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 1st and 2nd 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 2nd line therapies were calculated.
Results: Plasma virus from 160/185 (86%) participants was sequenced; 112(70%) on 1st line and 48 (30%) on 2nd 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 1st and 2nd line failures respectively (p< 0.001). The lower rate of DRMs on 2nd 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 1st line failures; PI DRMs were detected in a minority (10%) of subjects failing 2nd 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 1st line failures switching to current PI based 2nd line therapies and TLD respectively. The substitution of AZT for TDF in TLD could optimize 2nd line therapy to achieve a tGSS>2.
Conclusions: Current recommended PI based 2nd line therapies may provide effective treatment for viremic youth failing 1st line ART, but are poorly tolerated and demonstrate low rates of adherence. In 1st 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 2nd and 3rd line ART, while novel combinations and/or new agents are needed for this hard to treat population that requires decades of ART.