Highlights
The study reveals three critical insights for clinicians managing cardiovascular risk in people with HIV (PWH):
- Clonal hematopoiesis of indeterminate potential (CHIP) is prevalent in PWH, affecting 18.6% of the REPRIEVE trial cohort.
- Only large CHIP clones—defined by a variant allele fraction (VAF) of 10% or greater—were significantly associated with an increased risk of myocardial infarction and revascularization.
- A lower CD4 T-cell count nadir is associated with larger CHIP clone sizes, suggesting a link between historical immune suppression and clonal expansion.
Background: The Intersection of HIV and Cardiovascular Risk
Despite the success of antiretroviral therapy (ART) in transforming HIV into a manageable chronic condition, people with HIV (PWH) face a disproportionate burden of age-related comorbidities. Chief among these is cardiovascular disease (CVD). PWH experience cardiovascular event rates roughly 1.5 to 2 times higher than the general population, a gap that persists even when traditional risk factors like smoking, hypertension, and dyslipidemia are well-controlled. This excess risk is often attributed to chronic immune activation and systemic inflammation.
Clonal hematopoiesis of indeterminate potential (CHIP) has recently emerged as a potent, non-traditional cardiovascular risk factor. CHIP occurs when somatic mutations in hematopoietic stem cells—most commonly in genes such as DNMT3A, TET2, and ASXL1—confer a competitive advantage, leading to a genetically distinct subpopulation of leukocytes. In the general population, CHIP is associated with a 40% increase in coronary heart disease risk, likely mediated by pro-inflammatory cytokine production (such as IL-1β and IL-6) from mutated myeloid cells. Given the heightened inflammatory state in PWH, researchers have hypothesized that CHIP may play a more aggressive role in driving major adverse cardiovascular events (MACE) in this population.
Study Design: Deep Sequencing in the REPRIEVE Trial
To investigate this, researchers utilized data from the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) trial, a landmark global study designed to assess the efficacy of pitavastatin in primary CVD prevention among PWH. The investigators performed high-coverage targeted sequencing on 4,490 participants who had no known cardiovascular disease at baseline. The cohort was notably diverse, including 36.8% female participants and 45.4% Black participants, with a median age of 50 years.
The primary objective was to determine whether the presence of CHIP at baseline was associated with the prospective risk of MACE. MACE was broadly defined as a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral artery disease, revascularization, or death from undetermined causes. Furthermore, the study examined whether HIV-specific factors, such as CD4 counts and duration of ART, influenced the prevalence or size of CHIP clones.
Key Findings: The Importance of Clone Size
The study found that CHIP is indeed common among PWH, with 837 participants (18.6%) harboring at least one CHIP driver mutation. However, the clinical impact of these mutations was highly dependent on the clone size, measured as the variant allele fraction (VAF).
Prevalence and Risk Stratification
While 18.6% of the cohort had CHIP at any level, only 8.6% had a VAF of 2% or greater, and a small minority (1.4%) had large clones with a VAF of 10% or greater. In the primary analysis, the mere presence of CHIP (at any VAF) was not significantly associated with the overall composite MACE endpoint. This finding differs from some studies in the general population, where even smaller clones have been linked to risk, potentially due to the different cardiovascular risk profile of the REPRIEVE cohort, which was at low-to-moderate risk at baseline.
Figure 2. HIV-Specific risk factors and odds of CHIP.
(A) CD4 nadir and ART duration with the presence of CHIP; (B) CD4 nadir and ART duration with the maximum CHIP VAF per individual. ART, antiretroviral therapy; CHIP, Clonal Hematopoiesis of Indeterminate Potential; VAF, variant allele fraction
Large Clones and Myocardial Infarction
A different picture emerged when looking at large clones. Participants with a VAF ≥10% faced significantly increased odds for specific cardiac events. Specifically, large CHIP was associated with a higher risk of the first occurrence of myocardial infarction or the need for cardiac catheterization and revascularization. This association remained robust even after adjusting for traditional risk factors and pitavastatin treatment, suggesting that CHIP-driven risk operates through pathways that are not fully mitigated by standard LDL-lowering therapies.
HIV-Specific Associations
The researchers identified a compelling link between the history of HIV infection and CHIP dynamics. A lower CD4 nadir—the lowest recorded CD4 count prior to the study—was significantly associated with a larger CHIP clone size. This suggests that periods of profound immune suppression or the inflammatory environment present before ART initiation may provide a selective pressure that allows mutated hematopoietic clones to expand.
Expert Commentary: Mechanistic Insights and Clinical Implications
The finding that only large CHIP clones (VAF ≥10%) predicted events in this HIV cohort is of significant clinical interest. Mechanistically, this suggests a “threshold effect” where a certain volume of mutated, pro-inflammatory leukocytes must be present to significantly accelerate atherogenesis or trigger plaque instability. The lack of attenuation by pitavastatin is also notable; it suggests that while statins are effective at reducing overall risk in PWH (as shown in the main REPRIEVE results), they may not fully address the specific inflammatory pathways activated by CHIP-mutated cells, such as the NLRP3 inflammasome.
From a clinical perspective, these results suggest that while CHIP is a relevant biomarker, not all CHIP is created equal. Routine screening for CHIP in PWH is not yet supported by the data, but for those who undergo genomic sequencing for other reasons, the presence of a clone with a VAF ≥10% should be viewed as a high-risk marker. It may warrant more aggressive management of other modifiable risk factors or closer monitoring for ischemic heart disease.
Limitations of the study include the relatively low overall event rate in the REPRIEVE cohort, which may have limited the statistical power to detect associations between smaller CHIP clones and MACE. Additionally, as an observational sub-study, it cannot definitively prove a causal link between CD4 nadir and clone expansion.
Conclusion: A Nuanced View of Hematopoietic Aging in HIV
The REPRIEVE trial insights refine our understanding of cardiovascular risk in the modern ART era. They demonstrate that while clonal hematopoiesis is a common feature of the aging hematopoietic system in PWH, its clinical significance is primarily concentrated in individuals with large clone sizes. The association between historical immune suppression (CD4 nadir) and clone expansion further emphasizes the importance of early HIV diagnosis and treatment to minimize long-term systemic consequences. Future research should focus on whether targeted anti-inflammatory therapies can specifically mitigate the cardiovascular risk posed by large CHIP clones in this vulnerable population.
Funding and Registration
The REPRIEVE trial was supported by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID). ClinicalTrials.gov Identifier: NCT02344290.
References
- Xue L, Bhattacharya R, Uddin MM, et al. Clonal Hematopoiesis and Major Adverse Cardiac Events in People With HIV: Insights From the REPRIEVE Trial. Arterioscler Thromb Vasc Biol. 2026;46(1):168-177. doi:10.1161/ATVBAHA.125.322896 IF: 7.4 Q1 .
- Grinspoon SK, Fitch KV, Zanni MV, et al. Pitavastatin to Prevent Cardiovascular Disease in HIV Infection. N Engl J Med. 2023;389(8):687-699.
- Jaiswal S, Natarajan P, Bick AG, et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med. 2017;377(2):111-121.
- Bick AG, Pirruccello JP, Griffin GK, et al. Genetic Interleukin-6 Signaling Deficiency Ameliorates Cardiovascular Risk Associated with Clonal Hematopoiesis. Circulation. 2020;141(2):124-131.
