Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection

Abstract

In the antiretroviral therapy (ART) era, serious non-AIDS events (SNAEs) have become the major causes of morbidity and mortality in HIV-infected persons. Early ART initiation has the strongest evidence for reducing SNAEs and mortality. Biomarkers of immune activation, inflammation and coagulopathy do not fully normalize despite virologic suppression and persistent immune activation is an important contributor to SNAEs. A number of strategies aimed to reduce persistent immune activation including ART intensification to reduce residual viremia; treatment of co-infections to reduce chronic antigen stimulation; the use of anti-inflammatory agents, reducing microbial translocation as well as interventions to improve immune recovery through cytokine administration and reducing lymphoid tissue fibrosis, have been investigated. To date, there is little conclusive evidence on which strategies beyond treatment of hepatitis B and C co-infections and reducing cardiovascular risk factors will result in clinical benefits in patients already on ART with viral suppression. The use of statins seems to show early promise and larger clinical trials are underway to confirm their efficacy. At this stage, clinical care of HIV-infected patients should therefore focus on early diagnosis and prompt ART initiation, treatment of active co-infections and the aggressive management of co-morbidities until further data are available.

Figure 1. Factors contributing to the pathogenesis of SNAEs

HIV infection can lead to immune activation in a number of ways. Firstly, HIV can directly stimulate innate immune cells and HIV-specific CD4 and CD8 T cells. Secondly, HIV causes depletion of CD4 T cells in the gut as well as disruption of intestinal tight junction, allowing translocation of luminal microbial products, further exacerbating immune activation. Thirdly, the presence of and reactivation of coinfections such as HBV, HCV, CMV and EBV also contribute. Finally, HIV associated CD4 T cell depletion may stimulate physiologic homeostatic proliferation and aggravate immune activation. A vicious cycle is thus set up whereby on-going immune activation leads to further CD4 T cell depletion and thus more immune activation. Immune activation is also associated with increased numbers of regulatory T cells (Tregs) in the lymphoid tissues. Tregs secrete Transforming Growth Factor-β (TGF-β), triggering collagen production and deposition by fibroblasts; resulting in structural damage and fibrosis of the lymph node reducing the regeneration and survival of CD4 T cells thus worsening immunodeficiency. Activated monocytes and macrophages express increased levels of tissue factor (TF), potentially activating coagulation cascades, contributing to thrombus formation and atherosclerosis. The direct effect of HIV, the impact of immunodeficiency, the presence of underlying co-infections and co-morbidities, ART toxicities and persistent immune activation and coagulopathy all contribute to SNAES.

Figure 2. Potential strategies to reduce SNAEs in treated HIV infection

Early ART initiation is the most critical intervention to reduce SNAEs and mortality in HIV infection. Other potential strategies to reduce SNAEs in treated HIV infection include the selection of ART with less adverse effects; the management of cardiovascular risk factors through smoking cessation, controlling hypertension, diabetes and dyslipidemia as well as improving lipodystrophy and associated insulin resistance; reducing chronic immune activation through treatment of co-infections and residual HIV viremia, reducing microbial translocation and the use of anti-inflammatory agents; and improving immune recovery through cytokine stimulation and reduction of lymphoid tissue fibrosis. Interventions supported by evidence of reducing SNAEs are in red.