similar between treatment groups and in the total group was 79/137 (58%) White, 23/137 (17%) Black, 28/137 (20%) Asian, 4/137 (3%) Hispanic, and 3/137 (2%) 'Other'.

Treatment groups were well matched for disease factors although baseline serum HBV DNA levels were somewhat higher in the lamivudine group (mean 198.9 pg/mL±306.8) than in the placebo group (mean 107.3 pg/mL±128.3). The median HAI score at baseline was 10.0 in the lamivudine-treated group and 11.0 in those receiving placebo. Six percent (6%) of lamivudine-treated patients and 14% of placebo-treated patients had cirrhosis at the baseline biopsy. Baseline ALT was similar between treatments, with mean ALT 3.5 times the upper limit of normal (ULN) in lamivudine-treated patients and 3.8 x ULN in placebo-treated patients.

Histologic response was significantly higher in lamivudine-treated patients than in those patients receiving placebo (52% versus 23%, P<0.001). Lamivudine patients had a median HAI reduction of 3 points at week 52, while the median change in placebo patients' score was 0. The necroinflammatory component of the HAI also significantly improved in 35 of 66 (53%) lamivudine-treated patients versus 17 of 71 (24%) patients receiving placebo (P<0.001). In blinded "ranked" assessments of biopsies pre- and post-therapy, placebo patients were more likely to exhibit progression in hepatic fibrosis than lamivudine-treated patients (20% versus 5%, P=0.007).

After 52 weeks of therapy, lamivudine patients were more likely to experience HBeAg seroconversion than placebo patients (17% versus 6%, P=0.036). HBeAg loss was observed in 21 of 66 (32%) of lamivudine-treated and 8/71 (11%) placebo-treated patients at week 52 and occurred between weeks 12 and 52. This response was still present in >80% of these patients at week 68 (ie, after the no-treatment follow-up period). HBsAg loss occurred in a single lamivudine-treated patient, at week 24.

Overall, in patients with evaluable data, median HBV DNA levels decreased by 97% within 2 weeks of starting lamivudine treatment. In lamivudine-treated patients, the median time to first HBV DNA response was 4 weeks. HBV DNA was undetectable by week 20 in 59/63 (94%) of lamivudine-treated patients.

Among patients with elevated ALT levels at baseline, 45/66 (68%) lamivudine-treated and 18/68 (26%) placebo-treated patients demonstrated an ALT response (ALT normalization), an outcome which was sustained in 27/66 (41%) lamivudine-treated and 5/68 (7%) placebo-treated patients during the treatment period.

Lamivudine was generally well-tolerated throughout the study with a safety profile similar to placebo during treatment. Ninety percent (90%) of patients treated with lamivudine and 96% of patients on placebo reported at least one adverse event during treatment, but most events were mild to moderate in intensity. No deaths occurred during the study. Serious adverse events occurred in 8 of 70 (11%) lamivudine-treated patients (26 serious adverse events) and 10 of 71 (14%) placebo-treated patients (14 serious adverse events). A total of 40 serious adverse events were noted; however, none was considered to be drug related by the investigators.

Grade 2 (2.1-3 x baseline) or Grade 3 (3.1-10 x baseline) ALT toxicities occurred in a similar number of patients (<15%) during treatment on either treatment arm, and no Grade 4 (>10 x baseline) ALT toxicities occurred during treatment. Elevated HBV DNA and serum aminotransferases recurred after lamivudine treatment discontinuation (ie, after week 52), reflecting a return of hepatitis B. Patients with a maximum toxicity grade of 3, posttreatment, were more common in lamivudine-treated patients compared with placebo-treated patients (22% versus 6%). Grade 4 ALT posttreatment toxicities were rare (<3%) on either treatment arm.

In summary, in this controlled phase III trial, lamivudine treatment significantly improved liver histology and increased the HBeAg seroconversion rate in previously untreated patients with chronic hepatitis B. In addition, the safety profile of lamivudine appeared comparable with placebo treatment during the 52-week treatment period. An apparent mild increase in posttreatment ALT elevations was noted in the lamivudine-treated cohort. These posttreatment ALT elevations were generally mild to moderate in severity, transient, and not associated with hepatic insufficiency or clinical signs.

Thus, in this placebo-controlled phase III trial, treatment with lamivudine appeared generally well tolerated and effective as a therapeutic agent for therapy-naïve patients with chronic hepatitis B.

