ABSTRACT: In vitro resistance studies have demonstrated significant cross-resistance among mutant strains of HIV-1 resistant to currently approved non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs). Little data exists on the efficacy of sequential NNRTI combination therapy. In a sub-study of the Sustiva (efavirenz) Expanded Access Program, patients with prior NNRTI experience were followed after a switch to efavirenz combination therapy. Among 44 patients enrolled in the study, 70% reported prior use of nevirapine and 36% prior reported prior use of delavirdine (some used both). Among 28 patients for whom 3 month follow-up data was available, 57% (16) had plasma viral loads „400 copies/ml (non-responders) and 43% (12) achieved viral loads </= 400 copies/ml (responders). The log10of the median baseline viral load of responders was 4.50 compared to 5.19 for non-responders.
Prior protease inhibitor (PI) usage averaged 2.5 PIs for responders compared to 3.3 PIs for non-responders. Prior nelfinavir usage also differed [25% (3/12) in responders and 94% (15/16) in non-responders]. Among patients for whom a baseline genotype was obtained, 78% (32/41) had one or more NNRTI mutations. The three most common genotypes were K103N (20%), Y181C (9.8%) and a K103N plus Y181C double mutant (24%). 7/8 of the patients with the double mutant at baseline were non-responders at 3 months, as were 3/6 of the patients with K103N and 3/3 of the patients with Y181C. A quantitative mutation detection assay identified two additional responder patients with a low proportion of K103N at baseline. After 3 months, viral genotypes from non-responders showed the acquisition of additional NNRTI mutations. Among 44 NNRTI-experienced patients assessed 3 months after a switch to efavirenz combination therapy, 16 had viral loads >400 copies/ml, 12 had viral loads <400 copies/ml, and 16 patients failed to complete 3 months. 7/8 patients with a K103N plus Y181C double mutation at baseline did not respond to the therapy. These data suggest a decreased likelihood of response to efavirenz combination therapy after failing an initial NNRTI.
