| Summary: | Background: There is a paucity of information on the contemporary burden, disease patterns, and immunological profile of people living with HIV who are co-infected with <i>C. cayetanensis</i> in the post-antiretroviral therapy era. Methods: For this cross-sectional study, stool samples of 640 HIV-positive and 83 HIV-negative individuals in Ghana were tested for <i>C. cayetanensis</i>. Additionally, sociodemographic parameters, clinical symptoms, medical drug intake, and immunological parameters were assessed. Results: The prevalence of <i>C. cayetanensis</i> was 8.75% (<i>n</i> = 56) in HIV-positive and 1.20% (<i>n</i> = 1) in HIV-negative participants (<i>p</i> = 0.015). Within the group of HIV-positive participants, the prevalence reached 13.6% in patients with CD4+ T cell counts below 200 cells/µl. Frequencies of the clinical manifestations of weight loss and diarrheal disease were significantly higher in patients with <i>C. cayetanensis</i> compared to those without co-infection (36.36% vs. 22.59%, <i>p</i> = 0.034 and 20.00% vs. 4.90%, <i>p</i> < 0.001, respectively). The expression of markers of immune activation and exhaustion of T lymphocyte sub-populations was significantly elevated in patients colonized with <i>C. cayetanensis</i>. Conclusions: In the modern post-combined antiretroviral therapy (cART) era, the acquisition of <i>C. cayetanensis</i> among PLWH in Ghana is driven largely by the immunosuppression profile characterized by high expression of markers of immune activation and immune exhaustion.
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