Sequential treatment with lamivudine and interferon- monotherapies in hepatitis B e antigen-negative Chinese patients and its suppression of lamivudine-resistant mutations

Shanghai Jiao Tong University, Shanghai, Shanghai Shi, China
Journal of Antimicrobial Chemotherapy (Impact Factor: 5.31). 11/2006; 58(5):1031-5. DOI: 10.1093/jac/dkl385
Source: PubMed


To assess the efficacy of sequential treatment with lamivudine and interferon-alpha monotherapies in Chinese patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B.
One hundred and sixty-two patients with HBeAg-negative chronic hepatitis B were included in this study. Ninety-eight were treated with lamivudine alone (100 mg per day) for 48 weeks (group B). Sixty-four were treated with lamivudine alone (100 mg per day) for 20 weeks, then combined with interferon-alpha-2b (5 million units three times per week) for 4 weeks and then treated for another 24 weeks with interferon-alpha-2b alone (5 million units three times per week) (group A). All patients were followed for an additional 24 weeks.
After 48 weeks of treatment, the percentage of patients with normalization of alanine aminotransferase (ALT) levels or hepatitis B virus (HBV) DNA levels below 1000 copies/mL was not significantly different between the lamivudine monotherapy group (55.10% and 55.10%, respectively) and the sequential treatment group (59.36% and 56.25%, respectively). The percentage of patients with normalized ALT levels was significantly higher in group A (53%) than in group B (36%) at week 72 (P<0.05). The percentage of patients with lamivudine-resistant mutations was significantly higher with lamivudine monotherapy (22.45%) than with sequential therapy (P<0.05).
Sequential treatment of chronic hepatitis B with lamivudine and interferon-alpha monotherapies is as effective as lamivudine-alone treatment in Chinese patients. However, sequential treatment can significantly suppress the emergence of lamivudine-resistant mutations.

