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Background Although periods of HIV antiretroviral therapy (ART) discontinuation have deleterious health effects, ART is not always sustained. Yet, little is known about factors that contribute to such ART non-persistence among long-term HIV survivors. The present study applied a convergent parallel mixed-methods design to explore the phenomena of stopping/starting and sustaining ART, focusing on low-socioeconomic status African American or Black and Latino persons living with HIV (PLWH) who face the greatest challenges. Methods Participants (N = 512) had poor engagement in HIV care and detectable HIV viral load. All received structured assessments and N = 48 were randomly selected for in-depth interviews. Quantitative analysis using negative binomial regression uncovered associations among multi-level factors and the number of times ART was stopped/started and the longest duration of sustained ART. Qualitative data were analyzed using a directed content analysis approach and results were integrated. Results Participants were diagnosed 18.2 years ago on average (SD = 8.6), started ART a median five times (Q1 = 3, Q3 = 10), and the median longest duration of sustained ART was 18 months (Q1 = 6, Q3 = 36). Factors associated with higher rates of stops/starts were male sex, transgender identity, cannabis use at moderate-to-high-risk levels, and ART- and care-related stigma. Factors associated with lower rates of stops/starts were older age, more years since diagnosis, motivation for care, and lifetime injection drug use (IDU). Factors associated with longer durations of sustained ART were Latino/Hispanic ethnicity, motivation for ART and care, and recent IDU. Factors associated with a shorter duration were African American/Black race, alcohol use at moderate-to-high-risk levels, and social support. Qualitative results uncovered a convergence of intersecting risk factors for stopping/starting ART and challenges inherent in managing HIV over decades in the context of poverty. These included unstable housing, which contributed to social isolation, mental health distress, and substance use concerns, the latter prompting selling (“diverting”) ART. Primarily complementary quantitative and qualitative findings described mechanisms by which risk/protective factors operated and ways PLWH successfully restart and/or sustain ART. Conclusions The field focuses substantially on ART adherence, but greater attention to reducing the frequency of ART non-persistence is needed, along with creating social/structural conditions favorable for sustained ART.

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