Lamivudine monotherapy can favour the emergence of viral quasispecies with lower susceptibility to other nucleos(t)ide analogues

MORICONI F, FLICHMAN D, CICCOROSSI P, COCO B, SACCO R, OLIVERI F, COLOMBATTO P, BONINO F , BRUNETTO M

Paris

Congreso; 9th Annual Meeting European Society for Clinical Virology; 2006

European Society for Clinical Virology

&amp;amp;amp;amp;lt;!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-GB;} @page Section1 {size:612.0pt 792.0pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --&amp;amp;amp;amp;gt; Background and Objectives: Mutations in the catalytic domain of HBV Polymerase/Reverse transcriptase (Pol/rt) were reported in patients (pts) under lamivudine (LAM), emtricitabine and telbivudine. Mutations affecting other regions of HBV rt were also reported, but at lower rates in pts under adefovir dipivoxil (ADV) or entevacvir. The aim of the study was to analyse HBV Pol/rt heterogeneity in 34 chronic hepatitis B (CHB) patients under LAM+ADV rescue therapy after virologic breakthrough during LAM. Methods: The virological response to combination therapy was defined by HBVDNA <200 cp/ml and evaluated at 48 and 96 weeks (w): 22 pts had HBVDNA <200 cp/ml at 48 w (early responders, ER); 3 pts had HBVDNA <200 copies/ml at 96 w (late responders, LR); the remaining 6 pts maintained detectable HBV-DNA at 96 w (non responders, NR). B-C-D-E Pol/rt domains of HBV isolates were directly sequenced in 1 to 4 serum samples obtained at basal, before and during the combination therapy in all but 2 ER. Results: Baseline (before addition of AV) viral loads were significantly different in the 3 groups: 5.9 (range 3.2-7.7) logs in ER, 8.7 (range 8.4-8.9) logs in LR and 7.7 (range 6.5-8.2) logs in NR (p=0.003). Before starting ADV we found YMDD mutations in 26 of 29 (89.6%) pts, associated with rtL180M substitution in 20 cases (60.0%). Additional mutations were not found in ER and LR, but in 4 of 6 NR: a new variant rtA181S in 2 (one was the only without YMDD or other mutations) and rtT184S in the other 2. During ADV treatment the HBV Pol/rt sequence remained unchanged. Conclusion: The finding of HBV Pol/rt variants (rtA181S and rtT181S) in baseline sera of 67% (4 of 6) of LAM resistant pts with poor virological response to ADV supports the view that LAM monotherapy can favour the emergence of viral quasispecies with lower susceptibility to other nucleos(t)ide analogues. The evidence that baseline pre-ADV viral loads were lower in NR than in LR supports the hypothesis of direct role of HBV-Pol/rt variants in ADV treatment failure.