Growing evidence indicates that chronic obstructive pulmonary disease (COPD) is an important cause of respiratory impairment in HIV+ persons and will likely increase as the HIV+ population continues to age. In the HIV-uninfected population, COPD frequently co-exists with cardiac disease including atherosclerosis and pulmonary hypertension. Our work has demonstrated that a syndrome of """"""""cardiopulmonary dysfunction"""""""" exists even in non-smoking or antiretroviral-treated HIV+ individuals and is associated with increased respiratory symptoms as well as with mortality. HMG CoA reductase inhibitors (statins) have anti-inflammatory and other effects in the lungs and vasculature that might benefit cardiopulmonary dysfunction in HIV. These agents have a long history of clinical use in cardiovascular disease and are currently being investigated in HIV, COPD, and pulmonary hypertension. In preliminary analyses, HIV+ individuals who received statin therapy within the past year tended to have better diffusing capacity for carbon monoxide, less airway obstruction, lower pulmonary artery pressures and cardiac strain, lower peripheral cytokines, and decreased sputum neutrophils despite being older and having a similar smoking history to those not using statins. We hypothesize that statin therapy will decrease inflammation and slow progression of cardiopulmonary abnormalities in HIV. We will test effects of rosuvastatin compared to placebo in an adaptive response design to determine effect size, estimate sample size, and develop a novel composite endpoint in preparation for a full-scale trial. We will utilize our existing HIV+ cohorts of over 400 individuals established through our Lung HIV and Lung HIV Microbiome Projects via collaborations with our local HIV clinic, the Multicenter AIDS Cohort Study, and the Women's Interagency Health Study. The study will not only evaluate treatments, but will allow for a bedside- to-bench-to-bedside approach to determine mechanisms of cardiopulmonary dysfunction in HIV. We will perform a pilot study to establish the basis for a future, Phase III clinical trial by completing the following aims:
Aim 1 : To establsh a network of clinical investigators, statisticians, and translational scientists to study interventons in HIV-associated cardiopulmonary disease.
Aim 2 : To complete a pilot study of statin therapy in HIV-associated cardiopulmonary dysfunction to determine effect size and impact on physiologic outcomes and biomarkers.
Aim 3 : To create a translational core establishing infrastructure for future bedside- to-bench-to-bedside studies of mechanisms of cardiopulmonary dysfunction in HIV infection. Participants in the trial will be randomized to treatment or placebo with 3 and 6 month measures of pulmonary function, computed tomography, echocardiography, carotid intima media thickness, flow-mediated dilation and inflammatory biomarkers. Successful completion of the aims will establish a clinical trials network, provide proof-of-concept data, and establish a translational core to enhance understanding of HIV cardiopulmonary dysfunction and to guide a large-scale clinical trial of treatment for an important co-morbidity in HIV.
Chronic obstructive lung disease is increased in HIV, and a syndrome of cardiopulmonary dysfunction exists even in non-smoking or antiretroviral-treated HIV+ individuals. Statins have anti-inflammatory and other effects in the lungs and vasculature that might benefit cardiopulmonary dysfunction in HIV. The proposed research is relevant to public health and is directly responsive to RFA-12-034 (Management of HIV-Related Lung Disease and Cardiovascular Co-Morbidity) by testing rosuvastatin as a novel therapy to improve management of HIV-associated lung disease with cardiac co-morbidity.
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