Clonal hematopoiesis does not predict solid tumor malignancy in people living with HIV

Abstract Background: Clonal hematopoiesis (CH) is more common in people living with HIV (PLWH) than HIV-negative individuals in recent studies and has emerged as a potential risk factor for incident solid malignancies in the general population through inflammatory and tumor microenvironment mechanisms. PLWH experience increased systemic inflammation and face elevated risks for certain solid malignancies compared to HIV-negative populations. However, the clinical impact of CH in PLWH, particularly its contribution to solid tumor malignancy, is not well understood. We aimed to determine CH prevalence in PLWH and evaluate whether CH is associated with increased risk of solid tumor malignancy in this population. Methods We analyzed phenotype and whole exome sequencing data from Mount Sinai BioMe Biobank participants. CH was identified by excluding patients with myeloid malignancies at time of cohort entry. We called for somatic mutations using mutect2 variant caller and filtered for predefined myeloid CH mutations in 76 genes with variant allele fraction (VAF) ≥ 2%. HIV and cancer diagnoses were defined using ICD-9 and ICD-10 codes and confirmed using manual record review. We conducted 5:1 propensity score matching of HIV-negative controls to PLWH by age, sex, ethnicity, and smoking status. We calculated adjusted odds ratio (aOR) for CH prevalance in PLWH compared to HIV-negative controls and for incident solid tumor diagnosis in PLWH with CH versus without CH. Results We matched 1,204 patients with HIV to 6,020 patients without HIV. Among the cohort of PLWH, we identified 96 patients with CH (7.97%) compared to 413 patients in the cohort without HIV (6.86%). When examining baseline characteristics as predictors of CH in PLWH, age was the only characteristic with a significant association (p<0.0001). The aOR of CH in PLWH compared to people without HIV was 1.02 (CI 0.80 – 1.29, p=0.87). Incident solid tumors were identified in 14.2% of the PLWH cohort compared to 8.99% in the cohort without HIV. The most common solid tumor diagnoses in the HIV+ cohort with CH were hepatocellular carcinoma (n=6), Kaposi Sarcoma (n=3), anal cancer (n=3), and oropharyngeal cancer (n=3). Older age was significantly associated with solid tumor diagnosis in PLWH [OR 1.048 (1.03 – 1.06, p <0.0001)]. After adjusting for age, among the cohort of PLWH, the aOR of solid tumor diagnosis for those with CH compared to those without CH was 1.185 (0.69 – 2.04, p=0.54). Conclusions CH prevalence was similar between PLWH and matched HIV-negative comparators. Among PLWH, CH was not associated with increased solid tumor diagnoses. Given the strong age associations with both CH and solid tumor diagnosis in PLWH, additional studies are underway to determine if methylation patterns account for the age-related differences in PLWH and if this may correlate with risk of malignancy, as well as to investigate the impact of CH on solid tumor outcomes in PLWH.