Risk factors for clonal hematopoiesis of indeterminate potential in people with HIV: a report from the REPRIEVE trial

Abstract

Clonal hematopoiesis of Indeterminate Potential (CHIP), the clonal expansion of myeloid cells with leukemogenic mutations, results in increased coronary artery disease (CAD) risk. CHIP is more prevalent among people with HIV (PWH) but the risk factors are unknown. CHIP was identified among PWH in REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) using whole exome sequencing (WES). Logistic regression was used to associate sociodemographic factors and HIV-specific factors with CHIP adjusting for age, sex, and smoking status. In the studied global cohort of 4,486 PWH, mean (SD) age was 49.9 (6.4) years, 1650 (36.8%) were female, and 3418 (76.2%) were non-White. CHIP was identified in 223/4486 (4.97%), and in 38/373 (10.2%) among those 60 years of age or older. Age (OR 1.07, 95%CI 1.05-1.09, p<0.0001) and smoking (OR 1.37, 95%CI 1.14-1.66, p<0.001) associated with increased odds of CHIP. Globally, participants outside of North America had lower odds of CHIP including Sub-Saharan Africa (OR 0.57, 95%CI 0.4-0.81, p=0.0019), South Asia (OR 0.45, 95%CI 0.23-0.80, p=0.01), and Latin America/Caribbean (OR 0.56, 95%CI 0.34-0.87, p=0.014). Hispanic/Latino ethnicity (OR 0.38, 95%CI 0.23-0.54, p=0.002) associated with significantly lower odds of CHIP. Among HIV-specific factors, CD4 nadir <50 cells/mm3 associated with a 1.9-fold (95%CI 1.21-3.05, p=0.006) increased odds of CHIP, with the effect being significantly stronger among individuals with short duration of antiretroviral therapy (ART) (OR 4.15, 95%CI 1.51-11.1, p=0.005) (pinteraction=0.0492). Among PWH at low-to-moderate CAD risk on stable ART, smoking, CD4 nadir, North American origin, and non-Hispanic ethnicity associated with increased odds of CHIP. Clinical Trials Registration: NCT02344290-

Clonal hematopoiesis in people with advanced HIV and associated inflammatory syndromes

“…Comparing the CH prevalence in our HIV cohort to other published cohorts of PWH is limited by variability in sequencing methodology and cohort characteristics (25)(26)(27)(28)(29). Studies in PWH using whole-exome data, with a lower sensitivity to detect CH at a VAF of 2% or greater, have found prevalences between 4% and 14% (26)(27)(28).…”

“…CH is associated with increased mortality due to a greater risk of CVD in older populations (15,35). Early studies of CH prevalence in PWH have JCI Insight 2024;9(9):e174783 https://doi.org/10.1172/jci.insight.174783 identified increased rates compared with non-HIV populations, providing a possible mechanism for the increased CVD and non-AIDS, nonhepatic cancer risk in PWH (25)(26)(27)(28)(29). These studies primarily focused on age-matched comparisons to non-HIV populations and included older adults with median ages over 50 years, whereas our cohort was younger (median age 42 years), with greater rates of prior advanced HIV and OIs.…”

“…Comparing the CH prevalence in our HIV cohort to other published cohorts of PWH is limited by variability in sequencing methodology and cohort characteristics (25)(26)(27)(28)(29). Studies in PWH using whole-exome data, with a lower sensitivity to detect CH at a VAF of 2% or greater, have found prevalences between 4% and 14% (26)(27)(28). Using a 24-gene panel, a study by van however, their cohort was notably older, with a median age of 63 years, and only 34.6% had a CD4 + nadir of less than 200 cells/μL, with 17% having a prior AIDS-defining condition (25).…”

“…Due to the known link between CH and hyperinflammatory pathways, we hypothesized that CH could accelerate in PWH, and lead to higher rates of chronic inflammation and comorbidities even after HIV is well controlled. Recent studies identified an increased prevalence of CH in PWH, highest in those with lower nadir CD4 + counts (25)(26)(27)(28). However, published studies included fewer patients with a nadir CD4 + count below 200 cells/μL, and the impact of CH in HIV cohorts with prior AIDS and/or IRIS remains unexplored (29).…”

Inflammation in HIV and Its Impact on Atherosclerotic Cardiovascular Disease

“…Smoking and age were associated with increased odds of CHIP. 127 The ongoing inflammatory conditions in HIV may foster clonal dominance of specific mutated hematopoietic stem cells, potentially explaining the higher occurrence of clonal hematopoiesis in individuals with HIV. Furthermore, the weakened immune response during acute HIV or the persistent inflammation and immune activation in chronic HIV could impede the body's ability to survey and eliminate these clonal hematopoietic stem cell populations, further contributing to the elevated prevalence of CHIP in PLWH.…”