Adefovir Dipivoxil (Hepsera) and Lamivudine (Epivir-HBV) Combination Therapy Prevents Emergence of ADV Resistance Mutations in Patients with LAM-Resistant HBV
The experience in HIV-1 therapy demonstrated that combination regimens significantly reduced the incidence of drug resistance in HIV-infected patients. Current treatment for chronic hepatitis B (CHB) still largely relies on sequential monotherapy.
The objective of the current study was to analyze the incidence of adefovir/ADV (Hepsera) resistance in CHB patients who failed LAM monotherapy at baseline and received ADV+LAM combination therapies in clinical trials.
?span style='font:7.0pt "Times New Roman"'> 467 patients were enrolled in study 435 (n=241 post-liver transplantation, n=226 wait-listed for liver transplantation). 3
?span style='font:7.0pt "Times New Roman"'> 5 patients co-infected with HIV were enrolled in study 460i.
?span style='font:7.0pt "Times New Roman"'> All patients failed LAM therapy at baseline.
?span style='font:7.0pt "Times New Roman"'> Over 98% of all genotyped baseline HBV samples were showed to harbor the LAM-resistant YMDD mutations.
?span style='font:7.0pt "Times New Roman"'> Most patients received ADV in addition to ongoing LAM in these two studies.
?span style='font:7.0pt "Times New Roman"'> Serum HBV DNA levels were determined by PCR assays.
?span style='font:7.0pt "Times New Roman"'> ADV resistance mutations were determined by sequencing HBV RT domain.
?span style='font:7.0pt "Times New Roman"'> Annual resistance surveillance was performed for 131, 144, and 76 patients with available serum samples at weeks 48, 96, and 144, respectively.
?span style='font:7.0pt "Times New Roman"'> HBV isolates from HBV DNA PCR positive serum samples were sequenced.
?span style='font:7.0pt "Times New Roman"'> Upon the completion of study 435, 8 of the 467 patients from this study were identified to show confirmed serum HBV DNA rebound (> 1 log increase from nadir) at the last two visits.
?span style='font:7.0pt "Times New Roman"'> HBV genotyping was also performed for these 8 patients. A total of 4 patients developed the adefovir resistance mutation rtN236T. All 4 patients demonstrated serum HBV DNA rebound (> 1 log) and ALT elevations (2 to 10xULN).
?span style='font:7.0pt "Times New Roman"'> Investigation of treatment histories of the four patients revealed that all four patients had stopped lamivudine therapy before the development of ADV resistance mutation rtN236T.
?span style='font:7.0pt "Times New Roman"'> Genotypic analyses showed that the baseline YMDD mutations became undetectable when rtN236T mutant HBV emerged in these four patients.
?span style='font:7.0pt "Times New Roman"'> The disappearance of the YMDD mutations may be due to either the removal of selective pressure from lamivudine or replication deficiency of the dual N236T and YMDD mutant in patients.
?span style='font:7.0pt "Times New Roman"'> Preliminary in vitro studies suggested that an HBV strain carrying both N236T and YMDD mutations replicated less efficiently than wild-type, N236T mutant, and YMDD mutant HBV in cell culture.
Conclusions
In conclusion, the authors write, 揘o patients developed ADV resistance mutation while on ADV and LAM combination therapies. Combination of ADV and LAM appears to reduce the rate of resistance development relative to monotherapy with either agent.?/span>
05/16/05
Reference
Combination of Adefovir Dipivoxil and Lamivudine Prevented Emergence of ADV Resistance Mutations in Chronic Hepatitis B Patients with LAM-Resistant HBV Abstract 945. Digestive Disease Week 2005. May 14-19, 2005. Chicago, IL.
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发表于 2005-5-31 03:20
