HIV Treatment as Prevention (TasP) initiatives promote antiretroviral therapy (ART) access and optimal adherence (>= 95 %) to produce viral suppression among people living with HIV (PLHIV) and prevent the onward transmission of HIV. ART treatment interruptions are common among PLHIV who use drugs and undermine the effectiveness of TasP. Semi-structured interviews were conducted with 39 PLHIV who use drugs who had experienced treatment ART interruptions in a setting with a community-wide TasP initiative (Vancouver, Canada) to examine influences on these outcomes. While study participants attributed ART interruptions to "treatment fatigue," our analysis revealed individual, social, and structural influences on these events, including: (1) prior adverse ART-related experiences among those with long-term treatment histories; (2) experiences of social isolation; and, (3) breakdowns in the continuity of HIV care following disruptive events (e.g., eviction, incarceration). Findings reconceptualise 'treatment fatigue' by focusing attention on its underlying mechanisms, while demonstrating the need for comprehensive structural reforms and targeted interventions to optimize TasP among drug-using PLHIV.