Quantification of the impact of HIV-1 reverse transcriptase and protease mutations on the efficacy of rescue HAART

The reduction in the efficacy of rescue treatment (administered on a clinic al basis) due to drug resistance was retrospectively quantified in 55 human immunodeficiency virus type 1 (HIV-1)-infected patients failing highly act ive antiretroviral therapy (HAART) by using a novel score calculation syste m based upon HIV-1 reverse transcriptase (RT) and protease (PR) mutations. Patients were all naive for nelfinavir (NFV) and efavirenz (EFV) and were a ssigned to one of the following rescue therapy schedules: (i) 17 patients r eceived NFV + EFV + stavudine (d4T) (group A); (ii) 14 patients received NF V + saquinavir (SQV) + lamivudine (3TC) + d4T/zidovudine (AZT) (group B): ( iii) 19 patients received NFV + d4T + didanosine (ddI)/3TC/zalcitabine (ddC ) (group C); (iv) five patients received miscellaneous treatments including NFV (group D). Responders were considered patients showing a drop in HIV-1 RNA level > 0.5 log(10) after 3 months of therapy. Forty-eight (28 respond ers and 20 non-responders) out of 55 patients completed the first 3 months of rescue therapy and reduction in HIV-1 viral load was found to be signifi cantly higher in group A compared to groups B and C (81.2% responders vs. 3 8.5 and 40.0%, respectively). At baseline, no patient carried EFV- or d4T-r esistant HIV-1 strains, despite prolonged administration of d4T, while 41/4 8 (87.2%) patients had mutations conferring resistance to NFV in the absenc e of previous treatment with this drug. A significant inverse correlation b etween reduction in viral load and reduction in therapy efficacy due to dru g resistance, as determined by the score calculation system, was found (r = 0.62). A cut-off value of 36% reduction in therapy efficacy showed a posit ive predictive value (capacity to detect failure of rescue treatment) of 81 .2% and a negative predictive value (ability to detect successful treatment ) of 75.8%. In addition, 45 out of 48 patients completed also the 9-12 mont h period of rescue therapy and 10/28 responders had a rebound in HIV-1 vira l load level detected after the first 3 months of rescue therapy. Of these, 5/7 (71.4%) showed a further reduction in rescue therapy efficacy due to t he emergence of new mutations. (C) 2000 Elsevier Science B.V. All rights re served.