People living with HIV who start antiretroviral therapy (ART) face various challenges that hinder medication adherence and appointment attendance. Issues such as depression, substance use, stigma, food insecurity, transportation difficulties, and gender inequity contribute to these struggles. The SUSTAIN trial in Cape Town, South Africa, investigates ways to improve adherence through monitoring and support across three clinics. Researchers conducted interviews with 60 participants within six months of starting ART to explore these multi-level challenges. They found that coping mechanisms varied, with substance use impacting adherence during significant life events. Stigma influenced participants’ decisions about disclosing their HIV status, which in turn affected their social support networks and motivation to adhere to treatment. Gender inequity exacerbated experiences of stigma, while food insecurity led to feelings of shame related to ART-related appetite changes. Health system factors, such as unclear information on dosing schedules and negative clinician attitudes, also affected adherence. Participants expressed fear of traveling to clinics due to safety concerns, particularly for women. The study suggests that enhanced counseling and interventions addressing these barriers may improve ART adherence, alongside broader efforts to tackle systemic issues like gender inequity and security.