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    ABSTRACT: Objectives: This study aimed to compare the efficacy of the α-interferon treatment with α-interferon plus lamivudine for cases of chronic hepatitis B. Materials and methods: Sixty-one HBeAg negative naive chronic hepatitis B patients were randomly evaluated in two groups prospectively. In group 1, 30 patients were simultaneously given α-interferon 2a 9 MU, 3 days a week by s.c. injection plus lamivudine 100 mg a day for 12 months. In group II, there were 31 patients who only was received the same dosage of α-interferon and no lamivudine over the same period of time. Results: In group 1 the initial mean value of alanine aminotransferase (ALT) was 144±59 IU/L and decreased to 38.8±19.3 IU/L; in group II, initial mean values of ALT was 141±52 IU/L and decreased to 53.2±14.7 IU/L at the end of 12 th month of the therapy (P<0.05). Hepatitis B virus DNA (HBV-DNA) clearance was obtained in 13 of 30 patients (43.3%) in group I patients and 15 of 31 (48.4%) in group II at the end of the therapy (p=0.692). The number of patients with complete response was found to be 14 out of 30 (48.4%) in group 1 and 15 out of 31 cases (46.7%) in group II, six months after the end of the therapy (P=0.893).
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    ABSTRACT: The main goals of chronic hepatitis B treatment should be the long-term suppression of viral replication to minimize disease progression and the risk for the development of hepatocellular carcinoma. Treatment end-points, depending on surrogate markers alone, in particular hepatitis B e-antigen seroconversion, may not be ideal for patients who acquire the disease early in life. Currently-available drugs include interferons and oral nucleoside/nucleotide analogs. Although interferon therapy provides a finite treatment period, a significant proportion of patients may not respond, and long-term outcome is inconclusive. Long-term efficacy has been demonstrated for both lamivudine and adefovir. However, prolonged nucleoside/nucleotide analog therapy is associated with the emergence of drug-resistant mutations. Therefore, nucleoside/nucleotide analogs with a high genetic barrier and potent antiviral activity, such as entecavir, should be used to reduce the chance of developing drug-resistant mutations. Drugs with a low genetic barrier, including lamivudine and telbivudine, should be used in conjunction with early testing for antiviral response. This can predict favorable outcomes in the long term. The early detection of drug-resistant mutations should prompt clinicians to either add or switch to another agent with a different drug-resistance profile. There are currently no treatment models in the use of combination or sequential therapy in treatment-naïve patients. To date, long-term treatment appears to be the most effective option. Despite recent advances made with better understanding on the natural history of chronic hepatitis B infection and with newer antiviral drugs available, challenges remain with respect to treatment criteria, treatment end-points, and duration of treatment.
    Journal of Gastroenterology and Hepatology 08/2008; 23(8 Pt 1):1182-92. DOI:10.1111/j.1440-1746.2008.05400.x · 3.50 Impact Factor
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    ABSTRACT: Synthesize evidence of the natural history of chronic hepatitis B (CHB) and effects and harms of antiviral drugs on clinical, virological, histological, and biochemical outcomes. MEDLINE, electronic databases, and manual searches of systematic reviews. We included original observational studies to assess natural history and randomized controlled trials (RCTs) of adults with CHB published in English to assess treatment effects and harms if they reported mortality, incidence of hepato-cellular carcinoma (HCC), cirrhosis or failure, HBeAg or HBsAg, viral load (HBV DNA), alanine aminotransferase (ALT) levels, histological necroinflammatory and fibrosis scores, and adverse events after interferon alfa-2b, pegylated interferon alfa 2-a, lamivudine, adefovir, entecavir, tenovir or telbivudine. We excluded pregnant women, transplant patients, and individuals undergoing cancer chemotherapy. We calculated relative risk or absolute risk differences at end of treatment and post-treatment. Observational studies (41 publications) suggested that male gender, coinfection with hepatitis C, D, or HIV, increased HBV DNA, and cirrhosis were associated with increased risk of HCC and death. Drugs did not reduce death, liver failure, or HCC in 16 RCTs not designed to test long-term clinical outcomes. Evidence from 93 publications of 60 RCTs suggested drug effects on viral load or replication, liver enzymes, and histology at end of treatment and lasting from 3 to 6 months off treatment. No one treatment improved all outcomes and there was limited evidence on comparative effects. Two RCTs suggested interferon alfa-2b increased CHB solution versus placebo. Interferon alfa-2b or lamivudine improved off treatment HBV DNA and HBeAg clearance and seroconversion and ALT normalization. Adefovir improved off treatment ALT normalization and HBV DNA clearance. Pegylated interferon alfa 2-a versus lamivudine improved off-treatment HBV DNA and HBeAg clearance and seroconversion, ALT normalization and liver histology. Lamivudine combined with interferon alfa-2b versus lamivudine improved off treatment HBV DNA clearance and HBeAg seroconversion and reduced HBV DNA mutations. Pegylated interferon alfa 2-a plus lamivudine improved off treatment HBV DNA and HBeAg clearance and seroconversion and ALT normalization compared to lamivudine but not pegylated interferon alfa 2-a monotherapy. Adverse events were common but generally mild and did not result in increased treatment discontinuation. Longer hepatitis duration, male gender, baseline viral load and genotype, HBeAg, and histological status may modify treatment effect on intermediate outcomes. Adefovir and pegylated interferon alfa 2-a with lamivudine improved off treatment viral clearance in HBeAg negative patients. There was insufficient evidence to determine if biochemical, viral, or histological measures are valid surrogates of treatment effect on mortality, liver failure, or cancer. Adults with CHB have an increased risk of death, hepatic decompensation, and HCC. Mono or combined drug therapy improves selected virological, biochemical, and histological markers with no consistent effects on all examined outcomes. Patient and disease characteristics may modify treatment-induced intermediate outcomes. Evidence was insufficient to assess treatment effect on clinical outcomes, predict individualized patient response, or determine if intermediate measures are reliable surrogates. Future research should assess long-term drug effects on clinical outcomes and among patient subpopulations.
    Evidence report/technology assessment 11/2008;
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