JAC Advance Access originally published online on June 13, 2007
Journal of Antimicrobial Chemotherapy 2007 60(2):341-349; doi:10.1093/jac/dkm187
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Emergence of hepatitis B virus quasispecies with lower susceptibility to nucleos(t)ide analogues during lamivudine treatment
1 UO Gastroenterologia ed Epatologia Ospedaliera, University Hospital of Pisa, Pisa, Italy 2 Fondazione IRCCS Policlinico, Via Francesco Sforza 28, 20122 Milano, Italy
Received 8 March 2007; returned 20 April 2007; revised 27 April 2007; accepted 1 May 2007
* Correspondence address. UO Gastroenterologia ed Epatologia Ospedaliera, Azienda Ospedaliero-Universitaria Pisana, Via Paradisa 2, 56124 Cisanello Pisa, Italia. Tel: +39-050-996857; Fax: +39-050-995456; E-mail: brunetto{at}med-club.com
Objectives: We studied the impact of hepatitis B virus (HBV) polymerase/reverse transcriptase (Pol/Rt) heterogeneity on adefovir rescue therapy in 34 consecutive chronic hepatitis B patients with viral breakthrough during lamivudine monotherapy.
Methods: The Pol/Rt A–F domains were directly sequenced in all patients at baseline, and 12 and 24 months. Response to therapy was evaluated at 3, 6, 12 and 24 months by quantitative HBV-DNA.
Results: Primary treatment failures did not occur. At 6 months 24/34 (70.6%) patients had viraemia < 104 copies/mL [initial viral response (IVR)]; at 12 and 24 months 23 (71.9%) and 26 (81.3%) of 32 had HBV-DNA < 200 copies/mL [complete viral response (CVR)]. IVR or CVR patients did not show viral breakthroughs, which occurred in one of the six remaining patients. All but three patients had baseline rtM204I/V substitutions associated with rtL180M in 23, rtL80I/V in 14, rtV173L in 4, rtT184S in 3, rtQ215S in 2 and rtA181S in 2 cases. rtA181S without rtM204I/V was found in one patient. Four of the six patients (67%) without 24 month CVR showed rtA181S or rtT184S substitutions either alone or with typical lamivudine resistance profiles. Baseline HBV-DNA levels were negatively associated with IVR (univariate analysis, P = 0.023). At least one of rtA181S and rtT184S substitutions correlated negatively with IVR and CVR (univariate analysis, P = 0.001) and was independently associated with absence of CVR (P = 0.016).
Conclusions: Lamivudine monotherapy favours the emergence of viral quasispecies that influence the response rate to adefovir rescue therapy independently from baseline viraemia and lower the susceptibility to other nucleos(t)ide analogues.
Keywords: antivirals , HBV , viral load , resistance