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This study investigates the roles of social support and substance use as mediators in the relationship between mental health and antiretroviral therapy (ART) adherence among PLHIV in a multisite, international context. Cross-sectional data from\n                    <jats:italic>N<\/jats:italic>\n                    \u2009=\u20091598 PLHIV across eight countries were analyzed using parallel mediation analyses in R. Results indicated that both social support and substance use independently mediated the relationship between mental health and ART adherence. Hallucinogens mediated the mental health-adherence link. Cocaine, Amphetamine-type stimulants, inhalants, and opioids directly influenced adherence but did not mediate this relationship. In contrast, no significant effects were observed for tobacco, alcohol, cannabis or sedatives. This large-scale, nurse-led, international study offers critical insights into the roles of social support and substance use as psychosocial influencers in the cascade of care for PLHIV. Clinical implications include prioritizing educative, preventative, and harm-reductive approaches to specific substances that impact ART adherence. Findings may also inform interventions that emphasize strengthening social support to improve adherence in ART and care while addressing substance use as a barrier to care and well-being.\n                  <\/jats:p>","DOI":"10.1007\/s10461-025-04944-z","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T17:06:03Z","timestamp":1769101563000},"page":"3272-3287","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mental Health and ART Adherence in a Multisite International Study: The Mediating Roles of Social Support and Substance Use in People with HIV","Salud mental y adherencia a la TAR en un estudio internacional multic\u00e9ntrico: el papel mediador del apoyo social y el consumo de sustancias en personas con VIH"],"prefix":"10.1007","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8758-518X","authenticated-orcid":false,"given":"Joseph","family":"Awad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxiu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8202-226X","authenticated-orcid":false,"given":"Diane","family":"Santa Maria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2184-4045","authenticated-orcid":false,"given":"Rebecca","family":"Schnall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panta","family":"Apiruknapanond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3374-1078","authenticated-orcid":false,"given":"Tongyao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9558-4146","authenticated-orcid":false,"given":"Claudia Patricia","family":"Valencia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3686-4391","authenticated-orcid":false,"given":"Christine","family":"Horvat Davey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2563-6307","authenticated-orcid":false,"given":"Solymar","family":"Solis Baez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0261-7218","authenticated-orcid":false,"given":"Emilia","family":"Iwu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5181-6534","authenticated-orcid":false,"given":"Motshedisi","family":"Sabone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lufuno","family":"Makhado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5674-4741","authenticated-orcid":false,"given":"Yvette P.","family":"Cuca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6697-0515","authenticated-orcid":false,"given":"J. 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Mary-Lynn Brecht and Shiu Chengshi for their advice and guidance regarding aspects of this work\u2019s statistical analysis. Awad extends appreciation to Drs. Laramie Smith and Chair Anjeanette Oberg for their steadfast support and years of mentorship.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}]}}