BACKGROUND: Associations between HIV and schizophrenia in people with and without substance use disorders and the effect on timeliness of HIV diagnosis, antiretroviral therapy (ART), and treatment outcomes are poorly understood. We aimed to assess the association between HIV and schizophrenia and the effect on HIV treatment outcomes in people with and without substance use disorders.

METHODS: We did a population-based cohort study with data from nationwide registries in Denmark to investigate the risk of schizophrenia after a diagnosis of HIV and the risk of HIV after a diagnosis of schizophrenia, accounting for substance misuse, timeliness of HIV diagnosis, and treatment success in relation to schizophrenia. We selected the cohort from people born in Denmark between Jan 1, 1955, and Dec 31, 1995, who we followed up from their 16th birthday or Jan 1, 1995 (whichever occurred last) until their death, emigration from Denmark, onset of schizophrenia, or Dec 31, 2011 (whichever came first). We estimated incidence rate ratios (IRRs) with Poisson and Cox regression, with adjustment for calendar period, and age and its interaction with sex.

FINDINGS: We identified 2,786,286 individuals, of whom we included 2,646,154 people in analyses of risk of schizophrenia diagnosis and 2,658,662 people in analyses of risk of HIV diagnosis. In 35,353,633 person-years of follow up, HIV was associated with an increased risk of schizophrenia (IRR 4·09, 95% CI 2·73-5·83) and acute psychosis (7·15, 4·45-10·8); the IRR was highest within the first year of HIV diagnosis for both disorders (8·24, 2·95-17·7 and 12·7, 3·15-32·9, respectively). Schizophrenia was not associated with an increased risk of HIV in individuals without substance misuse disorders (IRR 1·42, 95% CI 0·81-2·27). The risk of schizophrenia in individuals with HIV decreased after ART (IRR 0·53, 0·32-0·87). The risk of acute psychosis did not differ between HIV-infected individuals receiving antiretroviral regimens with and without efavirenz (IRR 0·70, 95% CI 0·32-1·54). We recorded no differences in CD4 cell counts, time to ART, or viral suppression between individuals with schizophrenia with HIV and those without schizophrenia when substance use was taken into account. Between 1999 and 2011, the mortality rate ratio comparing HIV-infected individuals with schizophrenia with HIV-negative individuals without schizophrenia was 25·8 (95% CI 18·8-34·3).

INTERPRETATION: Our findings emphasise the need for interventions to prevent HIV in people with schizophrenia, especially for those with substance use disorders, and for accessible mental health services for individuals with HIV.

FUNDING: Stanley Medical Research Institute, Lundbeck Foundation, Preben and Anna Simonsen Fund, Novo Nordisk Foundation, The Danish AIDS Foundation, and the Augustinus Foundation.