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

EFFECT OF MUTATIONS IN THE RT CONNECTION DOMAIN ON PHENOTYPIC SUSCEPTIBILITY AND VIROLOGIC RESPONSE TO ETRAVIRINE

Antivir Ther 2009; 14 Suppl 1:A35 (abstract no. 33)

J Vingerhoets¹, L Tambuyzer¹, R Paredes², S Nijs¹, B Clotet², JM Schapiro³ and G Picchio^4
1Tibotec BVBA, Mechelen, Belgium; ²IrsiCaixa Foundation, Hospital Universitari Germans Trias I Pujol, Universitat Autonoma Barcelona, Catalonia, Spain; ³National Hemophilia Center, Sheba Medical Center, Israel; ⁴Tibotec, Inc., Yardley, PA, USA

BACKGROUND: Connection domain mutations (CDMs) in HIV RT are coselected with thymidine analogue-associated mutations (TAMs), but also modulate the virologic outcome of NNRTI-based treatment. This study analysed the effect of CDMs on phenotype and virologic response to etravirine (ETR; TMC125) in the DUET studies.

METHODS: Seventeen CDMs (L283I, E312Q, G333D/E, G335C/D, N348I, A360I/T/V, V365I, T369I, A371V, A376S, I393L and E399D/G) were studied. Prevalence and effect on ETR FC were analysed using DUET baseline resistance data. The effect on virologic response (<50 copies/ml at week 24) was studied in ETR-treated DUET patients not using de novo enfuvirtide and excluding discontinuations for reasons other than virologic failure (n=406). Reduced virologic response was defined as <75% of the response in patients without baseline NNRTI RAMs. Covariation between CDMs, ETR resistance-associated mutations (RAMs) and TAMs was assessed using phi correlation coefficients.

RESULTS: The most prevalent CDMs were A371V (27%), E399D (22%), A376S (16%), N348I (14%), A360T (14%), G333E (12%) and L283I (11%). 37% of samples harbored only 1 CDM. The overall distribution of samples by number of ETR RAMs was similar with or without CDMs. Phi correlation analysis confirmed the lack of association between CDMs and ETR RAMs. Conversely, CDMs occurred more frequently in samples with more TAMs. No CDM had a clear effect on ETR FC, except for A376S for which the proportion of resistant samples (FC>13) with this mutation was higher than without the mutation (18.4% versus 13.3%, respectively). Virologic responses were unaffected by most CDMs, except for G333D, G335D and A376S for which the reduction in virologic response was close to the predefined threshold. This effect was not evident in a subgroup of patients with less active ARVs (ETR FC>3, DRV FC>10; sufficient numbers only available for A376S). Multivariate analysis taking into account baseline VL and DRV FC demonstrated that addition of these CDMs to the ETR weighted genotypic score did not significantly improve the association with virologic response to ETR.

CONCLUSIONS: This analysis showed no clear effect of the CDMs on phenotypic susceptibility and virologic response to ETR.

2009-06-09
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