Long-Term Therapy of Chronic Hepatitis B With Lamivudine

Lau, Daryl T.Y.; Khokhar, M. Farooq; Doo, Edward; Ghany, Marc G.; Herion, David; Park, Yoon; Kleiner, David E.; Schmid, Peter; Condreay, Lynn D.; Gauthier, Josée; Kuhns, Mary C.; Liang, T. Jake; Hoofnagle, Jay H.

doi:10.1053/jhep.2000.17912

Cited by 328 publications

(244 citation statements)

References 33 publications

Supporting

Mentioning

219

Contrasting

Unclassified

Order By: Relevance

“…All subjects had been followed in the Liver Diseases Section, NIDDK, National Institutes of Health for Ͼ2 years, tested negative for Abs to HIV and hepatitis C virus (HCV), and gave written informed consent to this institutional review board-approved study. Preliminary results of the outcome of lamivudine therapy (100 mg daily) in a subgroup of these patients have been reported (25). Sixteen healthy blood donors without any history of hepatitis and without HBsAg or anti-HBc in serum served as controls.…”

Section: Patient Populationmentioning

confidence: 99%

“…Samples with HBV DNA of Ͻ1 mEq/ml were tested by quantitative PCR (National Genetics Institute, Los Angeles, CA) with a lower limit of detection of 100 copies/ml and by qualitative nested PCR as described (8). RFLP assay was used to detect virological lamivudine resistance defined by either YIDD mutants (methionine-to-isoleucine substitution at codon 552 (M552I)) or YVDD mutants (methionine-to-valine substitution at codon 52 (M552V)) in conjunction with a leucine-to-methionine substitution at codon 528 (L528M) of the HBV polymerase gene (24,27,28) as previously described (25). The lower limit of detection of this method was ϳ500 copies viral DNA/ml serum.…”

Section: Laboratory and Virologic Testingmentioning

confidence: 99%

See 1 more Smart Citation

Cellular Immune Responses to the Hepatitis B Virus Polymerase

Mizukoshi

Sidney

Livingston³

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

CD4+ T cells play an important role in hepatitis B virus (HBV) infection by secretion of Th1 cytokines that down-regulate HBV replication, and by promoting CD8+ T cell and B cell responses. We have identified and characterized 10 CD4+ T cell epitopes within polymerase and used them to analyze the immunological effects of long-term antiviral therapy as compared with spontaneous recovery from HBV infection. Candidate epitopes were tested for binding to 14 HLA-DR molecules and in IFN-γ ELISPOT and cytotoxicity assays using peripheral blood lymphocytes from 66 HBV-infected patients and 16 uninfected controls. All 10 epitopes bound with high affinity to the most prevalent HLA-DR Ags, were conserved among HBV genomes, and induced IFN-γ responses from HBV-specific CD4+ T cells. Several epitopes contained nested MHC class I motifs and stimulated HBV-specific IFN-γ production and cytotoxicity of CD8+ T cells. HBV polymerase-specific responses were more frequent during acute, self-limited hepatitis and after recovery (12 of 18; 67%) than during chronic hepatitis (16 of 48 (33%); p = 0.02). Antiviral therapy of chronic patients restored HBV polymerase and core-specific T cell responses during the first year of treatment, but thereafter, responses decreased and, after 3 years, were no more frequent than in untreated patients. Decreased T cell responsiveness during prolonged therapy was associated with increased prevalence of lamivudine-resistant HBV mutants and increased HBV titers. The data provide a rationale for the combination of antiviral and immunostimulatory therapy. These newly described HBV polymerase epitopes could be a valuable component of a therapeutic vaccine for a large and ethnically diverse patient population.

show abstract

Section: Patient Populationmentioning

confidence: 99%

Section: Laboratory and Virologic Testingmentioning

confidence: 99%

Cellular Immune Responses to the Hepatitis B Virus Polymerase

Mizukoshi

Sidney

Livingston³

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Although efficacious and well tolerated, lamivudine therapy is associated with a high rate of viral resistance [6][7][8][9] that may reach up to 70% after 4 years of treatment [6,10,11]. While some studies have suggested that continuing lamivudine in the presence of resistance may promote HBeAg seroconversion and maintain lower alanine aminotransferase (ALT) and HBV DNA levels than were present at baseline [11][12][13], accumulated evidence now shows that there is no benefit to continuing lamivudine in this population.…”

