HIV‐1 drug resistance mutations in children after failure of first‐line nonnucleoside reverse transcriptase inhibitor‐based antiretroviral therapy

Abstract

ObjectivesThe aim of the study was to assess the prevalence, predictors and patterns of genotypic resistance mutations in children after failure of World Health Organization-recommended initial nonnucleoside reverse transcriptase inhibitor (NNRTI)-based treatment regimens. MethodsWe carried out a multicentre retrospective study of genotyping tests performed for all HIV-infected children at eight paediatric centres in Thailand who experienced failure of NNRTI therapy at a time when virological monitoring was not routinely available. ResultsOne hundred and twenty children were included in the study. Their median age (interquartile range) was 9.1 (6.8-11.0) years, the median duration of their NNRTI regimens was 23.7 (15.7-32.6) months, their median CD4 percentage was 12% (4-20%), and their median plasma HIV RNA at the time of genotype testing was 4.8 (4.3-5.2) log 10 HIV-1 RNA copies/mL. The nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations found were as follows: 85% of the children had M184V/I, 23% had at least four thymidine analogue mutations, 12% had the Q151M complex, 5% had K65R, and 1% had the 69 insertion. Ninety-eight per cent of the children had at least one NNRTI resistance mutation, and 48% had etravirine mutation-weighted scores 4. CD4 percentage o15% prior to switching regimens [odds ratio (OR) 5.49; 95% confidence interval (CI) 2.02-14.93] and plasma HIV RNA45 log 10 copies/mL (OR 2.46; 95% CI 1.04-5.82) were independent predictors of at least four thymidine analogue mutations, the Q151M complex or the 69 insertion. ConclusionsIn settings without routine viral load monitoring, second-line antiretroviral therapy regimens should be designed assuming that clinical or immunological failure is associated with high rates of multi-NRTI resistance and NNRTI resistance, including resistance to etravirine. IntroductionThe widespread use of antiretroviral therapy (ART) for the treatment of HIV-infected children has dramatically changed the course of HIV infection, leading to reductions in morbidity and mortality [1][2][3]. A triple drug combination including two nucleoside reverse transcriptase inhibitors (NRTIs) plus one nonnucleoside reverse transcriptase inhibitor (NNRTI) or one protease inhibitor (PI) [4] is widely recommended as first-line therapy. For resource-limited settings, the World Health Organization (WHO) recommends an NNRTI-based regimen, which is preferred because it is effective, well tolerated and inexpensive. Plasma HIV RNA monitoring after initiation of ART is usually not available through treatment programmes in resource-limited settings [5]. For example, the Thai national AIDS programme provides antiretroviral drugs for HIVinfected patients and CD4 monitoring every 6 months. Annual plasma HIV viral load monitoring was only recently incorporated into the national programme in 2008. Thus, in the past, the majority of Thai children were diagnosed with treatment failure when they had clinical or immunological failure, that is a long time after virological replication had ...

Extensive Drug Resistance in HIV-Infected Cambodian Children Who Are Undetected as Failing First-Line Antiretroviral Therapy by WHO 2010 Guidelines

“…22,23 Similar information from Cambodia is limited. In prior reports from Cambodia before 2007, extensive resistance was reported at 14% (5/36) after 12 months of first-line ART 29 and at 27% (6/22) after 24 months.…”

“…This is an important consequence to consider, particularly in children who will require ART for long periods of time. According to reviewed pediatric data from RLS 28 and specifically from Cambodia [29][30][31] and Thailand, 13,22,23 57-100% of children failing first-line NNRTI-based ART had extensive NRTI and NNRTI resistance, with most common NRTI mutations M184V/I and D67N, and NNRTI mutations Y181C and G190A. Our results confirm and extend these observations, contribute to the limited genotypic data available for children failing first-line therapy in Cambodia, and emphasize the risk of the development of extensive drug resistance when guidelines that are not based on routine VL monitoring are used.…”

“…Most first-line failure data in this HIV subtype are reported from Thailand, with NNRTI and NRTI resistance of 89-95% and 42-58% in adults and 97% and 98% in children, respectively. 13,[22][23][24][25][26][27] Data on drug resistance in Cambodian children failing ART are limited. In a recent systematic review of first-line ART failure among children, 28 within 30 reviewed studies on 3,241 children, only 265 (8%) were from Cambodia and only 74 (2%) of those had genotypes available, some available only in poster form and after second-line ART failure.…”

Response of Simian Immunodeficiency Virus to the Novel Nucleoside Reverse Transcriptase Inhibitor 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine In Vitro and In Vivo

“…There are seven NRTIs approved for current clinical use, including the nucleoside emtricitabine (FTC) and the nucleotide tenofovir (TFV). Unfortunately, the frequent use of these drugs has resulted in the emergence of resistant virus strains (7,8,10,18). New compounds with potent activity on a wide range of isolates, including NRTI-resistant strains, are critically needed.…”

Profile of etravirine in the treatment of HIV in pediatrics

“…Puthanakit et al described 120 HIV-infected children from Thailand on NNRTI-containing regimens for a median of 23.7 months undergoing genotypic resistance testing for virologic failure. 57 NNRTI mutations were found in 98.3% of children. Four different NNRTI mutations associated with etravirine resistance were reported (L100I, Y181C, G190S, and G190A).…”