Life expectancy has substantially increased in humans with the immunodeficiency virus (HIV) infection. Insulin resistance, diabetes, dyslipidemia, lipodystrophy, hypothyroidism, hypogonadism, muscle weakness, and osteoporosis are commonly seen as the combined effect of viral factors, host immune response or HIV-treatment drugs. In the long term, HIV infection results in a condition of persistent low-grade inflammation associated with changes in cell trafficking through the endothelial barrier, formation of proatherogenic monocytes, altered response and metabolism of steroid hormones, all contributing to metabolic and cardiovascular failure. Aim of the study is to describe at the molecular level such changes and test whether the inhibition of phosphodiesterase type-5 (PDE5i) can improve endothelial function in HIV controlling the chronic inflammation and improving metabolism. A group of 16 investigators from 3 Departments - 2 full professors, 5 associate and 3 junior professors and 6 young researchers (PhD or post-doc) - have designed a clinical trial addressing this hypothesis based on solid data accumulated in conditions mirroring some of the long-term alterations observed in HIV: metabolic syndrome, adipose tissue dysfunction, hypogonadism, and glucocorticoid excess. The group has published several clinical trials, and experimental studies, in HIV, steroid hormones, and the pharmacological modulation of the PDE5 on such outcomes, with a track record generating nearly >460 points of IF from non-duplicated publications. The project is reverse translational -from bed to benchside- with the potential to disclose novel diagnostic and therapeutic tools targeting end-organ complications in chronic inflammation. The homogenous composition of the group with participants at every level, from senior to young researchers, the experience in the field and the availability of co-funding offer a greater warrant of success of output delivery.
The proposed research moves from an observational collection of clinical evidence to a molecular and pharmacological approach using the advantage of an RCT and the ex-vivo approach on isolated cells. The observational study appears entirely novel as compared to the old single-output study-design, selectively investigating the bone or the gonadal function in HIV, to a multi-level wide-angle approach using hormonal profiling and composite outcomes. This will be the first study addressing adrenal steroidogenesis in HIV using wide steroid profiling by LC/MS-MS. The translational design is unique in the filed using mechanistic investigations to identify novel causal relationships and pathologic links between inflammation and endothelial dysfunction in HIV.
The prevalence of non-AIDS-related comorbidities, including CVD, remains increased among HIV-infected individuals, even those taking newer antiretroviral therapy who are virally suppressed and with fewer metabolic side effects, suggesting that other mechanisms are involved. Substantial data show that the increased CVD risk is associated with chronic inflammation, endothelial activation and microvascular dysfunction among HIV patients. A multidisciplinary approach will allow us to characterize the endocrine, metabolic, immune and vascular profile of HIV patients through a complete clinical and biological assessment, that goes beyond infectious disease management.
To date, there are no specific treatments to prevent or reduce cardiovascular risk in these patients. Lifestyle modification and treatment of traditional risk factors are important initial strategies, but likely not enough. There is evidence that other strategies may be needed, as the risk of hypertension and diabetes, although increased among HIV-infected individuals, does not fully account for the marked increase in CVD in this population. The scientific community also has recognized this important gap in knowledge of HIV disease.
Several studies have demonstrated that PDE5is have cardioprotective effects and modulate inflammation and tissue repair preserving endothelial cell function. Our study will evaluate if PDE5 inhibition could become a new target for immune dysregulation in HIV patients. We aim to study the pharmacological modulation of circulating biomarker of inflammation and endothelial activation in the setting of HIV patients to identify a tailored therapy targeting the main pathophysiological mechanisms involved in CVD. If PDE5 is found to be effective in improving endothelial function in the proposed studies, then this inexpensive, safe, and the widely available drug can be studied in larger trials to reduce cardiovascular endpoints in HIV-infected patients. The detection of new therapies will allow a more rapid and effective clinical response, saving the cost given by diagnosis and therapy of chronic complications HIV related.