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

PREVALENCE AND CLINICAL SIGNIFICANCE OF TRANSMITTED DRUG-RESISTANT (TDR) HIV MUTATIONS BY ULTRA-DEEP SEQUENCING (UDS) IN HIV-INFECTED ARV-NAÏVE SUBJECTS IN CASTLE STUDY

Antivir Ther 2009; 14 Suppl 1:A44 (abstract no. 42)

M Lataillade^1,2, J Chiarella², R Yang¹, S Schnittman¹, V Wirtz¹, M Mancini¹, J Uy¹, D Seekins¹, M Krystal¹, D McGrath¹, B Simen³, M Egholm³ and M Kozal^2
1Bristol–Myers Squibb Resistance Working Group, Research and Development, Wallingford, CT, USA; ²Yale University School of Medicine and Veterans Affairs Health Care Systems, New Haven, CT, USA; ³454 Life Sciences-Roche Company, Branford, CT, USA

BACKGROUND: CASTLE compared the efficacy of atazanavir/ ritonavir with lopinavir/ritonavir, each in combination with tenofovir-emtricitabine in ARV-naïve subjects from five continents. Little is known about the prevalence of low and high abundance TDR variants that exist in diverse ARV-naïve populations and the clinical significance of low abundance resistant variants on boosted PI-based HAART. We aimed to determine the baseline prevalence and clinical significance of TDR mutations using UDS in ARV-naïve subjects in CASTLE.

METHODS: A case control study was performed on baseline samples for all 53 week 48 virological failures (VF) and 95 virological successes (VS) randomly selected and matched by baseline CD4+ T-cell count and viral load. TDR mutations were defined using 2009 WHO criteria. The limit of detection for TDRs by UDS was restricted to ≥1% of the viral population. UDS was performed using 454 Life Sciences/Roche technology.

RESULTS: Of 148 samples, 141 had successful UDS (86 subtype B and 55 non-B subtypes). Overall, 30.5% of subjects had a TDR mutation at baseline; 15.6% only had TDR(s) at <20% of the viral population. There was no difference in the prevalence of TDRs by B (30%) or non-B subtypes (31%). Eighteen subjects (12.8%) had multiclass TDRs. Sixteen (11.3%) subjects had NNRTI TDRs (15 with at least 1 K103N, Y181C/I or 190A/E). Of 35 (24.8%) subjects with NRTI TDRs, 26 had TAMs, 9 had M184V/I and 2 had K65R. Overall, VS and VF had similar rates of any TDRs (33% versus 25%), NNRTI TDRs (11% versus 12%) and NRTI TDRs (24% versus 25%). Of 9 (6.4%) subjects with M184V/I (7 at <20% levels), 6 experienced virological failure (4 had TAMs and 1 had K65R+TAMs). Sixteen (11.3%) subjects had multiple TAMs, 7 experienced virological failure. Three (2.1%) subjects had both multiple TAMs+M184V, all experienced virological failure. Of 14 (9.9%) subjects with PI TDRs (11 at <20% levels), 13 did not experience virological failure; 10 only had a solitary PI TDR (for example, 24I, 32I, 46I or 58E); 4 (2.8%) had multiple PI TDRs. One subject had multiple PI and NRTI TDRs at >20% levels and experienced virological failure.

CONCLUSION: Among a representative sample of ARV-naïve subjects in CASTLE, TDR mutations were common (30.5%); B and non-B subtypes had similar rates of TDRs. Subjects with multiple PI TDRs were infrequent. Overall, TDRs did not affect virological response for subjects on a boosted PI by week 48; however, a small subset of subjects with extensive NRTI backbone TDR patterns experienced virological failure.

2009-06-09
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