ABSTRACT: Purpose: Resistance mutations were examined in two studies of NRTI therapy: TARGET and ACTG 240. In TARGET, reverse transcriptase (RT) mutations in zidovudine-naïve, stavudine-experienced subjects and zidovudine-experienced subjects were compared. In ACTG 240, stavudine monotherapy versus zidovudine monotherapy was compared in therapy-naïve paediatric subjects.
Methods: HIV-1 RNA changes were assessed according to RT mutations. RT baseline genotype was obtained for 67 TARGET subjects who were either zidovudine-naïve, stavudine-experienced (34), zidovudine-experienced and stavudine-experienced (25), or zidovudine-experienced and stavudine-naïve (8). The ACTG 240 virology substudy consisted of 60 subjects treated with stavudine and 61 who received zidovudine. Plasma HIV-1 RNA and genotype were analyzed on all available samples at 0, 24, 36, 48, 72 and 96 weeks.
Results: In TARGET, 16/34 (47%) zidovudine-naïve subjects had 'zidovudine-like' resistance mutations (RM), most commonly at 215 (10/16). 16/33 (48%) zidovudine-experienced subjects had 'zidovudine-like' RM, most commonly at 215 (11/33). Previous experience did not predispose to acquiring these 'zidovudine' mutations (P=1.0). In ACTG 240, 13/58 (22%) subjects on stavudine developed new 'zidovudine' RM, while 31/43 (72%) subjects on zidovudine developed 'zidovudine' RM. 5/26 (19%) stavudine responders (-0.5 log10HIV-1 RNA) developed 'zidovudine' RM; 8/32 (25%) subjects who either rebounded or never responded at all to stavudine also developed 'zidovudine' RM. 'Zidovudine' RM were not associated with stavudine therapy failure (P=0.754). 7/13 (54%) of zidovudine responders developed 'zidovudine' RM compared with 24/30 (80%) of zidovudine rebounders or non-responders who developed zidovudine RM (P=0.137).
Conclusions: 'Zidovudine-like' RM (more appropriately 'thymidine analogue' RM) are selected by stavudine combination therapy in zidovudine-naïve adults and in pediatrics on monotherapy. In ACTG240 these mutations were selected at a lower rate in the stavudine arm than in the zidovudine arm, and were not associated with stavudine failure.
