HIV-1 phenotypic susceptibility to lopinavir (LPV) and genotypic analysis in LPV/r-naive subjects with prior protease inhibitor experience.
The relationship between phenotypic susceptibility to lopinavir (LPV) and genotypic pattern was investigated in LPV-naive, protease inhibitor (PI)-experienced subjects. Protease sequences of 100 HIV isolates with ascertained susceptibility (determined by Antivirogram) to LPV were analyzed (VircoGen). Two different thresholds (2.5- and 10-fold) were used for defining reduced susceptibility. Mutations were classified as LPV/r (the actual formulation of LPV that combines LPV with low-dose ritonavir) mutations according to the International AIDS Society-USA. Thirty-four isolates showed reduced LPV susceptibility (2.6- to 75.9-fold). Fold resistance to LPV correlated with the number of total and LPV/r mutations (Spearman coefficient = 0.62 and 0.74, respectively; P < 0.001). Current PI therapy (P = 0.002) and indinavir administration (P < 0.001), >5 LPV/r mutations (P < 0.0012), and detection of L10FIRV, K20MR, M46IL, I54VL, A71VT, G73SA, V82AFTS, I84V, and M90L were associated with LPV resistance in univariate analysis. Factors independently associated with LPV resistance were K20MR (odds ratio [OR], 13.9; 95% confidence interval [CI], 1.3-145.1; P = 0.028), I54VL (OR, 131.7; 95% CI, 10.5-1654.7; P < 0.001), G73SA (OR, 19.2; 95% CI, 1.4-273.7; P = 0.029), and I84V (OR, 177.5; 95% CI, 6.0-5232.5; P = 0.003) mutations and >9 protease mutations (OR, 18.6; 95% CI, 1.6-213.0; P = 0.019). Sixteen of 34 and 18 of 34 isolates with reduced LPV susceptibility showed >10-fold or <10-fold LPV resistance, respectively. Linear regression analysis demonstrated that each additional LPV mutation and I54VL accounted for much of the fold resistance to LPV (adjusted R2 = 0.70). In conclusion, for PI-experienced patients requiring salvage therapy, switching to LPV should be based on the number of baseline mutations and the presence of mutation 54.
Monno
Laura
L
Clinic of Infectious Diseases, University of Bari, Bari, Italy. l.monno@clininf.uniba.it
Saracino
Annalisa
A
Scudeller
Luigia
L
Pastore
Giuseppe
G
Bonora
Stefano
S
Cargnel
Antonietta
A
Carosi
Gianpiero
G
Angarano
Gioacchino
G
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011744:Pyrimidinones / Q000494:pharmacology*
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir