Changes in viral loads of lamivudine-resistant mutants and evolution of HBV sequences during adefovir dipivoxil therapy.
The addition of adefovir dipivoxil (ADV) to ongoing lamivudine therapy is effective against lamivudine-resistant virus in patients with hepatitis B virus (HBV) infection. We studied 39 patients who received ADV added to lamivudine for breakthrough hepatitis. We determined early viral changes (12 weeks) in YMDD mutants (rtM204I [YIDD sequence], rtM204V [YVDD]) and rtL180M in all 39 patients as well as amino acid changes in the polymerase reverse transcriptase (rt) region and precore/core promoter mutations in 15 patients who received long-term treatment (more than 1 year). Changes in rtM204I and rtL180M viral loads were greater than that of the rtM204V, albeit statistically insignificant. Moreover, the greatest change in viral load was seen for rtM204I without hepatitis B e antigen (HBeAg). The precore mutant was replaced with wild-type virus in three of eight patients after 1 year of added ADV therapy. Compared to baseline with lamivudine therapy only, new amino acid mutations were seen in the rt region at baseline with ADV in seven patients. At 1 year after ADV coadministration, the YMDD motif was replaced with wild-type (rt204M) in two patients, in whom mutations were fewer and of a different type. We conclude that the rtM204I may be more sensitive to ADV in vivo. ADV tended to select wild-type virus from precore mutants. Moreover, viruses that were wild-type in the rt region reappeared after 1 year of ADV coadministration in some patients.
Suzuki
Fumitaka
F
Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan. fumitakas@toranomon.gr.jp
Kumada
Hiromitsu
H
Nakamura
Hirotoshi
H
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral; D019143:Evolution, Molecular; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D006509:Hepatitis B / Q000188:drug therapy / Q000821:virology*; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D019259:Lamivudine / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D019562:Viral Load
D000998:Antiviral Agents; D063065:Organophosphonates; D019259:Lamivudine; D007372:Interferons; D012194:RNA-Directed DNA Polymerase; D000225:Adenine; C106812:adefovir dipivoxil