Treated HIV positive patients are at increased risk for cardiovascular disease (CVD), cancer, and other HIV- associated non-AIDS conditions. Ongoing immune activation, despite effective treatment with antiretroviral therapy (ART), increases risk for CVD and non-AIDS conditions, but also contributes to lymphatic tissue fibrosis, limiting immune recovery that further increases risk for non-AIDS conditions. Biologic aging also leads to systemic inflammation and waning immune function, and, thus, non-AIDS conditions and poly-morbidity will continue to increase as the HIV population ages. Identifying safe treatments that target this pathology represents a major unmet need for older HIV positive patients. We propose a randomized placebo-controlled trial of losartan (100mg daily) among n=120 antiretroviral-treated HIV positive persons age >50 years receiving effective ART with undetectable HIV RNA levels. We will study the treatment effects of losartan on changes in IL-6 levels over 6 months and changes in peripheral blood CD4 count over 12 months. We hypothesize that losartan treatment will: a) reduce systemic inflammation that will be accounted for through reductions in monocyte activation within peripheral blood, and b) lead to immune recovery, as reflected in blood CD4+ count, via down-regulating immune activation and TGF-?-mediated fibrosis in lymphatic tissues that will improve T- cell homeostasis and survival of naive T-cells. Our investigative team has helped define the role of inflammation in non-AIDS disease risk as well as developed the model that links lymph node fibrosis with impaired T-cell homeostasis. This work directly informed our choice of outcomes, which both test fundamental HIV pathogenesis questions and will determine if losartan improves immune activation and immune recovery to a degree that may be clinically relevant. Our methods and hypotheses are innovative, our intervention is novel in the context of HIV infection, and our approach provides essential randomized data to inform and justify the expense of subsequent clinical outcome trials. In summary, this translational trial addresses a high priority HIV research agenda to identify disease-modifying strategies for non-AIDS conditions among older patients.
Non-AIDS conditions such as cardiovascular disease and cancer are now the most common causes of morbidity and mortality for HIV positive persons, and risk is highest for older patients in particular. Factors unique to HIV disease that contribute to excess risk for non-AIDS conditions include ongoing immune activation and incomplete immune recovery (despite effective HIV treatment with viral suppression). This proposal is a randomized placebo-controlled trial to study the potential benefits of losartan for reducing non- AIDS disease risk, leveraging it's well-established anti-inflammatory and anti-fibrotic effects in HIV uninfected populations. We will determine if losartan reduces systemic inflammation (i.e., IL-6 levels) and improves immune recovery (i.e., CD4 count) among older HIV positive persons to a degree that is clinically relevant. An important pathologic consequence of ongoing immune activation is fibrosis in lymphatic tissues that impairs T- cell homeostasis and limits immune recovery. An important, and innovative, aspect of this study will be to test the hypothesis that limiting immune activation and fibrosis within lymphatic tissues will improve survival and propagation of naive T-cells thereby augmenting immune recovery. In summary, our proposal will test important mechanistic questions, and determine if losartan has meaningful positive effects on immune activation and immune recovery that will motivate subsequent clinical outcome trials.
|Longenecker, Chris T; Sullivan, Claire; Baker, Jason V (2016) Immune activation and cardiovascular disease in chronic HIV infection. Curr Opin HIV AIDS 11:216-25|