Background: Chronically infected youth receiving antiretroviral therapy (ART) struggle to maintain virologic suppression. In sub-Saharan Africa youth who are viremic on ART, have a high frequency of drug resistance mutations (DRMs) and limited affordable therapeutic options. The integrase strand inhibitor (INSTI) dolutegravir (DTG) combined with tenofovir (TDF) and lamivudine (3TC) (TLD) is a new single tablet regimen (STR) proposed for use in public ART programs in Africa.
Methods: We established a cohort of HIV-1 infected youth on long-term 1^st and 2^nd line ART with confirmed virologic failure (VL>1000 copies/mL). A genotypic analysis of plasma virus was conducted and susceptibility scores to TLD and current 2^nd line therapies were calculated.
Results: Plasma virus from 160/185 (86%) participants was sequenced; 112(70%) on 1^st line and 48 (30%) on 2^nd line regimens. Median (IQR) age was 18 (15-19) years, and median duration on ART(IQR) was 6(4-8) years. Median (IQR) viral load was 4.51 (4.05-4.93) log10 copies/ml. DRMs were present in 94% and 67% of 1^st and 2^nd line failures respectively (p< 0.001). The lower rate of DRMs on 2^nd line therapy suggests PI use may reflect poor adherence and poor tolerance. Dual class resistance to NRTIs and NNRTIs was detected in 96 (60%) of 1^st line failures; PI DRMs were detected in a minority (10%) of subjects failing 2^nd line regimens. A total genotypic susceptibility score (tGSS) ≤2 that may potentially result in PI or DTG monotherapy, was observed in 11% and 42% of 1^st line failures switching to current PI based 2^nd line therapies and TLD respectively. The substitution of AZT for TDF in TLD could optimize 2^nd line therapy to achieve a tGSS>2.
Conclusions: Current recommended PI based 2^nd line therapies may provide effective treatment for viremic youth failing 1^st line ART, but are poorly tolerated and demonstrate low rates of adherence. In 1^st line failure, TLD in the absence of genotyping may not be an optimal choice. Drug resistance data will inform strategies for the implementation of TLD as 2^nd and 3^rd line ART, while novel combinations and/or new agents are needed for this hard to treat population that requires decades of ART.