Cellular and virological mechanisms of HBV drug resistance

Locarnini, Stephen; Mason, William S.

doi:10.1016/j.jhep.2005.11.036

Cited by 149 publications

(120 citation statements)

References 102 publications

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“…27,28 This assumption is consistent with recent in vitro data showing that the A181V/T mutant has relatively reduced susceptibility to ETV compared with the N236T mutant. 29 In a phenotypical analysis of both LAM-resistant and ADV-resistant HBV mutants, the L180MϩM204V and L180MϩM204VϩN236T mutants showed no difference in susceptibility to ETV in vitro, although both displayed a 6.25-fold resistance to ETV compared with wild-type HBV. 17 In the current study, the A181V/T substitution was identified in 46% of patients with documented genotypical resistance to ADV, whereas the N236T substitution was in 24% (Table 2).…”

Section: Discussionmentioning

confidence: 95%

Efficacy of Entecavir in Patients with Chronic Hepatitis B Resistant to Both Lamivudine and Adefovir or to Lamivudine Alone†

et al. 2009

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Entecavir (ETV) is currently recommended as a rescue therapy purely for adefovir (ADV)-resistant chronic hepatitis B virus (HBV) infections.We evaluated the efficacy of ETV in patients who were resistant to lamivudine (LAM)/ADV sequential therapy and in those resistant to LAM monotherapy. Fifty LAM/ADV-resistant and 38 LAM-resistant patients who received ETV 1 mg/day for at least 48 weeks were enrolled. Mean baseline serum HBV DNA and alanine aminotransferase (ALT) levels were significantly lower in the LAM/ADVresistant group, compared with the LAM-resistant group (6.90 versus 7.62 log 10 copies/mL and 102.6 versus 160.2 IU/L; both P < 0.05); hepatitis B e antigen (HBeAg) status and LAM-resistant mutation patterns were similar in the two groups. At week 48, mean reductions in HBV DNA and ALT levels were significantly less in the LAM/ADV-resistant group (؊2.96 versus ؊4.86 log 10 copies/mL and ؊68.3 versus ؊128.9 IU/L; both P < 0.05). Achievement of undetectable HBV DNA was also less common in the LAM/ADV-resistant group (10.0% versus 34.2%; P ‫؍‬ 0.006), although the rates of HBeAg loss and ALT normalization did not differ between the two groups. Resistance to both LAM and ADV was an independent risk factor for failure of HBV DNA negativity at week 48 (odds ratio, 0.138; P ‫؍‬ 0.019). In both LAM/ADV-resistant and LAM-resistant groups, primary responders (>1 log decline in HBV DNA at week 12) achieved a significantly greater decrease in HBV DNA levels over the 48-week period, compared with primary nonresponders (؊4.18 versus ؊0.97 and ؊5.37 versus ؊2.15 log 10 copies/mL, respectively; both P < 0.05). Conclusion:The 48-week ETV treatment was less effective in LAM/ADV-resistant than in LAM-resistant patients. Continuing ETV monotherapy could be determined based on the virological response at 12 weeks in LAM/ADV-resistant patients. (HEPATOLOGY 2009;50:1064-1071

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Section: Discussionmentioning

confidence: 95%

Efficacy of Entecavir in Patients with Chronic Hepatitis B Resistant to Both Lamivudine and Adefovir or to Lamivudine Alone†

et al. 2009

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“…But Westland's study did not take ethnicity into consideration. The pharmacodynamic properties of ADV may vary from one ethnic population to another (Locarnini and Mason 2006).…”

Section: Determination Of Hbv Genotypementioning

confidence: 99%

Hepatitis B Virus Genotype-Associated Variability in Antiviral Response to Adefovir Dipivoxil Therapy in Chinese Han Population

Zeng

Deng

Yang

et al. 2008

Tohoku J. Exp. Med.

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It is well known that different genotypes of hepatitis B virus (HBV) have a different sensitivity to interferon-α or lamivudine (nucleoside analogue) antiviral therapy. However, for adefovir dipivoxil (ADV, a nucleotide analogue), the antiviral response of the different genotypes remains to be clarified. In order to evaluate the response of HBV genotypes to ADV therapy and to identify factors that might affect initial virological response, we performed a retrospective analysis on patients with chronic hepatitis B (CHB) in Chinese Han population. The study included 183 patients, who had been tested positive for hepatitis B e antigen (HBeAg) and had been treated with ADV (10 mg/day) for 48 weeks. The numbers of patients infected with HBV genotype B and genotype C were 98 and 75 cases, respectively, and the remaining 10 patients were mixture infection of genotypes B plus C or genotypes B plus D. The mean HBV-DNA reduction and HBV-DNA seroclearance of genotypes B and C at 48 weeks were 3.6 log 10 and 3.1log 10 copies/ml (p < 0.05) and 41.8% and 34.6% (p < 0.05), respectively. There were no statistically significant differences between genotypes B and C in terms of HBeAg loss, anti-HBe seroconversion and normalization of serum alanine aminotransferase (ALT). Multivariate analysis showed that young age, low pretreatment HBV-DNA and/or elevated ALT level might be independent predictive factors associated with initial virological response. Thus, in Han CHB patients who are HBeAg-positive, HBV genotype B shows a better virological response to ADV therapy than does genotype C.hepatitis B virus; genotype; initial virological response; adefovir dipivoxil; chronic hepatitis B.Tohoku

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“…cccDNA exists as episomes in the nucleus with an estimated copy number of 5-50 molecules per infected cell [4][5][6] and serves as the sole transcriptional template for the synthesis of viral RNAs. Transcription of cccDNA mainly relies on HBx and is regulated by multiple epigenetic mechanisms including methylation and acetylation [7,8]. PRMT1, a methyltransferase, has recently been identified as a novel binding partner of HBx and represses HBV transcription through its direct recruitment to the HBV cccDNA [9].…”

Section: Introductionmentioning

confidence: 99%