Cardiovascular disease (CVD) risk assessment of HIV medication regimens using hematopoietic CD34+ progenitor cells

Abstract

Background: To determine the effects of integrase inhibitor (INSTI) in comparison with non-INSTI-based regimens such as non-nucleoside reverse transcriptase inhibitors (NNRTIs)-based regimens on cardiovascular disease (CVD) risk in HIV+ patients without overt history of CVD or diabetes, with normal CD4:CD8 count. For CVD risk assessment we primarily used hematopoietic CD34+ progenitor cells, as a biomarker.

Methods: Nineteen male subjects, ages 32-61 years with BMI 21.0-36.0, were enrolled. This was a single time point, cross-sectional, observational study. Subjects were enrolled under 2 groups (either on INSTI-based regimen with 13 subjects or NNRTI (non-INSTI)-based regimens with 6 subjects) who were taking stable doses of HAART. The medication regimens were a combination of one NRTI (typically tenofovir-emtricitabine) plus one INSTI or NNRTI. Our outcome measures were focused on cardiovascular and endothelial cell function and systemic inflammation. Our primary outcome measures were peripheral blood-derived hematopoietic progenitor cell number (CD34 and CD133 positive), CD34+ cell function and gene expression studies. Our secondary outcomes were arterial stiffness measures and serum-based markers of inflammation.

Results: A significant increase in percentage number of progenitor cells, CD133+ cells (p = 0.004), was noted along with an increase of double progenitor mark positive CD133+/CD34+ progenitor cell population being observed in INSTI group as compared to NNRTI group, by flow cytometry. mRNA gene expression for antioxidant gene catalase was noted along with a trend toward a decrease in gene expression of inflammatory marker IL6 (p = 0.06) being observed in CD34+ from INSTI group vs NNRTI group. The plasma IL-6 and CRP levels did not change significantly between the groups. Neutrophil-Lymphocyte ratio (NLR), an important marker of inflammation, was noted to be lower in INSTI group. A mean fasting glucose level was also lower in the INSTI group compared to NNRTI group (p = 0.03). Interestingly, urine microalbumin levels were higher in the INSTI group compared to NNRTI group (p = 0.08), while eGFR levels were significantly lower in the INSTI group (p = 0.002). The arterial stiffness measures did not show statistically significant differences between the two groups.

Conclusion: We conclude that the INSTI regimen may provide a better CVD risk profile compared to NNRTI-based HAART regimen; however, the increased albuminuria along with lower eGFR, noted in INSTI group, is of concern. Because of the small size, these results would need replication in additional studies before changing clinical practice. Clinical trial registration https://ichgcp.net/clinical-trials-registry/NCT03782142?cond=Hiv&spons=Sabyasachi+sen&cntry=US&state=US%3ADC&city=Washington&draw=2&rank=1 .

Clinicaltrials: gov Identifier: NCT03782142.

Keywords: CVD; HIV; Integrase inhibitor; Non-nucleoside reverse transcriptase inhibitors.

Conflict of interest statement

S Sen is one of the Associate Editors of the journal and was not involved in the peer review process of the manuscript. There are no other competing interests from any authors.

© 2022. The Author(s).

Figures

Fig. 1

Cell based changes: a significant increase in percentage of CD133 positive hematopoietic progenitor cells (a, p = 0.004). A trend in increased dual positive CD34+ and CD133+ cells, close to statistical significance (b; p = 0.07) is observed in INSTI (n = 13) group as compared to NNRTI (n = 6) group

Fig. 2

The effect of INSTI and NNRTI on CD34+ve cell mRNA gene expressions: the important antioxidant gene Catalase (a) expression increased (p = 0.13) in INSTI (n = 13) group as compared to NNRTI (n = 6) group (a, p = 0.13). Concurrently, the inflammatory marker IL6 gene expression was lower (p = 0.06) in INSTI (n = 13) group as compared to NNRTI (n = 6) group, (b, p = 0.06). However, the results did not reach statistical significance

Fig. 3

Neutrophil and lymphocyte ratio (NLR): a non-statistically significant decrease in NLR (p = 0.11) was observed in INSTI (n = 13) group as compared to NNRTI (n = 6) group. A decrease in NLR is associated with reduced inflammation

Fig. 4

Effect on blood glucose: fasting glucose levels (a) were found to be lower in INSTI group, with statistically significant difference at p = 0.037. There was no difference in concomitant insulin values

Fig. 5

Urine microalbumin: interestingly, urine microalbumin levels were noted to be higher in INSTI (n = 13) group as compared to NNRTI (n = 6) group. The result was close to statistical significance (p = 0.08)

Fig. 6

Glomerular filtration rate: as an index of kidney function, eGFR values showed normal levels in the NNRTI (n = 6) group compared to abnormally low levels in INSTI (n = 13) group, which maybe an indication of CKD. The results were statistically significant (p = 0.002)