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Despite improvements in access to antiretroviral treatment over the past decade, sub-optimal HIV care outcomes persist among youth with HIV (YWH) in rural South Africa. Psychosocial stressors could impede improved HIV treatment outcomes within this population. We linked self-reported psychosocial health and demographic data from a cross-sectional survey conducted among YWH aged 12–24 in rural South Africa to individual medical record data, including facility visit history and viral load measurements. Poisson regression with robust standard errors was used to estimate the associations between five psychosocial stressors- heightened depressive symptoms (Center for Epidemiological Studies-Depression scale scores ≥ 16), lower social support (Medical Outcomes Social Support Scale scores ≤ 38), lower resilience (Conner-Davidson Resilience Scale scores ≤ 73), lower self-esteem (Rosenberg Self-Esteem Scale scores ≤ 21), and higher perceived stress (Sheldon Cohen Perceived Stress Scale scores ≥ 10)- and viral non-suppression (viral load ≥ 400 copies/mL) and loss to care (no documented clinic visits within the 90 days prior to survey), separately. A total of 359 YWH were included in this analysis. The median age of study participants was 21 (interquartile range: 16–23), and most were female (70.2%), single (82.4%), and attending school (54.7%). Over a quarter of participants (28.1%) had heightened depressive symptoms. Just 16.2% of all participants (n = 58) were lost to care at the time of survey, while 32.4% (n = 73) of the 225 participants with viral load data were non-suppressed. The prevalence of non-suppression in individuals with lower self-esteem was 1.71 (95% confidence interval: 1.12, 2.61) times the prevalence of non-suppression in those with higher self-esteem after adjustment. No meaningful association was observed between heightened depressive symptoms, lower social support, lower resilience, and higher perceived stress and viral non-suppression or loss to care in adjusted analyses. Retention in care and viral suppression among YWH in rural South Africa are below global targets. Interventions aimed at improving viral suppression among YWH should incorporate modules to improve participant’s self-esteem as low self-esteem is associated with viral non-suppression in this setting. Future studies should longitudinally explore the joint effects of co-occurring psychosocial stressors on HIV care outcomes in YWH and assess meaningful differences in these effects by age, gender, and route of transmission.   Supplementary Information  The online version contains supplementary material available at 10.1007/s10461-021-03198-9.

Associations Between Key Psychosocial Stressors and Viral Suppression and Retention in Care Among Youth with HIV in Rural South Africa