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

Abstract

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

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

“…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].…”

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

“…Genotypical analysis for ETV resistance was performed on a subset of patients showing virological breakthrough during follow-up using restriction fragment mass polymorphism analysis as previously described. 9 For restriction fragment mass polymorphism genotyping, viral DNA was amplified using PCR. Table 1 shows the sequences of forward and reverse primers used for PCR.…”

“…8 Sequential resistance to LAM and later ADV has been reported in patients who were switched to ADV monotherapy for LAM-resistant HBV. 9,10 Furthermore, ADV mutations emerged more commonly in LAM-resistant patients than in treatment-naïve patients. 9, 10 It was suggested that se-quential antiviral therapy leads to selection of multidrugresistant HBV, and evolution of mutations during continued treatment may select for mutants with increased replication fitness or maximal viral resistance.…”

“…9,10 Furthermore, ADV mutations emerged more commonly in LAM-resistant patients than in treatment-naïve patients. 9, 10 It was suggested that se-quential antiviral therapy leads to selection of multidrugresistant HBV, and evolution of mutations during continued treatment may select for mutants with increased replication fitness or maximal viral resistance. 11 In terms of salvage therapy for LAM-resistant or ADVresistant CHB, the American Association for the Study of Liver Diseases practice guideline recommended switching to ETV as an optimal strategy, 12 and this protocol has been widely applied in clinical practice.…”

Simultaneous detection of hepatitis B virus genotypes and mutations associated with resistance to lamivudine, adefovir, and telbivudine by the polymerase chain reaction-ligase detection reaction

“…16,17 Adefovir resistance mutations are much more common in patients who have previously received lamivudine therapy. 18 HBV infection is a heavy health burden in China. National surveys found that the prevalence of HBV was 9.8% in 1992 and 7.2% in 2006 among the population aged 1-59 years.…”