Resistance to dolutegravir as part of optimized background therapy is common in HIV-1-infected children but is not associated with virologic failure
Presented by Ceejay Boyce, PhD, Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle.
Prevalence and dynamics of drug resistance during dolutegravir-containing treatment in a pediatric population living with HIV-1 (IMPAACT P1093). Presented July 24, 2023.
Resistance to dolutegravir-containing antiretroviral therapy regimens is common but was not associated with virologic failure or intermittent viremia in children living with HIV, according to data from the phase I/II International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) P1093 study.
The study included 181 children age 4 weeks to less than 18 years from 9 countries in Africa, Americas, and Asia. Researchers led by Ceejay Boyce, PhD, Seattle Children's Research Institute, Center for Global Infectious Disease Research, Seattle, detected protocol-defined virologic failure or intermittent viremia in 49 (27.1%) of the participants.
A secondary objective of IMPAACT P1093 was to assess changes in HIV-1 genotypes and phenotypes in response to dolutegravir and optimized background therapy in children with and without intermittent viremia or protocol-defined virologic failure. Intermittent viremia was defined as 2 or more viral loads greater than 400 copies per mL after 24 weeks on study, and protocol-defined virologic failure was defined as 2 consecutive viral loads greater than 400 copies per mL after 24 weeks on study.
Plasma RNA was collected for HIV-1 genotyping for resistance, including minority variants, using PacBio sequencing, at screening and whenever intermittent viremia or protocol-defined virologic failure was detected.
The prevalence of resistance to dolutegravir and optimized background therapy was assessed using the Stanford HIV Database, with resistance to protease inhibitors, nucleotide reverse transcriptase inhibitors (NRTIs), and non nucleotide reverse transcriptase inhibitors (NNRTIs) defined by a genotypic susceptibility score of 30, and resistance to dolutegravir defined by a score greater than 10.
Genotyping at screening and enrollment was successful for 168 (92.8%) of the 181 participants.Resistance to protease inhibitors was detected in 20 (12.3%) of 163 samples, to NRTIs in 83 (49.4%) of 168, to NNRTIs in 76 (45.2%) of 168, and to participants’ optimized background therapy (≥ 1 optimized background therapy drug) in 67 (39.9%) of 168 using a mutation frequency threshold of 1%.
Minority variants were uncommon at screening and enrollment. Prior to initiation of dolutegravir, integrase strand-transfer inhibitor (INSTI) mutations were detected in 10 (5.9%) of 168 participants, all at less than 15% mutation frequency and with a genotypic susceptibility score of 10. Pre-dolutegravir resistance was not associated with protocol-defined virologic failure or intermittent viremia using a mutational frequency threshold of 20%, 5%, or 1%.
Intermittent viremia occurred in 3 participants and protocol-defined virologic failure occurred in 46, for a total of 49 (27.1%) of the 181 participants, with a median viral load of 5,644 copies/mL. Dolutegravir-associated mutations were detected 18.4% using a mutation frequency cutoff of 20% or higher, 22.5% at 5% or higher, and 24.5% at 1% or higher. Phenotypic analyses of 10 participants' genotypes found reduced dolutegravir susceptibility in all 7 who had major INSTI mutations and similar dolutegravir susceptibility in all 3 participants who had no or accessory-only INSTI mutations compared with screening and enrollment. The authors noted that bictegravir susceptibility appeared to be affected less by the same INSTI mutations compared with dolutegravir.
Participants who had dolutegravir resistance at the time of protocol-defined virologic failure or intermittent viremia had a trend toward being more likely to have viral suppression to less than 400 copies per mL (odds ratio 1.53; P = .28) compared with those with no dolutegravir resistance, “suggesting that intermittent adherence and/or low-level viremia contributes to the selection of dolutegravir-associated mutations,” the authors wrote in their poster presentation.
Overall support for IMPAACT was provided by the National Institute of Allergy and Infectious Diseases with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the National Institutes of Health.