ABSTRACT: Objective: A pilot open-label study to evaluate a GIGHAART drug combination in patients with multiple failures on prior highly active combination therapy (HAART) regiments with multiply resistant HIV strains.
Methods: Pretreated patients having received all three classes of antiretroviral drug were included with HIV RNA >50000 copies/ml while on protease inhibitor (PI)-containing regimen. Measurements included plasma HIV RNA, CD4 cells at baseline (weeks 1, 4, 8 and 12-16).
Results: Preliminary analysis involved 13 patients. At baseline the median viral load (VL) was 180000 copies/ml (range 4.78-6.09 log10), the median CD4 count was 80 cells/mm3 (0-168), median duration of antiretroviral therapy was 77 months and there was a median of 13 lines of prior antiretroviral therapy. The GIGHAART therapy consisted of eight drugs (n=8) or nine drugs (n=5) with stavudine (11/13), didanosine (11/13), lamivudine (11/13), abacavir (10/13), nevirapine (2/13), efavirenz (11/13), hydroxyurea 500 mg twice daily (13/13), ritonavir (13/13) 400 mg (11) or 200 mg twice daily (2); indinavir (9/13) 400 mg (7) or 800 mg twice daily (2); saquinavir (9/13) 400 mg (3), 600 mg (3) or 800 mg (3) twice daily and nelfinavir (8/13) 1250 mg twice daily (4) or 750 mg (4) three times daily. Overall seven patients discontinued therapy before week 12 owing to drug intolerance (n=5), Mycobacterium avium complex infection (n=1) or pneumopathy (n=1). Genotypic resistance profiles revealed mutations on the RT gene at codon 215 (12/13), 41 (11/13), 184 (9/13), insertion SS69 (2/13) and multidrug resistance mutation 151 (1/13). Only 2/13 were sensitive to non-nucleoside reverse transcriptase inhibitors (NNRTI) as K103N was found in 6/13, Y188L in 2/13 and G190A/S in 4/13. Only 2/13 were sensitive to protease inhibitors (PI). Major PI mutations were observed in most patients: G48V (2/13), V82A/F/T (5/13), I84V (4/13), L90M (10/13). In concordance with the genotype, 10/13 patients had extensive high-level phenotypic resistance, affecting all three classes of antiretroviral drug. In spite of resistance, the median change in viral load (VL) was -1.22 log10at week 4 (n=12), -1.86 log10at week 8 (n=9), -2.35 log10at weeks 12-16 (n=6). The number of patients with >1 log10reduction in VL was 6/12 at week 4, 5/9 at week 8, and 5/6 at weeks 12-16. Two patients were re-challenged with GIGHAART following discontinuation for adverse events and, after 2 months, had -3.87 log10and -2.46 log10reduction in VL compared to baseline value, respectively.
Conclusion: Despite resistance to multiple antiretroviral drugs following repeated therapeutic failures, a combination of eight to nine drugs can lead to a substantial decrease in VL. Long term efficacy of GIGHAART, and the potential maintenance strategies following GIGHAART, have to be determined and mechanisms of action understood.
