Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation

Fung, Scott; Andreone, Pietro; Han, Steve; Reddy, K. Rajender; Regev, Arie; Keeffe, Emmet B.; Hussain, Munira; Cursaro, Carmela; Richtmyer, Pamela A; Marrero, Jorge A.; Lok, Anna S.

doi:10.1016/j.jhep.2005.05.037

Cited by 190 publications

(162 citation statements)

References 23 publications

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“…Our data are in agreement with previous studies that show ADV-resistant mutations are infrequent and delayed in treatment-naïve patients. 10,11,22 However, in contrast to previous reports in which no ADV-resistant mutations were detected in LAM-resistant patients after 1 year of ADV therapy, 23,24 our study indicated that the emergence of those mutations in LAM-resistant patients was frequently detected after 1 year of ADV therapy.…”

Section: Discussioncontrasting

confidence: 99%

Increased risk of adefovir resistance in patients with lamivudine‐resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy†

et al. 2006

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Although adefovir dipivoxil (ADV) has a unique profile of delayed and infrequent resistance in treatment-naïve chronic hepatitis B patients, the association of ADV resistance with previous lamivudine (LAM) resistance is not well understood. We compared the emergence of the ADV-resistant mutations rtA181V/T and rtN236T between LAM-resistant patients and treatment-naïve patients at 48 weeks of ADV monotherapy. Fifty-seven LAM-resistant patients and 38 treatment-naïve patients were treated with 10 mg/d ADV for more than 48 weeks. Both baseline and 48-week blood samples were analyzed for ADV-resistant mutations via restriction fragment mass polymorphism analysis. Antiviral responses were evaluated according to changes in serum HBV DNA (measured via real-time polymerase chain reaction) and alanine aminotransferase (ALT) levels and loss of hepatitis B e antigen (HBeAg). After 48 weeks, 10 (18%) of the 57 LAM-resistant patients were found to have developed ADV-resistant mutations, whereas none of the 38 treatment-naïve patients developed such mutations (P < .01). Among LAM-resistant patients, the reduction in serum HBV DNA levels was significantly lower in patients with ADV-resistant mutations than in those without such mutations (؊1.04 vs. ؊2.63 log 10 copies/mL) (P ‫؍‬ .01). However, the rates of serum ALT normalization (60% vs. 55%) and HBeAg loss (14% vs. 21%) were not significantly different between the 2 groups (P > .05). In conclusion, the emergence of the rtA181V/T and rtN236T mutations was more common in LAM-resistant patients than in treatmentnaïve patients after 48 weeks of ADV therapy and was associated with reduced antiviral efficacy to drug treatment. (HEPATOLOGY 2006;43:1385-1391

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Section: Discussioncontrasting

confidence: 99%

Increased risk of adefovir resistance in patients with lamivudine‐resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy†

et al. 2006

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“…While early studies of patients with lamivudine-resistant HBV suggested that switching to adefovir was efficacious, subsequent work demonstrated the rapid emergence of adefovir resistance in this patient population [42][43][44]. The emergence of adefovir resistance in this setting can be associated with viral rebound and hepatic decompensation [45]. Adding adefovir to ongoing lamivudine for patients who have developed lamivudine resistance has been recommended as a strategy to reduce the subsequent emergence of adefovir resistance [25,46].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

et al. 2010

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Purpose Lamivudine treatment of chronic hepatitis B (CHB) is associated with frequent resistance and loss of clinical benefit. We present outcomes of lamivudinerefractory Japanese patients treated with entecavir for 3 years. Methods Eighty-two patients refractory to lamivudine therapy received entecavir 0.5 or 1 mg daily for 52 weeks in phase II study ETV-052, directly entered rollover study ETV-060, and received entecavir 1 mg daily. Responses were evaluated among patients with available samples.Results After 96 weeks in ETV-060 (148 weeks total entecavir treatment time), 55% (36/65) of patients had hepatitis B virus (HBV) DNA of [400 copies/mL, 85% (52/61) had alanine aminotransferase (ALT) of C1 9 upper limit of normal (ULN), and 14.6% (7/48) achieved HBe seroconversion. A subset of 42 patients received entecavir 1 mg from phase II baseline through 148 weeks: 54% (19/35) had HBV DNA of [400 copies/mL, 84% (27/32) had ALT of C1 9 ULN, and 15% (4/27) achieved HBe seroconversion. Sixteen patients in the 1-mg subset had baseline and week 148 evaluable biopsy pairs: 81% (13/16) showed histologic improvement and 38% (6/16) showed 123Hepatol Int (2010) 4:414-422 DOI 10.1007/s12072-009-9162-x improvement in fibrosis. Genotypic resistance to entecavir emerged in 31 patients for a 3-year cumulative resistance probability of 35.9%. Entecavir was generally well tolerated during ETV-060, with no on-treatment ALT flares. Conclusions Long-term entecavir treatment of lamivudine-refractory CHB resulted in virologic suppression, ALT normalization, and improvements in liver histology. Resistance was consistent with that observed in worldwide studies.

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“…[17][18][19] Although increasing evidence supports the therapeutic efficacy of ETV in LAMr patients, [13][14][15] limited clinical data are available on ADV-resistant patients showing prior LAM resistance. 20,21 A small cohort study showed that switching to ETV plus ADV was highly efficient in 13 CHB patients who failed sequential or combination therapy with LAM and ADV, with a 76.9% (10/13) HBV DNA clearance rate during a median 10 months of treatment (range, 4-16 months). 22 ETV was reported to be effective irrespective of baseline HBV DNA levels in treatment-naïve patients.…”

Section: Discussionmentioning

confidence: 99%

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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Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation

Cited by 190 publications

References 23 publications

Increased risk of adefovir resistance in patients with lamivudine‐resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy†

Increased risk of adefovir resistance in patients with lamivudine‐resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy†

Efficacy and resistance of entecavir following 3 years of treatment of Japanese patients with lamivudine-refractory chronic hepatitis B

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

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