Resistance surveillance of HBEAG— chronic hepatitis B (CHB) patients treated for two years with adefovir dipivoxil (ADV)

H epatitis B virus (HBV) is a major cause of chronic liver disease with an estimated 400 million chronic carriers worldwide. Treatment of chronic hepatitis B aims to achieve sustained suppression of HBV replication, normalization in alanine aminotransferase levels, loss of serologic markers of hepatitis B e antigen or hepatitis B surface antigen, and improvement in liver histology. Before the recent regulatory approval of adefovir dipivoxil for the treatment of chronic hepatitis B in the United States, lamivudine was the only oral agent indicated for this disease. However, a major drawback to long-term lamivudine therapy is the emergence of lamivudine-resistant HBV mutants in a significant proportion of patients. Resistance to lamivudine occurs in 16% to 32% of patients after 1 year of monotherapy and the incidence progressively increases to 67% at 4 years. 1,2 Single mutations (rtM204V or rtM204I) in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of HBV polymerase were shown to be less fit than wild-type HBV during in vitro studies. 3 However, in the majority of patients, YMDD mutations are accompanied by compensatory mutations. Secondary mutations of rtL180M and rtV173L have been observed in greater than 80% of lamivudine-resistant patients and these mutants are able to restore replication fitness of YMDD mutant HBV in vitro. 4,5 Furthermore, long-term data from patients harboring lamivudine-resistant HBV indicates that viral replica-

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“…A unique adefovir resistance mutation (rtN236T) was identified and is currently being characterized in vitro and in vivo. 36 Fig . 1.…”

Section: Discussionmentioning

confidence: 99%

Week 48 Resistance Surveillance in Two Phase 3 Clinical Studies of Adefovir Dipivoxil for Chronic Hepatitis B

Westland

2003

Hepatology

140

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“…In addition, in two phase 3 clinical studies of ADV in 695 chronic hepatitis B patients, no adefovir resistance mutations were identified after 48 weeks of therapy [15,16]. A recent report demonstrated that 2 years of ADV treatment selected for a novel N236T mutation in the D domain of the HBV polymerase in 2/124 (1.6%) of patients [22]. To date, this adefovir resistance mutation has not been reported in liver transplantation patients infected with HBV.…”

Section: Introductionmentioning

confidence: 99%

Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient

Villeneuve

Durantel

et al. 2003

Journal of Hepatology

281

238

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“…[16][17][18] Although no adefovir-associated resistance mutations were identified during treatment for up to 48 weeks, adefovir-resistant strains, which are susceptible to lamivudine therapy, have been identified in less than 2% (4/238) of subjects treated up to 96 weeks and in 18% of a cohort of HBeAg-negative subjects treated for up to 4 years. [19][20][21][22][23] This placebo-controlled study tested the antiviral efficacy and safety of ADV 10 mg once daily in Chinese subjects with HBeAg-positive CHB and also investigated the impact of cessation of therapy under double-blind conditions. The 52-week results are reported here.…”

mentioning

confidence: 99%

A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B

Zeng

Mao

Yao³

et al. 2006

Hepatology

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Four hundred and eighty Chinese subjects with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) were enrolled in a multicenter, double-blind, randomized, placebo-controlled study of adefovir dipivoxil (ADV) 10 mg once daily. There was a significant difference in reduction of serum hepatitis B virus (HBV) DNA after 12 weeks between subjects who received ADV and those who received the placebo (3.4 and 0.1 log 10 copies/mL, respectively, P < .001). Further reductions in serum HBV DNA and increases in the proportion of subjects with an HBV DNA level of at most 10 5 copies/mL, with HBV DNA undetectable, and with ALT normalization were observed in ADV-treated subjects at week 52 (median HBV DNA reduction of 4.5 log 10 copies/mL, 67% with HBV DNA < 10 5 copies/mL, 28% with HBV DNA undetectable, and 79% with ALT normalization). Subjects who initially received ADV lost some treatment benefit after being rerandomized to the placebo in week 40. Subjects with YMDD mutant HBV at baseline had virological, biochemical, and serological responses to treatment that were similar to those of subjects with wild-type HBV. The incidence of clinically adverse events was similar in nature and severity between the treatment groups, and there was no evidence of renal toxicity. No adefovirrelated HBV mutations were identified. In conclusion, treatment with ADV 10 mg daily over 52 weeks was safe and effective in Chinese subjects with HBeAg-positive CHB and did not lead to the emergence of drug resistance. The study is continuing for an additional 4 years with all subjects on open-label ADV 10 mg daily. (HEPATOLOGY 2006;44:108-116.)

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Resistance surveillance of HBEAG— chronic hepatitis B (CHB) patients treated for two years with adefovir dipivoxil (ADV)

Cited by 34 publications

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Week 48 Resistance Surveillance in Two Phase 3 Clinical Studies of Adefovir Dipivoxil for Chronic Hepatitis B

Week 48 Resistance Surveillance in Two Phase 3 Clinical Studies of Adefovir Dipivoxil for Chronic Hepatitis B

Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient

A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B

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