Abstract Form

EVOLVING GENOTYPIC RESISTANCE PATTERNS AND LONGTERM DURABILITY OF NEVIRAPINE-BASED REGIMENS IN HAART NAÏVE PATIENTS

Author: H Wheeler¹ C Skinner¹, M Murphy², J Norman², A Chowdury², C Aitken^2
1Royal London Hospital, London, St Bartholomew’ s Hospital , London , UK.

Objectives: To assess baseline and evolving genotypic resistance patterns in a cohort of antiretroviral naïve patients commenced on nevirapine (NEV) :a long term follow up.

Methods: A cohort of 52 antiretroviral naïve patients commencing NEV with 2 nucleoside analogues (NA) between April 1997 and March 1998 were followed. Data is available on 34/52. Genotypic resistance testing by the Tru-gene HIV-1 Tm assay (Visible Genetic Inc.) was performed retrospectively on pre-therapy plasma RNA samples and subsequently on patient who failed (VL>1000 copies/ml). Patients were categorized according to the results: sustained responders (VL<400 for>36 months), partial responders (VL reduction >0.5, VL remained >1000copies/ml), patients who were UD and rebounded, patients who were UD and discontinued treatment, patients with treatment limiting toxicity. Surrogate marker data is evaluated at 24 weeks unless stated.

Results: Median age of the cohort was 37 (range 27-64). Median baseline CD4 count 270 (range 40-810) and median VL 5 log₁₀ (range 2.2-6.2). 6 patients experienced treatment limiting toxicity and results are presented on the remaining 28 (OT) patients. Median time on NEV 31.5 months (range 6-50 months). Median change in CD4 count from baseline at 24 weeks was +90 (-50-+382),change in VL was –4.15 log₁₀ (-6.0-+0.7). 12/28 (42.8%) achieved an UD VL at 24 weeks. 8/28 (28%) were sustained responders (median CD4 increase 131 (82-747) at 36 months; 4/28 (14%) stopped therapy whilst UD; 7/28 (25%) became UD and rebounded after a median of 40 weeks (24-88). They continued on NEV for a median of 36 months (14-48 months). 9/28 (32%) were partial responders: median change in VL and CD4 count was –0.9 log₁₀ (-2.8-+0.7) and +30 (-40-+146) respectively. There were no significant baseline mutations. Of the 7 who had been UD and then rebounded, all developed an NNRTI mutation first ( K103N/K (5), K101E (1) Y181C (1)) and in addition 2 developed NA mutations. A further 3 later developed NA mutations. As the genotyping was performed retrospectively 5/7 continued NEV based regimes and at 12 months following testing the VL remained at least 1 log less than the baseline VL and the median increase in CD4 count was 163 (-85-+426). Of the 9 partial responders 7 developed NNRTI mutations: Y181C (3), Y188L (1), K103N(1), Y188XYLF(1), K103K(1) ) and in addition 4 developed NA mutations.

Conclusions:

1. There were no baseline mutations.
2. 28% of patients sustained undetectable VL for 3 years and a further 25% for a median of 40 weeks.
3. In failing regimens NNRTI mutations develop first. The K103N was the most common mutation in those who rebounded and there was a more mixed pattern in partial responders.
4. Despite the presence of NNRTI mutations VL did not rebound to pre-treatment levels in the majority of patients and a good immunological response was sustained.

Dr Helen Wheeler, Ambrose King Centre, The Royal London Hospital, London, E1 1BB.