Mutations linked to drug resistance, human immunodeficiency virus type 1 biologic phenotype and their association with disease progression in children receiving nucleoside reverse transcriptase inhibitors.
BACKGROUND
Few data are available concerning the impact of antiretroviral resistance in response to antiviral therapy in children. We evaluated the development of antiretroviral genotypic resistance and clinical outcome in a subgroup of children involved in a prospective antiretroviral therapy trial (Pediatric AIDS Clinical Trials Group Protocol 152).


METHODS
We studied 26 matched case/control pairs. A case was defined as having clinical disease progression during the study period; controls did not have disease progression. Cases and controls were matched by age and CD4+ cell count at baseline. Matched pairs received treatment with zidovudine (9 pairs), didanosine (12 pairs) or combined therapy (5 pairs). Multiple codons of the reverse transcriptase coding region (41, 67, 70, 74, 151, 184, 210, 215 and 219) were analyzed. Patients were evaluated for CD4+ cell count, HIV-1 viral load and HIV-1 biologic phenotype at baseline and clinical endpoint.


RESULTS
The presence of mutations associated with resistance after nucleoside antiretroviral therapy (P = 0.039) and syncytium-inducing phenotype (P = 0.031), were significantly associated with increased risk of clinical disease progression. The mean difference in HIV-1 RNA levels between cases and their matched controls after nucleoside antiretroviral therapy was 0.77 log10 copies/ml higher for cases (P = 0.003). The median difference between cases and controls for CD4+ cell count after nucleoside antiretroviral therapy was 349 cells/mm3 lower for cases (P < 0.001).


CONCLUSIONS
In this small prospective study of HIV-infected children, mutations in the reverse transcriptase coding region, syncytium-inducing viral phenotype, higher HIV-1 RNA load and lower CD4+ cell count were significantly correlated with increased risk of HIV clinical disease progression.
Englund
Janet A
JA
University of Chicago, Pritzker School of Medicine, Chicago, IL, USA.
Raskino
Claire
C
Vavro
Cindy
C
Palumbo
Paul
P
Ross
Lisa L
LL
McKinney
Ross
R
Nikolic-Djokic
Divna
D
Colgrove
Robert C
RC
Baker
Carol J
CJ
D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016049:Didanosine / Q000008:administration & dosage; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010597:Pharmacogenetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011336:Probability; D011446:Prospective Studies; D012367:RNA, Viral / Q000032:analysis; D012016:Reference Values; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D018709:Statistics, Nonparametric; D019562:Viral Load; D015215:Zidovudine / Q000008:administration & dosage
D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D016049:Didanosine