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BASIC SCIENCE: CONCISE COMMUNICATION

Antiretroviral therapy reduces but does not normalize immune and vascular inflammatory markers in adults with chronic HIV infection in Kenya

Temu, Tecla M.a; Zifodya, Jerry S.b; Polyak, Stephen J.c; Wagoner, Jessicac; Wanjalla, Celestine N.d; Masyuko, Saraha,e,f; Nyabiage, Jerushaa; Kinuthia, Johnf; Bloomfield, Gerald S.g; Page, Stephanie T.h,∗; Farquhar, Careya,h,i,∗

Author Information
doi: 10.1097/QAD.0000000000002729

Abstract

Introduction

Antiretroviral therapy (ART) has greatly reduced mortality associated with HIV; however, this success has been tempered by increased rates of cardiovascular diseases (CVD) [1–7]. Despite sub-Saharan Africa (SSA) carrying the highest burden of HIV, data on potential drivers of HIV-associated risk of CVD remain scant [2,8]. HIV has been associated with persistent immune activation and biomarkers of monocyte activation [soluble CD14 (sCD14) and sCD163] and vascular inflammation [soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular adhesion molecule 1 (sVCAM-1)] [6,9–19], have been associated with increased risk for premature CVD and mortality in people living with HIV (PLWH) in studies conducted in resource-rich settings [6,13,19–24]. The mechanisms underlying this immune dysregulation are not clear and may include ART toxicity, traditional CVD risk factors and coinfections. The effect of HIV independent of these factors is also likely to be substantial [6,25]. Although few studies in the SSA have reported an increase in markers of immune activation and inflammation among PLWH, the results may have been confounded by the lack of data on comorbid diseases, lack of thorough consideration for traditional CVD risk factors and HIV-specific risk factors, and the lack of HIV-negative reference group for comparison [26–29]. This is particularly important because there may be unique factors in SSA that promote inflammation (poor sanitation and nutrition) regardless of the HIV status [30–32].

We examined an independent association of HIV with markers of monocyte/macrophages activation and vascular inflammation after adjustment for all traditional CVD risk factors among PLWH and behaviorally similar (i.e. similar prevalence of tobacco use) HIV-negative adults. We also identified clinical and HIV-specific risk factors associated with residual immune activation during ART.

Methods

We analyzed samples from a cross-sectional study of 275 PLWH on stable ART for more than 6 months and 266 HIV-negative adults enrolled between 2017 and 2018 from the Kisumu District Hospital HIV clinic and voluntary HIV testing centers in western Kenya. Recruitment and study procedures have been described elsewhere [33]. Briefly, data were collected through a questionnaire; including anthropometric measurements; laboratory examination; and medical chart abstraction. The study sample was a convenience sample of adults at least 30 years old. Individuals with a recorded history of CVD, neoplasia, active infection, and those who at the time of recruitment were on medications that could influence their immune status were excluded. The Ethics and Research Committee of Kenyatta National Hospital and the Institutional Review Board at University of Washington approved the study. All participants provided written informed consent.

Dependent variable

Serum levels of intestinal-fatty acid binding protein (I-FABP), sCD14, and sCD163 were quantified using ELISA (Quantikine ELISA kit; R&D Systems, Minneapolis, Minnesota, USA) while sICAM-1 and sVCAM-1 were measured using multiplex ELISA-based assay (Meso-Scale Discovery). Assays were performed in the same UW laboratory in duplicate. The inter-assay coefficients of variation were less than 11%.

Independent variables

The main independent variable of interest was HIV status. Data on covariates such as age, alcohol use, smoking status, ART duration, type of ART regimen, and nadir CD4+ T-cell count were obtained from the participants and confirmed using medical records. BMI was calculated from weight and height measurements. Fasting blood samples were used to assess for blood glucose (FBG), lipids, current CD4+ T-cell count, and HIV RNA viral load. Elevated blood pressure was defined when SBP at least 140 mmHg or DBP at least 90 mmHg or if the participant was on antihypertensive patients. Diabetes mellitus was defined as FBG at least 126 mg/dl or the use of medications for diabetes. Dyslipidemia was defined as HDL less than 40 mg/dl or LDL at least 130 mg/dl, or triglycerides at least 150 mg/dl. Undetectable viremia was defined as viral load less than 50 copies/ml and viral suppression as viral load less than 1000 copies/ml per Kenyan guidelines [34].

