Effect of Antidepressant Therapy on the Outcomes of Human Immunodeficiency Virus Disease in HIV-infected Persons with Depression
Authors:   , Christensen Dina , Welles Seth L 
Published: July 2021

Background. Depression is the most prevalent psychiatric comorbidity of human immunodeficiency virus (HIV) which negatively impacts the outcomes of antiretroviral treatment (ART) and is associated with CD4 cell count decline, longer time to virologic suppression, accelerated progression to acquired immunodeficiency syndrome (AIDS), and shorter survival. The mechanism of the relationship between depression and HIV disease progression is poorly understood. One possible explanation of this relationship is indirectly through suboptimal adherence to ART. There are multiple studies linking depression to poor adherence to ART, while independently, previous clinical studies demonstrated that treatment success is dependent on almost perfect adherence to ART. Another causal pathway leading to worse HIV outcomes may be through systemic inflammation. The link between depression and inflammation has been established, however in the context of HIV disease the evidence of the relationship is sparse. Independently, systemic inflammation is a major determinant of AIDS pathogenesis. Additionally, it is not yet clear how antidepressant (AD) treatment fits in this causal mechanism and whether AD use mitigates the negative effect of depression on HIV outcomes. Aims. This dissertation investigates 1) the effect of pharmacologic antidepressant treatment on HIV outcomes - CD4 cell counts and virologic suppression - in HIV-positive individuals with depressive symptoms, 2) the association between depressive symptoms and markers of systemic inflammation (interleukin-6 (IL-6) and tumor necrosis factor-[alpha] (TNF-[alpha])), in the context of HIV disease, and 3) the causal pathways from depressive symptoms to HIV outcomes through suboptimal adherence to ART and systemic inflammation. Methods. This study uses data from Multicenter AIDS Cohort Study; a prospective study of HIV in homosexual and bisexual men in the USA. The study corresponding to aim 1 follows 1,027 HIV-positive subjects for 10 years. While studies respectively corresponding to aims 2 and 3 follow 1,050 and 976 HIV-positive subjects with available serologic data for the period of 5.5 years. To implement aim 1, we used multivariate models weighted by inverse probability of treatment and censoring weights in order to compare mean CD4 cell counts and the odds of virologic suppression (as defined by HIV RNA copies/ml <50) between subjects demonstrating chronic, intermittent, and no/limited depressive symptoms with consistent and inconsistent AD uptake. To implement aim 2, we used generalized estimating equations models to compare prevalence of elevated serum IL-6 and TNF-[alpha] between subjects who have chronic and intermittent depressive symptoms to those with no/limited depression as well as among those who report consistent and inconsistent uptake of AD therapy. To implement aim 3, we conducted a mediation analysis using a potential outcome approach and a regression-based method to quantify the direct and indirect effects of the association between chronic depressive symptoms and CD4 cells and virologic failure (HIV RNA copies/ml >=50) via ART utilization and elevated inflammatory markers. In addition, we investigated the role of AD therapy as a mediator of the association between depressive symptoms and HIV outcomes. Results. This study demonstrated that AD use modifies the effect of depressive symptoms on HIV laboratory outcomes, such as CD4 cell counts and virologic suppression. Importantly, when we compared men with intermittent and chronic depressive symptoms who consistently used AD therapy with those presenting no/limited depressive symptoms we found no difference in CD4 cell counts, as well as the odds of maintaining and achieving virologic suppression. While men who reported inconsistent uptake of AD and had chronic depressive episode had lower CD4 cell counts and lower odds of virologic suppression than men without depression. Additionally, this study provides evidence of the association between depressive symptoms and elevated inflammation in the context of HIV disease. Men with chronic depressive symptoms were more likely to have elevated IL-6 compared to men with no/limited depression, while men with intermittent, but not chronic depressive symptoms, were more likely to have elevated TNF-[alpha]. Furthermore, inconsistent use of AD predicted higher prevalence of increased IL-6 in those with chronic depressive symptoms, and higher likelihood of increased TNF-[alpha] in those with intermittent and chronic depressive symptoms compared to men with no depression. Mediation analysis of the relationship between chronic depressive symptoms and HIV outcomes demonstrated that systemic inflammation and ART utilization explain 35% of the association between chronic depression and CD4 cells and 30% of the association with virologic failure. AD use mitigated the effect of chronic depression on HIV outcomes. Importantly, the controlled direct effect of chronic depression on both HIV outcomes was null when AD use was fixed to present and was larger than the total effect when AD use was fixed to absent, indicating the effect of treated and untreated depressive symptoms. In addition, the mediation analysis uncovered interaction between the depressive symptoms and i) TNF-[alpha], and ii) ART utilization for CD4 cells, and iii) IL-6 and iv) ART utilization for virologic suppression. Conclusions. This dissertation demonstrates that consistent use of AD therapy benefits men with HIV and depression comorbidity in terms of their HIV disease outcomes. Inconsistent AD use in chronic depression is associated with the risk of impeded immunologic response and decrease in the likelihood of virologic suppression. Additionally, positive relationship between depressive symptoms and the risk of elevated systemic inflammation, which is particularly apparent in those individuals who report inconsistent AD use, further emphasizes clinical significance of the persistent depressive symptoms in HIV disease pathogenesis. Furthermore, the finding that systemic inflammation and ART utilization explain a small part of the association between chronic depression and HIV outcomes points at the existence of either another causal pathway or the direct effect of depression on HIV disease progression. Together, the findings of our study emphasize the importance of compliant antidepressant treatment consistent with the duration of depressive symptomatology in HIV-positive individuals.