Resistance testing in children changing human immunodeficiency virus type 1 protease inhibitor
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Updated: Oct 1, 2026
Rapid Screening of HIV Reverse Transcriptase and Integrase Inhibitors
Published on: April 9, 2014
Jean Servais1, Marc Hainaut, Véronique Schmitz
1Laboratoire de Rétrovirologie, Centre de Recherche Public-Santé, Luxembourg, Luxembourg. servais.j@retrovirology.lu
Insights
HIV resistance testing in children failing protease inhibitor (PI) therapy can predict treatment response. Genotypic and phenotypic testing identified mutations correlating with nelfinavir cross-resistance, guiding salvage therapy decisions.
Area of Science:
- Virology
- Pediatric Infectious Diseases
- Pharmacogenomics
Background:
- First-line protease inhibitor (PI) therapy failure in children with HIV-1 infection necessitates effective salvage strategies.
- Understanding drug resistance patterns is crucial for optimizing treatment outcomes in pediatric HIV management.
Purpose of the Study:
- To evaluate the utility of genotypic and phenotypic resistance testing in children with HIV-1 experiencing treatment failure on their initial PI-based regimen.
- To correlate resistance profiles with virologic response to salvage therapy.
Main Methods:
- A multicenter observational study involving 21 HIV-1-infected children (ages 3-16) who failed first-line PI therapy.
- Genotypic and phenotypic resistance testing (direct sequencing and recombinant virus assay) performed at therapy switch.
- Analysis of mutations associated with resistance to ritonavir and cross-resistance to other PIs like nelfinavir.
Main Results:
- 21 genotypic and 15 phenotypic resistance profiles were obtained.
- While many viruses showed reverse transcriptase mutations, 7 isolates had wild-type protease.
- Specific mutations (e.g., 82, 54, 46) and secondary mutations (e.g., T74A, L10I) were associated with ritonavir resistance and cross-resistance to nelfinavir.
- Genotype (mutations 82, 54, 46) or phenotype (> or = 8-fold nelfinavir cross-resistance) predicted poor virologic response to nelfinavir salvage therapy.
Conclusions:
- In heavily pretreated children, HIV resistance testing can predict response to nelfinavir salvage therapy after ritonavir-based treatment failure.
- A strong correlation exists between ritonavir-selected mutations and in vitro nelfinavir cross-resistance.
- Further prospective studies are warranted to confirm the clinical utility of resistance-guided regimen changes in pediatric HIV patients.
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.
Conclusion:
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.
