Background: Clonal hematopoiesis (CH), defined by the expansion of hematopoietic cells with somatic mutations in leukemogenic genes (CH of indeterminate potential (CHIP)) or with mosaic chromosomal alterations (mCAs), is associated with aging and adverse health outcomes in the general population. CHIP prevalence is higher in People with HIV (PWH) than in controls. However, the full spectrum, prevalence, and clinical consequences of CH in PWH remain incompletely understood.

Methods: We assessed CHIP and mCAs in a large sample of PWH (N∼2,500) from the Swiss HIV Cohort Study. Using high-depth targeted sequencing of CHIP genes and genome-wide genotyping to call mCAs, we quantified the prevalence and clone size of both CH types and investigated an association of CH with clinical variables.

Results: CHIP (25% of individuals) and mCAs (16% of individuals) were common, positively correlated with age, often co-occurring (OR=1.7, p=0.02 for autosomal mCAs), and associated with various clinical outcomes, including all-cause mortality (HR=1.3, p=0.02 for CHIP) and hematologic malignancies (HR=9.4, p=0.01 for the effect of CHIP on the risk of myeloid cancer; HR>20, p<0.001 for the effect of co-occurring CHIP and mCAs on the risk of lymphoid cancer). We also observed associations of CH with several proxies of inflammatory status (CD4:CD8 ratio, HIV viral load, late initiation of antiretroviral therapy, and toxicity of antiretroviral drugs).

Conclusion: The study provides a comprehensive assessment of the CH landscape in PWH, highlighting potential causes and consequences in this population and suggesting an interaction between CH and chronic immune activation.