Impact of drug resistance mutations on virologic response to salvage therapy

Objective: To assess the prognostic significance of drug-associated mutatio ns in the protease and reverse transcriptase (RT) genes on virological resp onse to salvage therapy. Patients: All patients from four centres of the Swiss HIV Cohort Study who were switched, between February and October 1997, to nelfinavir plus other antiretroviral drugs following failure of highly active antiretroviral ther apy (HIV-1 RNA >1000 copies/ml after > 3 months). Methods: Direct sequencing of RT and protease genes derived from plasma RNA was performed in 62 patients before salvage therapy. Baseline predictors ( drug-resistance mutations, drug exposure, clinical and biological parameter s) of virological response after 4-12 weeks of therapy were assessed by lin ear regression analyses. Results: Patients had been treated with RT inhibitors and protease inhibito rs for a median duration of 35.6 and 12.2 months, respectively. Baseline me dian CD4 cell count was 113 x 10(6)/l and HIV-1 RNA 5.16 log(10) copies/ml. The median decrease of HIV-1 RNA was 0.38 log(10); 32% of the patients sho wed > 1 log(10) decrease. At baseline, 90% of the patients had RT inhibitor -resistance mutations with a median number per patient of four (range, 0-7) . Primary and secondary protease inhibitor-resistance mutations were detect ed in 69% and 89% of the patients, respectively. The median number of total protease inhibitor-resistance mutations per patient was four (range, 0-9). In univariate analysis, virological response to salvage therapy was associ ated with number of RT inhibitors, primary and secondary protease inhibitor -resistance mutations, history of protease inhibitor use (duration and numb er), but not with clinical stage, HIV-1 RNA level or CD4 cell count. After adjustment for all variables, the number of RT inhibitor plus protease inhi bitor-resistance mutations was the only independent predictor. Conclusions: In patients with advanced HIV infection, the virological respo nse to salvage therapy containing nelfinavir is best predicted by the numbe r of baseline RT inhibitor plus protease inhibitor-resistance mutations. (C ) 1999 Lippincott Williams & Wilkins.