Early emergence of raltegravir resistance mutations in patients receiving HAART salvage regimens.
The emergence of drug-resistance mutations in HIV-1 integrase of patients receiving HAART salvage regimens including raltegravir was investigated in 11 heavily pretreated patients (median number of treatment failures 12, range 5-22) within an expanded access program in Pavia, Italy. HIV-1 RNA levels in plasma, CD4(+) T-cell counts and sequencing of HIV-1 reverse transcriptase (RT), protease (PR), gp41, and integrase genes were performed at baseline and after 1, 2, 3, 6, and 12 months. The treatment baseline median HIV-1 RNA levels in plasma decreased from 7,510 (range 118-407,107) to <50 copies/ml (range <50-7,562), while median CD4(+) T-cell counts remained unchanged (from 212 cells/microl, range 10-764 to 262 cells/microl, range 13-760). Mutations at positions involved in raltegravir resistance (E92G, G140S, Q148H, and N155H) were detected in 4 of 11 (36.3%) patients as early as 1 month after initiating salvage HAART. Of note, the E --> G change at codon 92 was not reported previously. In two patients with raltegravir resistance, the simultaneous appearance of additional mutations (Y143R and E170A) with an unclear impact on susceptibility to raltegravir or on integrase activity was observed. It is concluded that raltegravir resistant HIV-1 strains may emerge as early as 1 month after initiating HAART salvage regimens. A new mutation associated with the emergence of raltegravir resistance is described, and the simultaneous appearance of primary and secondary mutations was observed. The effect of single and multiple mutations on integrase activity, raltegravir susceptibility, and on the capacity of viral replication remains to be elucidated.
Baldanti
Fausto
F
Virology Unit, Foundation IRCCS Policlinico San Matteo, Pavia, Italy. f.baldanti@smatteo.pv.it
Paolucci
Stefania
S
Gulminetti
Roberto
R
Brandolini
Micaela
M
Barbarini
Giorgio
G
Maserati
Renato
R
D000328:Adult; D000595:Amino Acid Sequence; D023241:Antiretroviral Therapy, Highly Active; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000187:drug effects / Q000235:genetics; D019428:HIV Integrase Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011760:Pyrrolidinones / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D016879:Salvage Therapy; D016415:Sequence Alignment; D013997:Time Factors
D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1