Occurrence of Adefovir-Resistance Mutations in Lamivudine-Resistant Hepatitis B Patients

HBV resistance to adefovir (Hepsera) tends to take longer to develop than lamivudine resistance, but it eventually emerges nonetheless. Resistance is associated with various HBV polymerase gene mutations, including rtA181V/T, rtN236T, and rtP237H.

Recent research has shown that primary resistance to adefovir -- that is, pre-existing resistance in patients who never used the drug -- can occur in patients who received prolonged treatment with lamivudine (Epivir-HBV).

A study presented at the recent Digestive Disease Week conference in Los Angeles attempted to clarify how often this type of adefovir resistance occurs among patients who harbor HBV with the YMDD lamivudine-resistance mutation, and to assess the clinical course of these patients.

The study included 293 patients with chronic hepatitis B who switched from lamivudine to adefovir due to the emergence of the YMDD mutation and consequent lamivudine resistance; 28 patients without the YMDD mutation (including 13 with a history of prior lamivudine use) were selected as controls. Adefovir-resistance mutations were assessed using restriction fragment mass polymorphism analysis for rt181, rt236, rt237 and rt238, and were confirmed by direct sequencing of the HBV polymerase gene.

Results

11 out of the 293 patients with the YMDD mutation (3.75%) had a primary adefovir-resistance mutation (two with rtA181V/T, nine with rtP237H). None of the control patients without the YMDD mutation had any adefovir-resistance mutations During a median follow-up period of 14 months (range 9-25) after switching to adefovir, HBV DNA became undetectable and remained undetectable in all patients but one (for whom the lowest HBV DNA level was 13.7 pg/mL). ALT levels decreased to below the upper limit of normal and remained normal (23 ± 9 IU/L) in all patients. There were no significant differences in the duration of lamivudine use, baseline ALT, pretreatment HBV DNA level, or frequency of baseline HBeAg positivity between the patients who developed an adefovir-resistance mutation and those who did not (P > 0.05).

Conclusion

The authors concluded that the incidence of primary adefovir-resistance mutations was 3.7% in patients with a pre-existing YMDD mutation and resistance to lamivudine. Although phenotypic (clinically evident) resistance was rare among patients with primary adefovir-resistance mutations during short-term follow-up in this study, they suggested that longer-term observation may be required to clarify the clinical significance of such mutations.

Risk of Adefovir Resistance

A related study published in the June 2006 issue of Hepatology also looked at the rate and consequences of adefovir resistance, although it focused on mutations that developed during adefovir therapy, rather than pre-existing primary resistance mutations.

The researchers compared the emergence of the adefovir-resistance mutations rtA181V/T and rtN236T in 57 lamivudine-resistant and 38 treatment-naïve patients treated with 10 mg daily adefovir monotherapy for 48 weeks or longer. Here, too, resistance mutations were assessed using restriction fragment mass polymorphism analysis.

Results

After 48 weeks, 10 out of 57 patients (18%) with lamivudine resistance developed adefovir-resistance mutations, compared with none of the 38 treatment-naïve patients (P < 0.01). Among the patients with lamivudine resistance, the reduction in serum HBV DNA was significantly smaller in patients who developed adefovir-resistance mutations than in patients without such mutations (1.04 vs 2.63 log copies/mL; P = 0.01. Rates of ALT normalization (60% vs 55%, respectively) and HBeAg loss (14% vs 21%, respectively) were not significantly different in the two groups (P > 0.05).

Conclusion

The researchers concluded that the emergence of the rtA181V/T and rtN236T adefovir-resistance mutations was more common among patients who had previously developed resistance to lamivudine than in treatment-naïve patients after 48 weeks of treatment with adefovir.

Unlike the previous study, however, here the development of adefovir-resistance mutations was associated with reduced virological suppression, although ALT normalization and HBeAg loss remained similar after one year in patients with and without such mutations.

6/13/06

References

D Kim, J Lee, D Lee, and others. Occurrence of primary adefovir resistance mutation in hepatitis B patients with YMDD mutation and lamivudine resistance. Digestive Disease Week 2006. Abstract T1843. Digestive Disease Week 2006. May 20-25, 2006. Los Angeles, CA.

YS Lee, DJ Suh, YS Lim, and others. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology 43(6): 1385-1391. June 2006.