Statistical analyses

Comparison between groups were analyzed using χ2 test, t test or Wilcoxon rank-sum test. We used multivariate logistic regression to estimate the association between HIV-infection and prevalence of elevated [highest quartile (>75th percentile) vs. lower three quartiles] biomarkers. Fully adjusted model included covariates such as age, hypertension, diabetes, smoking status, alcohol consumption status, triglycerides, HDL, and BMI. Secondary analyses stratified HIV status by CD4+ T-cell count, ART duration, and viral load were done.

Additional analysis was done to determine factors associated with elevated biomarkers in PLWH with additional adjustment for nadir and current CD4+ T-cell count, ART regimen, and ART duration. Significance was set at a P value less than 0.05. Analyses were performed using STATA version 13 (San Antonio, Texas, USA).

Results

Study participants characteristics are presented in Supplementary Table 1, https://links.lww.com/QAD/B881. Compared with HIV-negative participants, PLWH were older and less likely to be hypertensive, diabetic or obese (P < 0.05 for all). Almost all PLWH (97%) were virally suppressed. The median current CD4+ T-cell count was 509 cells/μl. Only 13% were on protease inhibitors.

HIV-infection is associated with elevated biomarkers of monocyte activation and inflammation

Age-adjusted levels of sCD14, sCD163, I-FABP, sICAM-1, and sVCAM-1 were higher among PLWH compared with the HIV-negative participants (Fig. 1). HIV-infection was associated with elevated I-FABP [odds ratio (OR), 3.59; P < 0.001], sCD14 (OR, 8.58; P < 0.001), sCD163 (OR, 2.03; P = 0.007), sICAM-1 (OR, 3.17; P < 0.001), and sVCAM-1 (OR, 1.92; P = 0.001) in unadjusted analysis. The association remained unchanged after adjustment for CVD risk factors (Supplementary Table 2, https://links.lww.com/QAD/B881).

F1
Fig. 1:
Serum levels of biomarkers by HIV serostatus, (a) CD4+ T-cell count and (b) viral load.

When we further stratified PLWH by HIV-specific factors, those with CD4+ cell count 200 cells/μl or less, detectable viremia, and those on ART less than 4 years had the highest prevalence of elevated biomarkers when compared with the HIV-negative persons (Table 1). However, the odds of having elevated biomarkers remained high for PLWH with undetectable viral load and CD4+ T-cell count at least 500 cells/μl compared with the HIV-negative persons. When we stratified by duration of ART use (<4, 4–10, >10 years), we observed a trend that the odds of elevated biomarkers decreased with longer ART exposure. In fact, only PLWH on ART for less than 4 years had statistically significant elevated sVCAM-1 and sICAM-1 compared with HIV-negative participants.

Table 1 - Association of HIV-specific characteristics and elevated biomarkers.
sCD14aOR (95% CI) sCD163aOR (95% CI) I-FABPaOR (95% CI) sVCAM-1aOR (95% CI) sICAM-1aOR (95% CI)
Stratified by HIV status and current CD4+ cell count (cells/μl)
 HIV− 1.00 1.00 1.00 1.00 1.00
 HIV+, CD4+ ≥ 500 7.87 (4.36–12.22) 7.70 (1.56–5.38) 2.21 (1.31–3.77) 2.34 (1.24–3.14) 3.86 (2.25–6.63)
 HIV+, 200 > CD4+ < 500 8.79 (4.66–15.59) 2.39 (1.10–5.21) 3.43 (1.95–6.02) 1.73 (1.17–3.08) 3.54 (1.94–6.45)
 HIV+, CD4+ ≤ 200 9.32 (3.49–22.85) 2.49 (1.11–5.88) 4.59 (1.80–11.72) 2.36 (1.05–6.10) 3.61 (1.33–9.74)
Stratified by HIV status and viral load (copies/ml)
 HIV− 1.00 1.00 1.00 1.00 1.00
 HIV+, VL < 50 7.61 (3.06–15.95) 2.40 (1.28–4.55) 2.71 (1.76–4.35) 1.91 (1.21–3.02) 3.65 (2.22–5.99)
 HIV+, VL ≥ 50 8.61 (4.94–14.99) 4.88 (1.71–9.97) 3.26 (1.38–7.69) 3.97 (1.71–9.19) 5.29 (2.20–12.67)
Stratified by HIV status and ART duration (years)
 HIV− 1.00 1.00 1.00 1.00 1.00
 HIV+, ART < 4 8.35 (4.77–18.33) 3.53 (1.73–5.88) 3.74 (2.04–6.87) 3.10 (1.71–5.62) 4.42 (2.36–8.28)
 HIV+, ART 4–10 7.83 (4.23–13.65) 2.83 (1.42–4.93) 2.91 (1.67–5.06) 1.05 (0.882.70) 1.01 (0.78–3.26)
 HIV+, ART > 10 7.29 (3.92–12.52) 1.81 (1.33–4.01) 2.61 (1.48–4.59) 1.02 (0.822.56) 1.08 (0.79–3.48)
ART, antiretroviral therapy; CI, confidence interval; I-FABP, intestinal-fatty acid binding protein; OR, odds ratio; sCD14, soluble CD14; sICAM-1, soluble intercellular adhesion molecule 1; sVCAM-1, soluble vascular adhesion molecule 1; VL, viral load.Bold indicates that the odds of elevated biomarkers decreased with longer ART exposure such that the odds of elevated sICAM-1/sVCAM-1 for PWH on ARTð for >4 years was not statistically different from the HIV-1.
aModel are adjusted for age, dyslipidemia, BMI, hypertension, diabetes, smoking status.

