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We modeled influence of substance use and duration of HIV infection on biomarkers at baseline and over 24 weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to participants enrolled &amp;gt;30 days after HIV acquisition, participants enrolled during acute infection (\u226430 days) had higher mean interferon (IFN)\u2013\u03b3 and IFN-\u03b12a (1.7-fold and 3.8-fold interquartile range [IQR] higher, respectively). Participants enrolled &amp;gt;30 days after HIV acquisition had higher mean baseline CD8+ cell count (2.7 times the IQR). Alcohol use (positive phosphatidylethanol level) was associated with elevated IFN-\u03b3, tumor necrosis factor alpha (TNF-\u03b1), and interleukin 12p70 (IL-12p70), and smoking was associated with higher macrophage inflammatory protein 1\u03b1, TNF-\u03b1, and IL-12p70. Most biomarkers declined more quickly in participants who initiated ART immediately; however, substance use and duration of HIV infection at enrollment had little influence on rate of decline.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>IFN-\u03b3 and other biomarkers are elevated during early primary infection, when exposure to HIV antigens is high. Immune activation decreased most quickly in those who started ART during acute\/early primary infection. Higher CD8+ cell counts and a trend toward higher soluble CD163 levels during the 30 days after acquisition suggest the onset of compensatory responses and immune exhaustion.<\/jats:p><\/jats:sec>","DOI":"10.1093\/ofid\/ofac155","type":"journal-article","created":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T18:52:14Z","timestamp":1648234334000},"source":"Crossref","is-referenced-by-count":1,"title":["Immune Activation in Primary Human Immunodeficiency Virus: Influence of Duration of Infection, Treatment, and Substance Use"],"prefix":"10.1093","volume":"9","author":[{"given":"Trupti","family":"Gilada","sequence":"first","affiliation":[{"name":"Unison Medicine and Research Centre , Mumbai , India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel R","family":"Schnittman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Massachusetts General Hospital , Boston, Massachusetts , 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