Rapid Development of Antiretroviral Drug Resistance Mutations in HIV-Infected Children Less Than Two Years of Age Initiating Protease Inhibitor-Based Therapy in South Africa

Abstract

Data on the development of antiretroviral drug resistance in HIV-1-infected children receiving protease inhibitor (PI)-based antiretroviral therapy (ART) are limited. We examined antiretroviral resistance among a cohort of 323 South African HIV-infected children < 2 years old exposed to nevirapine for prevention of mother-to-child transmission. Ritonavir (RTV) was used initially for 138 children who were < 6 months old or receiving antimycobacterial therapy; otherwise children received lopinavir/ritonavir (LPV/r)-based ART. HIV-1 population sequencing of the pol gene was conducted on all pretreatment samples and on posttreatment samples for children who did not achieve HIV-1 plasma RNA < 400 copies/ml by 52 weeks. Among children in the cohort, 38 died, 22 had < 24 weeks follow-up, 209 achieved virologic suppression, and 54 did not. Of 41 children without virologic suppression with posttreatment HIV genotype data available, major resistance mutations were found in 32 (78%): 14 (36%) had PI mutations including V82A, M46I, and L90M; 29 (71%) had M184V/I; and three had NNRTI mutations (K103N, Y181C, and G190A). Among the children who did not achieve virologic suppression, none of the seven children treated exclusively with LPV/r developed PI-related mutations, compared with 14 of 32 (44%) who received RTV-based regimens ( p = 0.036); PI genotypes were unavailable for two children. Seventy-eight percent of children without virologic suppression developed resistance mutations that impact second-line ART options. Only children who received RTV-based ART developed major PI-related resistance mutations, and use of this regimen should be avoided.

Consequences of Prior Use of Full-dose Ritonavir as Single Protease Inhibitor as Part of Combination Antiretroviral Regimens on the Future Therapy Choices in HIV-1–Infected Children

“…We found PI mutations in 73% of genotypes, substantially higher than the 17% to 44% reported in previous South African studies of children failing PI regimens, although these earlier studies included children on LPV/r-regimens in addition to RTV-sPI-regimens. 7,17,18 In Brazil, almost half of the children on either RTV-sPI or nelfinavir-based ART had PI mutations, 19 while in another South African study, major PI mutations were found in 71% of children with treatment failure and prior RTV-sPI exposure, a result that is very similar to the present findings. 10 The intriguing finding that use of PI-regimens is protective against development of resistance against co-administered antiretroviral drugs has been described in adults in relation to the M184V and K65R mutations.…”

“…6,18 ART drug classes and drugs themselves have different genetic barriers to resistance. Lamivudine and the NNRTIs, for example, have a low barrier to resistance, with a single mutation enough to confer complete resistance.…”

Non-AIDS Morbidity among HIV Patients

“…Increasing evidence suggests that, in young children for whom LPV/r-based regimens have failed, selection of major mutations to PI is rare and accumulation of thymidine analogue mutations is very limited (156,237,239,240). In this context and in the absence of robust second-line alternatives such as DRV/r-containing regimens, the Guidelines Development Group recommended that children younger than three years of age should be maintained on LPV/r until the age of three years, despite treatment failure.…”

“…The recommendations are now better informed by paediatric clinical trial data (156,158,237) and observational data (157). The Guidelines Development Group also considered operational and programmatic issues including the availability of heat-stable formulations and fixed-dose combinations for children.…”

Antiretroviral therapy for the management of HIV in children

“…Children failing LPV/r rarely have LPV/r resistance initially, unless previously given RTV monotherapy or TB therapy. [33,34] In children failing LPV/r as a first regimen, a resistance test and possibly LPV/r trough levels should be considered. We need more data on hair levels of LPV/r as a measure of long-term adherence before this strategy can be recommended.…”