Factors associated with elevated biomarkers among people living with HIV on antiretroviral therapy

When we restricted our analysis to PLWH, low nadir CD4+ cell count 200 cells/μl or less was associated with elevated sCD14 while ART use more than 4 years was associated with reduced sICAM-1 and sVCAM-1 (P < 0.05 for all; Supplementary Table 3, https://links.lww.com/QAD/B881). Other covariates associated with elevated biomarkers included: triglycerides more than 150 mg/dl with elevated sCD14, sICAM-1, and sVCAM-1; and BMI less than 18 kg/m2 with I-FABP.

Compared with a nevirapine-based regimen, protease inhibitor-based regimens were associated with elevated sCD163 [OR, 2.83, 95% confidence interval (CI); 1.98–5.47] and efavirenz-based regimens with elevated I-FABP (OR, 2.34, 95% CI; 1.31–4.18).

Discussion

In this well characterized African cohort, we observed a significantly higher prevalence of elevated monocyte/macrophages activation, and vascular inflammation in PLWH compared with HIV-negative individuals. This was evident among the virally suppressed and those with CD4+ T-cell count at least 500 cells/μl. Most importantly, we identified clinical and HIV-specific factors associated with this immune dysregulation. To our knowledge, this investigation is the largest and first of its kind to thoroughly investigate the relationship between HIV, traditional CVD risk factors, and markers of vascular inflammation, gut permeability and macrophage/monocyte activation among African PLWH in the ART era.

Our observation of persistent elevation of sCD14 and sCD163 while taking ART is of relevance since both markers have been linked to CVD risk and mortality among PLWH [18,19,35–37]. These findings concur with limited studies conducted in SSA that found minimal effect of ART on reducing these markers of monocyte/macrophage activation [23,24,27,29,38,39]. In a large African HIV cohort, sCD14 and sCD163 were significantly elevated in untreated adults and decreased during ART-mediated viral suppression compared with an HIV-negative group; notably, pre-ART levels of each of the biomarkers were the strongest predictors of residual immune activation during ART [27]. In a community-based, longitudinal, cohort study comprised of PLWH on ART and HIV-negative individuals in Uganda, there was persistent elevation of sCD14 and I-FABP among PLWH but not sCD163 and discordant to our study they found evidence of sex disparities where women tended to have significantly higher levels of these markers compared with men [24]. Our study also found that HIV and not CVD risk factors was a strong predictor for the residual monocyte/macrophage activation. In addition, we observed a negative association between nadir CD4+ T-cell count and sCD14 supporting the concept that early ART may be important for the prevention of future complications related to HIV-associated immune activation.

Our study results contrast three large US-based studies, the Multicenter AIDS Cohort Study [40] and the Women's Interagency Health Study [41] that showed normalization of inflammatory markers after ART initiation, and the Veterans Aging Cohort Study that reported a high prevalence of elevated sCD14 only in veteran with detectable viremia and those with low CD4+ T-cell count [38]. The low prevalence of CVD risk factors among our HIV-negative cohort compared with the HIV-negative participants in the aforementioned cohorts, differences in the type of ART drugs, and other unmeasured confounders unique and prevalent to the African setting (i.e. coinfections known to modulate host immunity) could account for the differences between our study and other studies.

