The goal of this proposal is to understand the relationship between acquired mutations in hematopoietic stem cells and coronary heart disease (CHD) among individuals living with HIV. With advances in HIV management, now non-AIDS-defining illnesses, particularly CHD, are major health issues for individuals living with HIV. The risk of CHD appears to be notably higher among those with HIV versus those without HIV, at least through heightened inflammation, but the fundamental reasons for the difference is not well-understood. Pre-cancerous shown to associate with CHD odds in the general population through inflammatory pathways. CHIP is more common among those in the general population who have elevated inflammatory biomarkers. Prior and new preliminary work suggest that CHIP may be particularly relevant to CHD in HIV, where inflammation is believed to play a particularly large role in accelerated aging phenomena such as CHD. Here, we propose to define the prevalence, risk factors, and clinical consequences of CHIP in HIV within a large, international, phase 4 cardiovascular disease prevention clinical trial among individuals with HIV (REPRIEVE) this will be the first extensive analyses of CHIP in HIV as well as the influence of statins on CHIP-associated CHD. REPRIEVE is the largest placebo-controlled statin trial among individuals with HIV with rigorously adjudicated cardiovascular events, extensive exposure data, and dense longitudinal phenotyping including imaging and biomarkers in a subgroup.
In Aim 1, we will identify carriers of CHIP among 5,000 REPRIEVE participants using whole exome sequencing of circulation white blood cells and define general and HIV-specific CHIP risk factors.
In Aim 2, we will estimate the relationship of CHIP with incident cardiovascular outcomes and death, as well as longitudinal inflammatory and imaging biomarkers.
In Aim 3, we will discover the mechanistic relationships of CHIP with HIV-associated outcomes through causal mediation analyses as well as germline genotype and telomere analyses compared with ~150,000 individuals without HIV. Completion of these aims will yield novel insights in CHD biology and prevention for tailored CHD prevention in HIV, including advancing the discovery of new therapeutic targets.
/ PUBLIC HEALTH RELEVANCE Despite advances in coronary heart disease (CHD) prevention in the general population, rates of CHD are climbing among people with HIV (PHIV) at least partly through heightened inflammation. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition of pre-cancerous mutations in circulating blood cells that predisposes to both cancer and CHD through inflammation, and its clinical outcomes may be mitigated through immunomodulation. This proposal seeks to establish CHIP has an unrecognized, common CHD risk factor in PHIV and show that PHIV with CHIP are more likely to benefit from pitavastatin, a statin that lowers inflammatory biomarkers, within a large, international statin randomized controlled clinical trial among PHIV (REPRIEVE).