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 clinical basis) due to drug resistance was retrospectively quantified in 55 human immunodeficiency virus type 1 (HIV-1)-infected patients failing highly active antiretroviral therapy (HAART) by using a novel score calculation system based upon HIV-1 reverse transcriptase (RT) and protease (PR) mutations. Patients were all naive for nelfinavir (NFV) and efavirenz (EFV) and were assigned to one of the following rescue therapy schedules: (i) 17 patients received NFV + EFV + stavudine (d4T) (group A); (ii) 14 patients received NFV + 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 log10 after 3 months of therapy. Forty-eight (28 responders 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 significantly higher in group A compared to groups B and C (81.2% responders vs. 38.5 and 40.0%, respectively). At baseline, no patient carried EFV- or d4T-resistant HIV-1 strains, despite prolonged administration of d4T, while 41/48 (87.2%) patients had mutations conferring resistance to NFV in the absence of previous treatment with this drug. A significant inverse correlation between reduction in viral load and reduction in therapy efficacy due to drug 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 positive 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 month period of rescue therapy and 10/28 responders had a rebound in HIV-1 viral 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 the emergence of new mutations.
Paolucci
S
S
Servizio di Virologia, IRCCS Policlinico S. Matteo, Pavia, Italy.
Baldanti
F
F
Maserati
R
R
Castelli
F
F
Suter
F
F
Maggiolo
F
F
Pan
A
A
Gerna
G
G
D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D016333:HIV Protease / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D009154:Mutation; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016333:HIV Protease