602 Mutation 36I of the Protease Region Before Starting Therapy Facilitates the Appearance of L90M in Patients Failing their First PI-HAART Regimen CF Perno*1, A Cozzi-Lepri2, C Balotta3, F Forbici1, M Violin3, A De Luca4, S Rusconi3, G Ballardini5, E Petrelli6, E Tufo7, AN Phillips2, A d'Arminio-Monforte3 1Inst Natl per le Malattie Infettive L Spallanzani, Rome, Italy; 2Royal Free Univ Coll Med Sch, London, UK; 3Univ of Milan, Italy; 4Catholic Univ, Rome, Italy; 5St Maria delle Croci Hosp, Ravenna, Utaly; 6San Salvatore Hosp, Pesaro, Italy; and 7Hosp of Latina, Italy
Methods: Plasma samples from 93 previously naïve patients (pts) experiencing VF to their first HAART were tested for genotypic resistance before starting HAART (baseline) and around the date of VF (first of 2 consecutive VL > 500 cps/ml after 24 wks of HAART). A mutation was defined as "new" if it was not detected at baseline. End-point was the probability of accumulating 90M. Logistic regression was used to identify factors associated with endpoint.
Results: The median time from baseline to the second genotypic test was 48 wks (range: 21-152); this test was performed 0–3/+24 wks around VF. Median VL was 5.04 log10 cps/ml (range: 2.78-6.00) at baseline and 3.65 (range: 2.71-5.80) at VF. All pts were under PI-containing therapy at the second genotypic test. Forty-seven (47; 50.5%) started hg saquinavir (hg-sqv), 29 (31.2%) indinavir (idv), 12 (12.9%) ritonavir (rit), and 5 (5.4%) nelfinavir (nel), all in combination with 2 NRTIs. At baseline, the most frequent protease region mutations (PRM) were the 10I/V (n = 9; 13.7%), 36I (n = 23; 34.8%), 71T/V (n = 6; 9.1%), and 77I (n = 23; 34.8%). At VF, the most frequent new PRM were 90M (n = 13; 19.4%), 71T/V (n = 12; 18.0%), 36I (n = 8; 11.9%), and 82A/S/T (n = 7; 10.5%). 3/9 pts (33.3%) carrying a mutation 10I/V at baseline vs 10/84 (4.8%) not carrying 10I/V accumulated 90M (p = 0.11); 6/23 (26.1%) pts carrying 36I at baseline, vs 7/70 (10.0%) not carrying 36I accumulated 90M (p = 0.08). There was no association between the presence of 71T/V or 77I at baseline and the probability of new 90M (p = 0.31 and p = 0.40). The percentage of new 90M according to the PI started were: 10.3% (n = 3) for idv, 0.0% for nel, 8.3% (n = 1) for rit and 19.2% (n = 9) for hg-sqv (p = 0.48). From fitting a logistic regression model, the presence of mutation 36I at baseline was associated with the probability of new 90M (but not with 82A/S/T) after adjusting for reduction in VL relative to baseline, use of 3TC and 10V/I at baseline (OR = 8.44, 95% CI: 1.80-39.68). The association was stronger in pts who started a sqv-sparing regimen (OR = 77.83, 95% CI: 3.64-999.00) compared to pts starting hg-sqv (OR = 2.79, 95% CI: 0.43-17.99).
Conclusions: Mutation 36I (naturally occurring in many B- and in > 90% of non-B HIV strains) seems to facilitate the appearance of new 90M in vivo in chronically infected patients experiencing VF to their first PI-containing HAART. In addition, these results provide ground for the common evolution to 90M of non-B pts failing after PI-containing regimens.
