Resistance testing in children changing human immunodeficiency virus type 1 protease inhibitor.
OBJECTIVE
To assess genotypic and phenotypic resistance testing in HIV-1-infected children failing a first protease inhibitor (PI) therapy.


METHODS
In a multicenter observational study 21 children, ages 3 to 16 years, were given two reverse transcriptase inhibitors and one PI (mainly ritonavir, n = 18). They were subsequently treated with single or dual PI-based therapy (predominantly nelfinavir, n = 10, or ritonavir-saquinavir, n = 7). Resistance testing was performed at the time of therapy switch via direct sequencing and a recombinant virus susceptibility assay.


RESULTS
A total of 21 genotypic and 15 phenotypic resistance profiles were obtained. Most viruses displayed several reverse transcriptase mutations; however, 7 isolates maintained a wild-type protease. Ritonavir targeted the well-known pathway containing 82, 54, 46 and other secondary (nonactive site) mutations including T74A. No in vitro cross-resistance, i.e. > or = 8-fold resistance to saquinavir or amprenavir, was encountered. Secondary mutations enhanced the prediction of ritonavir resistance (i.e. L10I) and in vitro nelfinavir cross-resistance (i.e. K20R/I) conferred by primary (active site) resistance mutations. Either the 82, 54, 46 mutational genotype or the phenotype showing > or = 8-fold nelfinavir cross-resistance predicted a poorer virologic response to nelfinavir salvage therapy.


CONCLUSIONS
In a small cohort of heavily pretreated pediatric patients, resistance testing appears to predict the response to nelfinavir as salvage for a ritonavir-based therapy. This is further supported by the correlation between ritonavir-selected mutations and in vitro nelfinavir cross-resistance. Prospective studies should assess clinical outcome in children undergoing regimen changes based on resistance testing.
Servais
Jean
J
Laboratoire de Rétrovirologie, Centre de Recherche Public-Santé, Luxembourg, Luxembourg. servais.j@retrovirology.lu
Hainaut
Marc
M
Schmitz
Véronique
V
Maes
Philip
P
Fransen
Katrien
K
Vaira
Dolores
D
Brichard
Bénédicte
B
Arendt
Vic
V
Schneider
François
F
Hemmer
Robert
R
Schmit
Jean-Claude
JC
D000293:Adolescent; D023241:Antiretroviral Therapy, Highly Active; D002648:Child; D002675:Child, Preschool; D024921:Drug Resistance, Multiple, Viral; D005260:Female; D005814:Genes, Viral / Q000235:genetics; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011237:Predictive Value of Tests; D017211:Treatment Failure
D017320:HIV Protease Inhibitors; D054303:HIV Reverse Transcriptase; D016333:HIV Protease