Section: Introductionmentioning

confidence: 99%

“…While some studies have suggested that continuing lamivudine in the presence of resistance may promote HBeAg seroconversion and maintain lower alanine aminotransferase (ALT) and HBV DNA levels than were present at baseline [11][12][13], accumulated evidence now shows that there is no benefit to continuing lamivudine in this population. Patients with lamivudine-resistant HBV who continue to receive lamivudine have been shown to experience increases in viral load [6,10,[14][15][16], hepatic flares that may lead to decompensation [15,[17][18][19], and reduction or reversal of histologic improvement [20]. These observations highlight the need for a treatment alternative for chronic hepatitis B patients who have developed lamivudine resistance.…”

Section: Introductionmentioning

confidence: 99%

Entecavir for the treatment of lamivudine-refractory chronic hepatitis B patients in China

Yao

Zhou

et al. 2007

Hepatol Int

View full text Add to dashboard Cite

Purpose This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and safety of entecavir in Chinese patients with lamivudinerefractory chronic hepatitis B.Methods One hundred forty-five lamivudine-refractory patients with chronic hepatitis B were randomized to double-blind treatment with oral entecavir 1 mg (n = 116) or placebo (n = 29) daily for 12 weeks, followed by 36 weeks of open-label entecavir treatment. The primary efficacy endpoint was the mean change from baseline in serum hepatitis B virus (HBV) DNA by polymerase chain reaction (PCR) assay at week 12.Results At week 12, the mean change from baseline in serum HBV DNA by PCR assay was -4.30 log 10 copies/ml for patients on entecavir compared to -0.15 log 10 copies/ ml for patients on placebo (P < .0001). Among patients with baseline serum alanine aminotransferase (ALT) >1 · upper limit of normal (ULN), a higher proportion of entecavir than placebo patients (68% vs. 6%, respectively) achieved ALT normalization by week 12 (P < .0001). After 48 weeks of entecavir treatment, the mean change in HBV DNA by PCR assay was -5.08 log 10 copies/ml, and 85% of patients with baseline ALT >1 · ULN had achieved ALT normalization. The safety profile of entecavir was similar to that of placebo during the first 12 weeks of blinded dosing. Entecavir was also well tolerated during 36 weeks of open-label treatment. Conclusions Lamivudine-refractory chronic hepatitis B patients treated with entecavir demonstrated marked HBV DNA reduction and normalization of ALT in most cases. Entecavir treatment for 48 weeks was well tolerated.

show abstract

“…[1][2][3][4][5] However, the response of these agents may not be durable after discontinuation of therapy and prolonged therapy leads to the emergence of resistant hepatitis B virus (HBV) mutants in an increasing proportion of patients. [6][7][8][9][10] Interferon alpha (IFN) has been shown to induce HBeAg seroconversion in approximately one third of patients, 11 but has considerable side effects. The efficacy of IFN therapy is improved by using its pegylated form, resulting in higher response rates in patients with chronic hepatitis B.…”

mentioning

confidence: 99%

Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: Relation to treatment response

et al. 2006

View full text Add to dashboard Cite

In chronic hepatitis B, it is difficult to predict an early therapeutic response. We investigated the viral decline during therapy with pegylated interferon alpha-2b (PEG-IFN) with or without lamivudine in 266 HBeAg-positive chronic hepatitis B patients. In patients treated with PEG-IFN and lamivudine, a uniform biphasic viral decline pattern was found during therapy and there were no marked differences in viral load between those who lost HBeAg at the end of follow-up (response) or not. In contrast, those treated with PEG-IFN monotherapy exhibited different viral decline patterns. A delayed decline of at least two log from baseline HBV DNA after week 4 but before week 32 was associated with the highest response rate (63%). In comparison, response was 52% for patients with an early decline (week 0-4), 38% for a late decline (week 32-52), 27% for a posttreatment decline (week 52-78) and 11% for patients with no substantial decline. The HBsAg loss was 22% in the delayed decline pattern compared to 4% for those with early decline and none for other decline patterns. In conclusion, different patterns of decline in viral load during treatment with PEG-IFN monotherapy were associated with different rates of HBeAg and HBsAg loss at the end of follow-up. Since there was a considerable response, even in patients with a late or posttreatment decline pattern, prediction of response based on viral decline during the first months of therapy was difficult. (HEPATOLOGY 2006;44:721-727.) Abbreviations: HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; IFN, interferon alpha; ALT, alanine aminotransferase; HBsAg, hepatitis B surface antigen; antibody to hepatitis B surface antigen; antibody to hepatitis B e antigen; ROC, receiver operating characteristic. From the

show abstract

Long-Term Therapy of Chronic Hepatitis B With Lamivudine

Cited by 328 publications

References 33 publications

Cellular Immune Responses to the Hepatitis B Virus Polymerase

Cellular Immune Responses to the Hepatitis B Virus Polymerase

Entecavir for the treatment of lamivudine-refractory chronic hepatitis B patients in China

Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: Relation to treatment response

Contact Info

Product

Resources

About