A publication of this study can be found at:

Dienstag JL, Schiff ER, Wright TL, et al. for The U.S. Lamivudine Investigator Group. Lamivudine as Initial Treatment for Chronic Hepatitis B in the United States. N Engl J Med. 1999;341:1256-1263.

A One-Year Trial of Lamivudine for Chronic
Hepatitis B.

The primary objectives were to compare the improvement in hepatitis and assess safety with oral lamivudine 25 mg, lamivudine 100 mg, and placebo, once daily for 1 year, in patients with chronic hepatitis B. Productivity impact assessment was a secondary objective. This was a randomized, double-blind, placebo-controlled study in 358 Asian patients at 7 centers in Hong Kong, Singapore, and Taiwan. Before randomization, patients were assigned to strata according to liver biopsy results. The primary efficacy analyses were: for Stratum 1 (moderate/severe hepatitis), improvement in hepatitis (Knodell HAI Necro-inflammatory Score); for Stratum 2 (mild hepatitis), decreased liver hepatitis B markers (hepatitis B core antigen and HBV DNA). Secondary efficacy analyses included: decreased liver hepatitis B markers (Stratum 1); improvement in hepatitis (Stratum 2); serum HBV DNA and ALT reduction, HBeAg loss, HBeAb positivity, HBsAg reduction (for all patients).

Lamivudine 25 mg or 100 mg once daily for 1 year resulted in a significant improvement in the necro-inflammatory activity of the liver compared with placebo. Lamivudine 100 mg once daily was significantly associated with a reduced progression to a more advanced stage of fibrosis compared with placebo. HBV DNA suppression was most rapidly and effectively sustained in patients receiving lamivudine 100 mg compared with either placebo or lamivudine 25 mg. HBeAg seroconversion was significantly more common with lamivudine 100 mg compared with placebo. The nature and incidence of adverse events in chronic hepatitis B patients were similar to placebo with each dose of lamivudine. Lamivudine 100 mg once daily is the recommended dose for the treatment of patients with chronic hepatitis B.

A publication of this study can be found at:

Lai C-L, Chien RN, Leung NW, et al. for The Asia Hepatitis Lamivudine Study Group. A One-Year Trial of Lamivudine for Chronic Hepatitis B. N Engl J Med. 1998;339:61-68.

A Randomised, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of 52 Weeks Lamivudine Treatment at a Dose of 3 mg/kg in Pediatric Subjects with Chronic Hepatitis B

The objectives of this study were to compare the efficacy and safety of lamivudine versus placebo in children with chronic hepatitis B. The primary endpoint was complete virologic response (HBeAg-ve and HBV DNA-ve) after 52 weeks of treatment, and the most important secondary endpoint was sustained normalization of serum ALT at week 52. The other secondary endpoints were: HBeAg loss; 2 and 3 component HBeAg seroconversion; HBV DNA response; HBsAg loss; HBsAg seroconversion; ALT response; and the incidence of AEs and laboratory abnormalities. The effect of development of YMDD variant HBV on the outcome of each of the above endpoints was also explored in the lamivudine treatment group.

After 52 weeks of treatment, lamivudine was found to be significantly more effective (P=0.037) than placebo at inducing a complete virologic response in pediatric patients with chronic hepatitis B. The proportion of patients at week 52 with sustained normalization of ALT was also significantly greater (P<0.001) with lamivudine treatment compared with placebo, indicating lamivudine was significantly more effective at reducing liver inflammation. In addition: Lamivudine was significantly more effective than placebo at reducing HBeAg and HBV DNA to undetectable levels by week 52; there were higher proportions of patients in the lamivudine treatment group with 2 and 3 component seroconversion at week 52; and 3 patients (all lamivudine treated) had undetectable HBsAg at week 52. The nature and incidence of AEs and laboratory abnormalities reported in the lamivudine treatment were similar to those of placebo. Patients with YMDD variant HBV had reduced HBeAg responses but maintained reductions in HBV DNA and ALT levels, and maintained a safety profile similar to that of placebo.

A publication of this study can be found at:

Jonas MM, Kelley DA, Mizerski J, et al. Clinical Trial of Lamivudine in Children with Chronic Hepatitis B. N Engl J Med. 2002;346(No. 22):1706-1713

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