Another interesting finding of this study is that PLWH with undetectable viremia had elevated vascular inflammation markers, independent of traditional risk factors. This is important as sICAM-1 and sVCAM-1 have been found to predict risk of future CVD events [9,10]. We also showed for the first time that long-term use of ART yielded a significant reduction of sICAM-1 and sVCAM-1 among African PLWH, suggesting that host factors and not ART toxicity may be directly involved in promoting vascular inflammation in this setting. Our findings are in keeping with a report from US-based study that showed significant reduction of levels of sICAM-1 and sVCAM-1 after a year of ART [42]. Our observation of elevated vascular inflammation markers among virally suppressed African PLWH is noteworthy because the majority had very low prevalence of CVD risk factors compared with PLWH in previous studies [43–45]. Thus, given that sICAM-1 and sVCAM-1 are expressed early in atherosclerosis, prospective studies correlating these markers with future cardiovascular events may offer insight into their prognostic value in African PLWH [46,47].

The drivers of this immune dysregulation in SSA are less clear and could be multifactorial [48–51]. The fact that long-term use of ART was associated with reduced levels of all biomarkers suggests features unique to PLWH per se and not ART as the likely contributors. Traditional CVD risk factors have been associated with HIV-associated inflammation [52–54]. In this study, only hypertriglyceridemia was associated with elevated sCD14, sICAM-1, and sVCAM-1 consistent with previous reports [6,13]. We found no influence of any other traditional CVD risk factors on the biomarkers. This finding, together with the fact that our PLWH did not have a higher burden of CVD risk factors than the HIV-negative participants further suggests that features unique in HIV may have provided the stimulus. More studies from Africa are warranted to confirm these findings.

The main strength of our study is the ability to assess the effect of HIV on a wide range of biomarkers and the thorough assessment of CVD risk factors that allowed us to control for confounders that were not accounted for in previous studies from Africa. The relatively matched HIV-negative persons allowed for direct comparison between groups and identification of factors that may be particularly unique for PLWH in SSA. Inclusion of equal number of women in this study also makes our results more generalizable. We acknowledge certain limitations to our study. We did not adequately assess the effect of individual ART drugs. We did not include data on other known CVD inflammatory risk factor [i.e., high sensitivity-C-reactive protein (hsCRP)]. However, based on previous reports demonstrating positive correlation between hsCRP and monocyte/macrophage activation markers, we hypothesize that hsCRP will be elevated among PLWH [21]. Future studies are needed to confirm this. As with any cross-sectional study, we cannot infer causation or control for unmeasured confounders.

In summary, monocyte/macrophage activation and vascular inflammation persist despite viral suppression and restoration of CD4+ T-cell count in African PLWH. Long-term receipt of ART resulted in significant reduction of vascular inflammation. Traditional risk factors such as hypertension and diabetes were not strong predictors of the immunological dysregulation observed during ART in this setting. Our findings have important implications for African PLWH and healthcare professionals. In addition to focusing on guideline-recommended HIV treatment, anti-inflammatory therapies may be necessary to prevent immune activation and vascular inflammation associated with chronic HIV-infection in this setting. Future studies are urgently needed to test whether anti-inflammatory therapies are able to prevent this immune dysregulation and improve health outcomes of African PLWH on long-term ART.

Acknowledgements

We thank Paul Macharia, Geoffrey Omondi, Victor Omodi, and Ana Gervassi, for their contribution. This project was supported by National Institutes of Health (NIH) grant R21TW010459, R21TW010459-02S1 from the Fogarty International Center (FIC), EDCTP2 programme supported by the European Union grant TMA-2016-1598-Kenya CVHIV, and Washington/Fred Hutch Center for AIDS Research, an NIH-funded program under award number AI027757. T.M.T. is supported by grant 3R01AI134130-03S1 from the National Institute of Allergy and Infectious Diseases. The funders did not participate in data collection or any activity that is directly related to the execution of the research. T.M.T., C.F., S.J.P., S.T.P. contributed to the conception and design of the study, the supervision, data acquisition, analysis and interpretation, and the critical revision of the article. J.S.Z., C.N.W., J.K., G.S.B., J.N., S.M. contributed to the data analysis, the data interpretation, the article drafting, and the critical revision of the article.

Conflicts of interest

There are no conflicts of interest.

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Stephanie T. Page and Carey Farquhar contributed equally as senior authors.

Keywords:

Africa; cardiovascular diseases; HIV; inflammation; monocyte activation

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