High predictive efficacy of integrase strand transfer inhibitors in perinatally HIV-1-infected African children in therapeutic failure of first- and second-line antiretroviral drug regimens recommended by the WHO

Abstract

Objectives The predictive efficacy of integrase (IN) strand transfer inhibitors (INSTIs) was investigated in HIV-infected children born to HIV-infected mothers in Africa. Methods Plasma was collected at the Complexe Pédiatrique of Bangui, Central African Republic, from INSTI-naive children ( n = 8) and adolescents ( n = 10) in virological failure (viral load >1000 copies/mL) after 5 years of first- and/or second-line combination ART (cART). IN, reverse transcriptase (RT) and protease (P) genes were genotyped and drug resistance mutations (DRMs) to INSTIs, NRTIs, NNRTIs and PIs were interpreted using the Stanford algorithm. Results Successful IN, RT and P genotypes were obtained for 18, 13 and 15 children (median age 11 years, range 5–18; 8 were female), respectively. Two (2/18; 11.1%) viruses from children treated with a first-line regimen had INSTI DRMs at codon 138 (E138K and E138T), which is known to harbour major resistance mutations, and also had the accessory mutations L74I, G140K, G140R and G163R. The majority (16/18; 88.9%) of HIV-1 IN sequences demonstrated full susceptibility to all major INSTIs with a high frequency of natural polymorphic mutations. Most (12/15; 80%) genotyped viruses harboured at least one major DRM conferring resistance to at least one of the WHO-recommended antiretroviral drugs (NNRTIs, NRTIs and PIs) prescribed in first- and second-line regimens. Conclusions INSTIs could be proposed in first-line regimens in the majority of African children or adolescents and may constitute relevant therapeutic alternatives as second- and third-line cART regimens in HIV-infected children and adolescents living in sub-Saharan Africa.

First report of computational protein–ligand docking to evaluate susceptibility to HIV integrase inhibitors in HIV-infected Iranian patients

“…In our samples, accessory mutations including G163R, Q95K, S230 N, M50I, V72I, V249I, and L74 M appeared, which can cause a substantial loss in susceptibility to INTIs alone or in combination. INTI drugs usually select G163R [ 76 ]; this mutation was reported in INTI-naive patients at a similar rate in our study [ 64 , 77 ]. On its own, our docking result revealed this mutation not only did not appear to be associated with reduced INTIs susceptibility, but also could even enhance the E value.…”

Added Value of Next Generation Sequencing in Characterizing the Evolution of HIV-1 Drug Resistance in Kenyan Youth

“…Children and adolescents living with HIV (CALWH) are more vulnerable than adults to developing treatment failure and drug resistance, particularly when infected perinatally, thus mandating life-long ART [ 13 , 14 , 15 ]. The vast majority (~90%) of CALWH failing ART in resource-limited settings have drug resistance [ 6 , 7 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Despite some emerging NGS data (e.g., Kemp et al, recently exploring drug resistance pathways in adults with HIV-1 subtype C failing 2nd-line ART, demonstrating extensive intra-host viral dynamics [ 23 ]), data on intra-host accumulation of DRMs over time, its impact, and the role of low-frequency DRMs in treatment experienced by CALWH in low-resource settings with diverse HIV-1 subtypes are limited [ 6 , 17 , 21 , 24 ].…”