Resistance to adefovir dipivoxil in lamivudine resistant chronic hepatitis B patients treated with adefovir dipivoxil

• Published in: Gut 2006-10, Vol.55 (10), p.1488-1495
• Main Authors: Yeon, J E, Yoo, W, Hong, S P, Chang, Y J, Yu, S K, Kim, J H, Seo, Y S, Chung, H J, Moon, M S, Kim, S-O, Byun, K S, Lee, C H
• Format: Article
• Language: English
• Subjects: adefovir dipivoxil; Adenine - analogs & derivatives; Adenine - therapeutic use; Adult; ADV; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antigens; Antiviral agents; Biological and medical sciences; CHB; chronic hepatitis B; compensated liver cirrhosis; decompensated liver cirrhosis; Deoxyribonucleic acid; DNA; DNA polymerase; drug resistance; Drug Resistance, Viral - genetics; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genotype; HBeAg; HBV; Hepatitis; hepatitis B e antigen; Hepatitis B virus; Hepatitis B, Chronic - drug therapy; Hepatitis B, Chronic - genetics; Human viral diseases; Humans; Infectious diseases; Interferon; lamivudine; Lamivudine - therapeutic use; LC-c; LC-d; Liver cirrhosis; LMV; Male; Medical sciences; Middle Aged; Mutation; Mutation - genetics; Organophosphonates - therapeutic use; Patients; PCR; Pharmacology. Drug treatments; Phenotype; polymerase chain reaction; Real time; restriction fragment mass polymorphism; Retrospective Studies; Reverse Transcriptase Inhibitors - therapeutic use; reverse transcription; RFMP; Viral diseases; Viral hepatitis; Viruses
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gut.2005.077099

Background: Adefovir dipivoxil (ADV) is a potent nucleotide analogue against both the wild-type and lamivudine (LMV) resistant hepatitis B virus (HBV). The cumulative incidence of ADV resistant mutations in the nucleoside/-tide treatment naïve chronic hepatitis B patient (CHB) at weeks 48, 96, and 144 was 0, 0.8–3%, and ∼5.9%, respectively. Aims: The aim of this study was to characterise the genotypic and phenotypic mutation profiles to ADV in 67 LMV resistant CHB patients who were treated with ADV. Methods: Serum HBV DNA was quantified by real time polymerase chain reaction. The ADV mutant was detected using matrix assisted laser desorption/ionisation time of flight mass spectrometry based genotyping assays, termed restriction fragment mass polymorphism (RFMP). Results: RFMP analysis revealed that a total of 11 amino acid substitutions developed in the rt domain of the HBV polymerase in nine patients. The cumulative incidence of genotypic ADV resistance at months 12 and 24 was 6.4% and 25.4%, respectively. The rtA181V, rtN236T, and rtA181T mutations were detected in five, four, and two of the 67 patients at treatment months 12–17, 3–19, and 7–20, respectively. Serial quantification of serum HBV DNA revealed that two patients with the rtA181V mutation, with or without the rtN236T mutation, and one patient with the rtA181T mutation displayed HBV DNA rebound. Conclusion: Emergence of the ADV mutation in LMV resistant patients who are treated with ADV appeared to present earlier and more frequently than was reported in previous studies on nucleoside/-tide treatment naïve patients.