Abstract
BackgroundAlthough the introduction of combined therapy with reverse transcriptase and protease inhibitors has resulted in considerable decrease in HIV related mortality; it has also induced the development of multiple drug-resistant HIV-1 variants.The few studies on HIV-1 mutagenesis in HIV infected children have not evaluated the impact of HIV-1 mutations on the clinical, virological and immunological presentation of HIV disease that is fundamental to optimizing the treatment regimens for these patients.ResultsA cross sectional study was conducted to evaluate the impact of treatment regimens and resistance mutation patterns on the clinical, virological, and immunological presentation of HIV disease in 41 children (25 male and 16 female) at the Robert Wood Johnson Pediatric AIDS Program in New Brunswick, New Jersey. The study participants were symptomatic and had preceding treatment history with combined ARV regimens including protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Fifteen (36.6%) children were treated with NRTI+NNRTI+ PI, 6 (14.6%) with NRTI+NNRTIs, 13 (31.7%) with NRTI+PIs, and the remaining 7 (17.1%) received NRTIs only.Combined ARV regimens did not significantly influence the incidence of NRTI and NNRTI associated mutations. The duration of ARV therapy and the child's age had no significant impact on the ARV related mutations. The clinico-immunological presentation of the HIV disease was not associated with ARV treatment regimens or number of resistance mutations. However, primary mutations in the protease (PR) gene increased the likelihood of plasma viral load (PVL) ≥ 10,000 copies/mL irrespective of the child's age, duration of ARV therapy, presence of NRTI and NNRTI mutation. Viremia ≥ 10,000 copies/mL was recorded in almost all the children with primary mutations in the PR region (n = 12/13, 92.3%) as compared with only 50.0% (n = 14/28) of HIV infected children without (PR-), P < 0.008. However, CD-4 T cells were not affected by the mutations in the PR gene of the HIV-1 isolates.ConclusionPrimary PR resistance mutations significantly increase the likelihood for high viral replication in pediatric patients with moderate/severe HIV-1 infection, which may affect the long-term clinical prognosis of the HIV infected children.
Highlights
The introduction of combined therapy with reverse transcriptase and protease inhibitors has resulted in considerable decrease in HIV related mortality; it has induced the development of multiple drug-resistant human immunodeficiency virus type 1 (HIV-1) variants.The few studies on HIV-1 mutagenesis in HIV infected children have not evaluated the impact of HIV-1 mutations on the clinical, virological and immunological presentation of HIV disease that is fundamental to optimizing the treatment regimens for these patients
It has been shown that antiretroviral therapy used in the presence of drug-resistant viruses may increase the risk of HIV-1 mutagenesis [2,3] and the expansion of resistant HIV mutants compromises the efficacy of the antiretroviral (ARV) therapy [4,5,6]
We previously reported the occurrence of mutations in the protease (PR) gene in a small group of HIV infected children treated with the protease inhibitor (PI) nelfinavir [11]
Summary
The few studies on HIV-1 mutagenesis in HIV infected children have not evaluated the impact of HIV-1 mutations on the clinical, virological and immunological presentation of HIV disease that is fundamental to optimizing the treatment regimens for these patients. HIV-1 mutants have been isolated both from both, ARV treated and untreated HIV infected Brazilian children [12] Several studies demonstrated that the failure of ARV therapy [13] and clinical disease progression [14] in HIV infected children is associated with a high frequency of primary mutations in the reverse transcriptase (RT) gene. Cognizance of the impact of resistance mutations on the subsequent response to ARV therapy is of importance in the optimization of treatment regimens, especially for HIV-1 infected pediatric patients.
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