Utilization of Absolute Monocyte Counts to Predict Cardiovascular Events in People Living With HIV

M Bogorodskaya; A Lyass; TF Mahoney; LH Borowsky; P Sen; FK Swirski; S Srinivasa; CT Longenecker; JM Massaro; RB D'Agostino Sr.; VA Triant


HIV Medicine. 2021;22(4):314-320. 

In This Article


This study is the first, to our knowledge, to investigate the association between peripheral AMC and future CVE in PLWH. Our results demonstrate that baseline AMC averaged over 2 years is not associated with CVEs over an average of 11 years of follow-up in PLWH. The findings suggest that while monocyte activation has been specifically implicated in HIV-associated atherosclerosis, the AMC obtained in routine clinical care is not independently associated with downstream CVEs and may not be a reliable clinical indicator of cardiovascular risk.

Studies assessing the relationship between baseline AMC and CVEs in the general population have produced varied results. Both observational data and a sub-study of randomized controlled trial data demonstrated AMC to be predictive of future CVE[14,15] while other observational studies have shown no difference in CVE based on AMC.[19]

Monocyte activation plays a central role in atherogenesis and progression of CVD in uninfected patients,[21–23] as atherosclerotic plaques form by the accumulation of macrophage-laden foam cells and lipoproteins.[22] Circulating monocyte subsets have been demonstrated to be independent predictors of CVEs[24] and associated with presence of non-calcified coronary plaque in asymptomatic individuals.[25] Furthermore, studies have shown that blockade of monocyte-stimulating factors and receptors significantly reduces plaque burden in mice.[26]

Similarly, the monocyte-mediated chronic inflammatory response is thought to play a role in early development of CVD in PLWH. Monocyte turnover has been implicated in the pathogenesis of AIDS independent of T-cell counts. Elevations in certain markers of monocyte activation (soluble CD14, soluble CD163, MCP-1) are seen in PLWH[9,27–29] and have been independently associated with cardiovascular and all-cause mortality,[30] subclinical atherosclerosis[13,28,31] and vascular inflammation.[32–34] Furthermore, studies have demonstrated an association between non-classical monocytes with coronary artery calcium score progression on CT angiography.[35] However, these biomarkers and monocyte subsets are not available in the clinical setting. No study to date has assessed the association between AMC and future CVE in PLWH. Peripheral AMCs are readily available in the clinical setting and obtained with every complete blood count measurement. The peripheral AMC measures the steady state of monocytes in the blood at a given time and can fluctuate diurnally, with stress and other infections. Therefore, they do not necessarily provide a consistent illustration of the degree of monocyte activation or turnover that is occurring within organ tissues. This may explain why AMC was not associated with future CVEs in our study, while markers of monocyte activation (sCD14 and sCD163) and certain monocyte subsets have shown an association in previous studies.

Our results are consistent with some of the previously published data. The Rana et al.[19] study among a non-HIV population found no association between monocytes and CVEs, and had a similar follow-up period to our study of 8 years. By contrast, the studies that found monocytes to be predictive of CVE in the general population looked at a shorter follow-up period of 1–3 years. As peripheral monocytes have a short turnover of 1–7 days,[17,18] absolute monocyte levels may be better able to predict short-term events. The low number of events in our cohort precluded us from looking at shorter follow-up periods. However, we did evaluate whether the most recent AMC available or the most recent prior to a CVE in those who had events was associated with having a CVE and we did not find a statistically significant association. We applied rigorous exclusion criteria to ensure the monocyte counts were not attributed to acute periods of inflammation, and we attempted to account for acute fluctuations in levels by using an average of multiple monocyte counts drawn routinely over a span of 2 years. Our results may also reflect a differing mechanism of monocyte involvement in PLWH compared with uninfected individuals. Certain monocyte subsets are known to be elevated in PLWH compared with controls,[36] yet these may not translate into a change in total circulating absolute monocyte levels.

We observed an association between CD4 cell count and CVE independent of AMC, consistent with multiple prior studies showing an association between lower CD4 cell count and increased CVE.[37,38] Immune dysregulation, as demonstrated by the association of low CD4 cell counts with CVE, is a known risk factor for CVD in HIV. Although higher VL[39,40] has also been associated with increased CVEs, we did not observe this association in the current study. Traditional CVD risk factors, including age, diabetes mellitus and smoking, were significantly associated with CVE.

Our study was observational in nature and subject to limitations. Ascertainment of clinical variables may have been limited by reliance on using diagnostic codes and limitations in capturing outside-system events. Confounding bias is also a common limitation of observational data. We controlled for all variables that it was feasible to obtain accurately from an electronic medical record that could affect the incidence of a CVE. We were not able to adjust for family history or obesity, or for many behaviours such as drug use, dietary intake and physical activity level, which can also increase risk for future CVE. The possibility of other unmeasured confounders also exists. To optimize power to detect an association, we employed a long period of follow-up from 2000 to 2017 to capture CVE events; this period spanned changes in contemporary HIV care, resulting in a heterogenous HIV population, and this could potentially dilute the association between AMC and future CVE. Nevertheless, this is the first study, to our knowledge, to assess the association between peripheral AMCs and CVE in PLWH.

Conclusions and Implications

In summary, our study demonstrated that baseline AMC may not be a useful marker to predict future CVE in PLWH over a span of 11 years. Further studies are needed to evaluate whether AMC is associated with CVEs within shorter follow-up intervals. Although monocyte activation is known to promote atherogenesis in PLWH, AMCs obtained in routine clinical encounters do not appear to enhance CVD risk stratification in this group. Additional specific markers of inflammation and immune dysregulation may be necessary to help identify PLWH at heightened CVD risk.