15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

CHANGING PREVALENCE OF ADEFOVIR- AND LAMIVUDINE ASSOCIATED MUTATIONS IN CLINICAL HBV SAMPLES SUBMITTED TO A NATIONAL REFERENCE LABORATORY

Antivir Ther. 2006, 11:S10 (abstract no. 8)

R Kagan, J Platt, H Hamdan, R Chen and M Lewinski
Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA

BACKGROUND: HBV chronically infects 400 million people worldwide and coinfects up to 25% of HIV-1 patients. We assessed the prevalence of mutations associated with resistance to drugs targeting the HBV polymerase (pol) in a national database.

METHODS: HBV polymerase sequences for 4,634 clinical samples were obtained between 6/2002 and 1/2006. Subtypes were determined by phylogenetic analysis of a 348-nt pol fragment. Resistance-associated mutations were defined for lamivudine (L180M, M204V/I, A181T), adefovir (A181V or N236T), famciclovir (V207I), entecavir (L180M+M204V/I + [T184G, S202I or M250V]), and tenofovir (L180M+M204V+A194T). Mutation data for pol codon 236, pre-core region (nucleotide 1896), and BCP region (nucleotides 1762 and 1764) were available for 3,327 samples tested after 5/2004.

RESULTS: The principal HBV subtypes were A (16.0%), B (32.2%) and C (39.1%). Lamivudine associated mutations decreased from 17.8% of tested samples in 2002-2003 to 14.9% in 2004 and 6.8% in 2005-6 (P<0.0001). Adefovir associated mutations increased from 0.5% (7/1,322) in 2004 to 1.9% (53/2,766) in 2005-6 (P<0.001). Predicted famciclovir resistance (V207I) was uncommon (0.9-1.2%), tenofovir resistance was predicted for one sample and entecavir resistance was not predicted. M204V and L180M were more prevalent in subtypes A (16.5% and 17.5%; P<0.001) and G (27.8% and 31.5%; P<0.001). V207I was more prevalent in subtype A (P<0.004). BCP mutations were more prevalent in subtype C (A1762T: 51.3% and G1764A: 55.3%; P<0.0001). The precore substitution was more prevalent in subtype B (47.9%; P<0.0001). M204V+L180M covaried (binomial correlation coefficient phi=0.87) as did M204I+L180M (phi=0.19), V173L+(M204V or L180M) (phi=0.38, 0.36) and A181V+N236T (phi=0.20). BCP substitutions covaried (phi=0.91) but were not correlated with pol mutations.

CONCLUSIONS: Adefovir-associated mutations are emerging in the clinical population while lamivudine-associated mutations are declining and tenofovir and entecavir resistance is not yet evident. BCP mutations, associated with improved interferon response of HbeAG(+) virus, were more prevalent in subtype C. The precore mutation, which may improve replicative capacity of lamivudine-resistant HBV, did not correlate with lamivudine mutations. Continued surveillance of clinical sequences may aid in the detection of emerging mutational patterns to HBV antivirals and combination therapies.

2006-06-13
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