Selection of Multiresistant Hepatitis B Virus during Sequential Nucleoside‐Analogue Therapy

Abstract

Hepatitis B virus (HBV) drug resistance to lamivudine is always accompanied by mutations in the viral polymerase gene at position 550, termed group 1 (M550V with L526M) or group 2 (M550I) mutations. The latter mutation has not been associated with famciclovir resistance. Thus, the addition of famciclovir to lamivudine therapy in persons with group 2 lamivudine resistance may lead to virus suppression. The effect of lamivudine/famciclovir combination therapy on HBV infection was monitored in 5 lamivudine-resistant patients by quantitative polymerase chain reaction and polymerase gene sequencing of serum virus. No patients treated with combination therapy had a decline in HBV load >1 log10. Continual evolution of the viral polymerase was detected in association with virologic resistance to both drugs. Cloning experiments identified the preexistence of these multidrug-resistant virus variants as minority species prior to addition of famciclovir therapy. HBV resistance to lamivudine monotherapy is associated with a complex mixture of variants that limit the efficacy of second-line nucleoside-analogue therapy. First-line potent combination therapy may reduce the emergence of HBV drug resistance.

Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic Hepatitis B virus infection

“…The second, was the selection of famciclovir resistant mutants, with mutations located in the B domain, ie L18OM, or the C domain, ie V206I (Bartholomeusz and Locarnini, 1997;Pichoud et al, 1999). The selection of the L180M mutant by famciclovir was also shown to predispose to a more rapid selection of lamivudine resistance when patients were switched from famciclovir to lamivudine after failure of the former drug (Mutimer et al, 2000;Seigneres et al, 2000).…”

Molecular, immunological and clinical properties of mutated hepatitis B viruses

“…Therefore mutations within and outsite the YMDD-domain might be selected during lamivudine monotherapy and could contribute to therapy failure [230]. In vivo the Leu to Met mutation at aa 528 has been observed in association with the mutation YVDD [231] and in association with the mutation YIDD [232]. Natural occurring YMDD variants frequently exhibit other aa substitutions like the change Leu-568 to Val [43], Ser-561 to Thr [233], Ile-511 to Val, Ala-548 to Val, Ser-567 to Ala, Ala-570 to Thr [234] or Val-521 to Leu [235].…”

Identification of a new variant in the YMDD motif of the hepatitis B virus polymerase gene selected during lamivudine therapy

“…In several clinical trials, lamivudine therapy resulted in a rapid decline of serum HBV DNA levels in a majority of patients [1][2][3][4][5]. However, as with other antiviral agents, HBV variants resistant to the drug may emerge during prolonged treatment [2,4,[6][7][8][9][10] and, after cessation of therapy, HBV DNA serum levels may return to pretreatment values. Even enhanced HBV replication, resulting in a hepatitis flare, has been described [11].…”

“…It has been attributed solely to variations in the so-called YMDD region of the polymerase gene, in which the methionine (rtM204) is replaced by either valine (rtV204) or isoleucine (rtI204). The replacement by valine is accompanied by a change of leucine (rtL180) to methionine (rtM180) [8,10]. This paper describes the identification of a new variant in the YMDD region and discusses the possible intermediates involved in its emergence.…”