18th International HIV Drug Resistance Workshop Basic Principles & Clinical Implications June 9–13 2009, Fort Myers, Florida, USA

LAMIVUDINE RESISTANCE MUTATIONS IN HBV REVERSE TRANSCRIPTASE CAN BE SELECTED EVEN AT EXTREMELY LOW LEVELS OF VIRAL REPLICATION

Antivir Ther 2009; 14 Suppl 1:A26 (abstract no. 24)

V Svicher¹, C Alteri¹, C Gori², R Salpini¹, F Marcuccilli¹, R Longo³, M Bernassola³, V Gallinaro⁴, S Romano³, M Visca³, A Ursitti³, M Feasi⁵, V Micheli⁶, M Angelico¹, G Cassola⁵, G Parruti⁷, G Gubertini⁶, GM De Sanctis⁴, F Ceccherini-Silberstein¹, G Cappiello³, A Spanò³ and CF Perno^1
1University of Rome Tor Vergata, Rome, Italy; ²INMI L Spallanzani Rome, Rome, Italy; ³S Pertini Hospital, Rome, Italy; ⁴University of Rome La Sapienza, Rome, Italy; ⁵Galliera Hospital, Genoa, Italy; ⁶L Sacco Hospital, Milan, Italy; ⁷Spirito Santo Hospital, Pescara, Italy

BACKGROUND: The objective of this study was to investigate whether lamivudine resistance can emerge even at undetectable HBV viremia (<12 IU/ml [69 copies/ml]) or at the very early stages of virological rebound (HBV viremia 12–345 IU/ml [69–2,000 copies/ml]).

METHODS: A total of 66 HBV-monoinfected patients were analysed: 25 patients were receiving first-line lamivudine monotherapy and experiencing for the first time a rebound of HBV viremia ranging from 12 IU/ml to 345 IU/ml; 25 patients received first-line lamivudine monotherapy with HBV viremia stably <12 IU/ml and 16 patients received lamivudine+adefovir with HBV viremia stably <12 IU/ml. Phylogenetic analysis was used to avoid potential problems with cross-contamination and PCR-generated errors during direct sequencing of HBV reverse transcriptase (RT).

RESULTS: HBV RT were successfully sequenced in 22 (88.0%) of lamivudine-treated patients with HBV viremia ranging from 12 IU/ml to 345 IU/ml, and in 10 (40.0%) and 5 (31.2%) patients receiving lamivudine or lamivudine+adefovir, respectively, with HBV viremia <12 IU/ml. Rebound of HBV viremia 12–345 IU/ml occurred after a median duration of lamivudine mono-therapy of 5.1 (IQR 2.3–6.1) years. Drug resistance mutations were observed in 17/22 (77.2%) patients: 8 with M204V, 7 with M204I, 1 with M204I/V and 1 with A181T, respectively. Such primary mutations were found together with 1 compensatory mutation in 8 (50.0%) patients and with ≥2 compensatory mutations in 7 (43.7%) patients, thus highlighting the existence of complex patterns of lamivudine resistance mutations even at the very early stages of virological rebound. Lamivudine resistance mutations were present also in lamivudine-treated patients with undetectable HBV viremia (<12 IU/ml; 4/10, 40%). In particular, M204V and M204I were each observed in 2 and 2 patients, respectively, after a median duration of lamivudine-treatment of 4.3 years (IQR 3.4–4.5). Their presence was predictive of subsequent rebound of HBV viremia and flare of transaminases. The adefovir resistance mutation V84M was also observed in 1 patient receiving lamivudine+adefovir therapy with HBV viremia <12 IU/ml.

CONCLUSION: HBV resistance mutations occur and can be detected even at very low/undetectable viremia, thus supporting their active search also at low level of viremia. The persistence of low levels of HBV replication, the consequent appearance of drug resistance mutations and their predictive value of subsequent virological failure should be considered in setting rational therapeutic strategies, including pro-active switches of successful antiviral therapies.

2009-06-09
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