16th International HIV Drug Resistance Workshop 12-16 June 2007, Barbados

INCREASING PREVALENCE OF HIV-1 NON-B SUBTYPES IN THE US AND IMPLICATIONS FOR PROTEASE INHIBITOR RESISTANCE MUTATION SCORES

Antivir Ther. 2007; 12:S51 (abstract no. 44)

R Kagan ¹, M Winters², L Li¹ and M Lewinski^1
1Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA; ²Center for AIDS Research, Stanford University, Stanford, CA, USA

INTRODUCTION: HIV-1 antiretroviral development has targeted subtype B, the primary subtype in the US Most resistance-associated mutations can be found in non-B subtypes and the genetic barrier to resistance is comparable. However, the number of minor protease amino acid substitutions varies between subtypes. Mutation scores have been developed for several protease inhibitors. In this work, we assessed the affect of subtype on mutation scores for atazanavir, darunavir, lopinavir and tipranavir.

METHODS: 186,381 reference laboratory samples sequenced from 2000–2006 were subtyped using BLASTN searches of the NCBI HIV-1 2005 subtype reference database. Subtype assignment was based on the highest scoring Blast hit. Mutation scores were calculated for subtypes A1, AE, AG, B, C, D and G. Cutoffs used were ≥3 (atazanavir and darunavir), ≥5 (tipranavir) and ≥6 (lopinavir).

RESULTS: The prevalence of HIV-1 non-B subtypes has increased from 0.18% in 1998 to 2.75% in 2006 (0.34%/yr; R²=0.96). Mutations from 3,277 non-B sequences collected in 2000–2006 were evaluated. Three tipranavir-score mutations (I13V, M36I, H69K) that occur as wild type variants in subtypes A1, AG and G were found in 80–98% of sequences for these subtypes. 5.1% of non-B subtypes had ≥5 tipranavir mutations versus 2.2% of B’s (OR=2.4, P<0.0001), including A1: 7.9%, AG: 6.8% and G: 5.5%. The atazanavir mutation G16E was more prevalent in subtypes A1 (15.6%), AE (17.4%) and AG (16.1%) versus B (3.4%). However, an atazanavir score of ≥3 occurred less frequently in most non-B subtypes (non-B: 4.8%; B: 9.8%; OR=0.47, P<0.0001) as did darunavir scores of ≥3 (non-B: 0.4%; B: 2.3%; OR=0.17, P<0.0001) and lopinavir resistance scores of ≥6 (non-B: 2.2%; B: 9.1%; OR=0.22 P<0.0001).

CONCLUSIONS: The prevalence of HIV-1 non-B subtypes is increasing in the tested population in the US. The higher frequency of tipranavir-score protease variants in non-B subtypes can result in more frequent predictions of tipranavir resistance in genotypic assays. The phenotypic and clinical consequences of these mutation patterns should be assessed and the need for subtype-specific mutation scores for non-B subtypes should be evaluated.

2007-06-12
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