| |
Cross-Resistance to Nelfinavir Can Be Predicted by Previous Antiretroviral Exposure in the Absence of D30N Mutation F. DRONDA*1, J. L. CASADO1, S. MORENO1, L. RUIZ2, A. ANTELA1, M. J. PEREZ-ELIAS1, and I. GARCIA-ARATA1 for the NELSANE Study.
1Ramon y Cajal Hosp., Madrid; and 2Retrovirology Fndn. “irsiCaixa”, Badalona, Spain Background: Cross-resistance to nelfinavir (NFV) is extensively observed for patients failing protease-inhibitor (PI) therapy. However, the key mutation D30N appears to be rare for NFV-naive patients. We conducted a study to evaluate genotypic changes associated with resistance to NFV, and to determine which factors could identify the presence of resistance to NFV after the failure of a PI-containing regimen.
Methods: Prospective study of 111 patients who had failed in previous PI-containing regimens and who were included in a salvage regimen including NFV. Genotypic resistance testing was performed in all the patients, and was correlated with phenotypic data (n=51) and virological outcome. Viral isolates were classified as susceptible (< 4 fold-resistance), intermediate (4-10 fold-resistance) or resistant (>10 fold-resistant).
Results: Sixty-nine percent of patients had previously received 2 or 3 PIs, during a median time of 534 days (range, 70-900), before inclusion in a regimen with nevirapine plus NFV plus saquinavir (SQV) (n=74), nevirapine plus NFV (32) or nevirapine plus NFV plus ritonavir (5). At entry, median CD4+ count was 208 cells/mmc (range, 7-785) and HIV RNA level was 4.6 log10 copies/ml (2.3-6.2). Median number of mutations in protease gene was 9 (2-25). At baseline, D30N mutation was not detected but 51% (26/51) and 14% (7/51) of patients showed viral isolates resistant or with intermediate resistance to NFV, respectively. Phenotypic data correlated with virological outcome, reaching viral load <200 copies/ml at 3rd month 40%, 14% and 0% of those patients with susceptible, intermediate or resistant viral isolates (p=0.003). Baseline phenotypic resistance was associated with the presence of the L90M mutation: 46% for resistant isolates vs 6% in susceptible strains (p=0.007). Also, the number of mutations in the protease gene correlated with the fold-increase in the IC50 against NFV (13, 9 and 6; p<0.001). For 74 patients who failed on NFV therapy, the D30N mutation was only detected in 1 patient (1%) at 6 months. In a logistic regression analysis, only the number of mutations in the protease gene (RR, 2.09 per each additional mutation; 95% CI: 1.23-3.55; p<0.01) was statistically associated with NFV cross-resistance and subsequently with the lack of viral suppression on a NFV-containing rescue regimen.
Conclusions: Cross-resistance to NFV for PI-experienced patients may be predicted by the number of mutations in the protease gene, with the presence of the L90M offering additional evidence. Phenotypic data closely correlated with virological outcome. The presence of the D30N mutation is exceptional in these patients, and it is not useful to identify resistant isolates.
Key Words: Cross-resistance, Genotype, Nelfinavir
|
