Secondary Logo

Journal Logo

Research Letter

HIV infection and arterial stiffness among older-adults taking antiretroviral therapy in rural Uganda

Siedner, Mark J.; Kim, June-Ho; Nakku, Ruth Sentongo; Hemphill, Linda; Triant, Virginia A.; Haberer, Jessica E.; Martin, Jeffrey N.; Boum, Yap II; Kwon, Douglas S.; Tsai, Alexander C.; Hunt, Peter W.; Okello, Samson; Bangsberg, David R.

Author Information
doi: 10.1097/QAD.0000000000000992



The expansion of HIV therapy to over nine million HIV-infected persons in sub-Saharan Africa has reduced morbidity and mortality from AIDS in the region [1], and is motivating increased attention to be paid to the long-term consequences of HIV [2,3]. In high-income countries, HIV infection is associated with increased prevalence of arterial stiffness [4–6], an important predictor of decreased quality of life, cardiovascular complications and mortality [7–10]. Although some preliminary data suggest that HIV infection might predispose to cardiovascular disease risk in sub-Saharan Africa [11–14], little is known about relationships between HIV infection and arterial stiffness in the region, where differences in genetics, higher rates of parasitic and other co-infections, and altered diet, smoking and physical activity are likely to impact the priority disease states. In this study, we assessed whether HIV infection is associated with arterial stiffness among people on stable antiretroviral therapy (ART) in rural Uganda.


Data for this analysis comes from the Ugandan Noncommunicable Diseases and Aging Cohort (UGANDAC) Study (NCT02445079), an ongoing cohort study of older-aged people living with HIV in southwestern Uganda [15], and an age and sex-matched, population-based control group of HIV-uninfected individuals enrolled from the clinic catchment area. HIV-infected participants were drawn from the UARTO cohort study, which has been described previously [16,17], and eligible if they were more than 40 years of age and had a minimum of 3 years of ART use. HIV-uninfected participants were recruited from Nyakabare Parish, located approximately 20 km from the clinic. Adults in the parish are part of a longitudinal community health survey. All parish residents are eligible for inclusion. We have achieved greater than 99% response rate, effectively making the study a whole-population survey. We randomly selected adults from the parish who were age and sex-matched to HIV-infected participants. After recruitment and informed consent procedures, an HIV test was performed to confirm their seronegative status.

Participants complete a questionnaire to assess smoking history, and undergo anthropomorphic measurements and blood collection for CD4+ cell count, viral load, lipid profile, and hemoglobin A1c testing (Bayer A1c Now+, Bayer Healthcare LLC, Whippany, New Jersey, USA). Our primary outcome of interest was an ankle brachial index (ABI) ≥ 1.2, a surrogate of systemic, calcification-related arterial stiffness, which has been correlated with increased risk of all-cause and cardiovascular mortality [7,18]. A research assistant who completed a 2-week training in cardiovascular diagnostics collected all ABI measurements using Doppler-detected (Summit Doppler, Wallach Surgical Devices, Trumbull, Connecticut, USA) systolic blood pressure of the brachial, dorsalis pedis, and posterior tibialis arteries bilaterally. We calculated ABI by dividing the highest of the four ankle pressures by the highest of the two brachial pressures [19].

We estimated the prevalence of arterial stiffness by sex and HIV serostatus, using a Z-test of proportions. We fit generalized linear models with a log link, specifying high ABI as the dependent variable, and adjusting for age, sex, body mass index (BMI), cumulative years of smoking, non-high-density lipoprotein cholesterol [20,21], and hemoglobin A1c. We fit additional models restricted to the following: participants less than 60 years old, to assess for evidence of early arteriosclerosis; and only HIV-infected participants to estimate associations between arterial stiffness and HIV-specific factors (CD4+ cell count and a current detectable viral load). Lastly, we included a sex-by-HIV interaction term to assess for differentials relationships between HIV infection and arterial stiffness between men and women. Statistical analyses were conducted with Stata, version 14 (StataCorp LP, College Station, Texas, USA). Study procedures were reviewed and approved by ethics review committees of Mbarara University of Science and Technology, the Ugandan National Council of Science and Technology, and Partners Healthcare. All participants gave written informed consent.


Approximately half of participants (105/205, 51%) were HIV-infected, with a median ART duration of 7 years (interquartile range, IQR 6.4–7.5), a median nadir CD4+ cell count of 122 (IQR 80–175), and 85/105 (81%) with an undetectable HIV RNA viral load (Supplemental Table 1, Both groups were 50% female and median age was 49 years (IQR 46–53). Participants in the HIV-uninfected control group were more likely to be current or former smokers (50 vs. 36%, P = 0.06), but had a similar median non-high-density lipoprotein cholesterol (107 vs. 113 mg/dl, P = 0.74) and median hemoglobin A1c (5.3 vs. 5.6%, P = 0.86).

The prevalence of vascular stiffness was 33% (17/51) among HIV-infected men, 18% (9/50) among HIV-uninfected men, 19% (10/54) in HIV-infected women, and 2% (1/50) in HIV-uninfected women (Figure S1, In multivariable models adjusted for cardiovascular risk factors, HIV infection was associated with an increased prevalence of arterial stiffness [adjusted prevalence ratio (APR) 2.86, 95% confidence interval (CI) 1.41–5.79, P = 0.003, Table 1]. This association was particularly pronounced among those less than 60 years old (APR 4.05, 95%CI 1.74–9.52, P = 0.001). We found no associations between nadir CD4+, current CD4+, or detectable viral load and arterial stiffness. The prevalence ratio of arterial stiffness by HIV-infection was 9.26 in women (19 vs. 2%) and 1.85 in men (33 vs. 18%), although the interaction term was not statistically significant (APR 5.00, P = 0.14).

Table 1
Table 1:
Generalized linear models estimating the relative prevalence of high ABI (>1.2) by known correlates of arterial stiffness.


HIV-infection is associated with a more than doubling in the prevalence of arterial stiffness in Uganda. Although we were not powered to discern a difference in association by sex, we found evidence of arterial stiffness in only 2% of HIV-uninfected women compared with nearly 20% of HIV-infected women. These associations have important implications for HIV programs in sub-Saharan Africa, home to over 25 million people with HIV infection, because arterial stiffness is strongly predictive of both cardiovascular events and all-cause mortality [9,10].

The pathophysiology of arterial stiffness in HIV infection is putatively caused by a combination of HIV-mediated endothelial dysfunction and viral infection of arterial smooth muscle [22,23]. The causative role of HIV replication is also supported by prior studies, which, in contrast to ours, detected an increasing risk of arterial stiffness with a decreasing nadir CD4+ cell count [5,24]. The lack of association seen in our study could be explained by the fact that over 80% of our study population had a CD4+ nadir less than 200. Alternatively, regional differences in genetics, diet, and locally relevant co-infections might also alter relationships between HIV-infection and cardiovascular disease risk. Our study also provides preliminary evidence of sex patterning in this setting. This finding requires confirmation, as prior studies in western populations comparing HIV-infected and uninfected groups have included few women [4] or have not assessed for an interaction effect by sex [5,25].

If our findings are corroborated, an important next step will be to identify modifiable behaviors or interventions for prevention and mitigation of HIV-associated arterial stiffness. Early initiation of ART might be preventive given prior associations between nadir CD4+ and arterial stiffness. Therapeutic options might also exist if ABI measurements were incorporated into routine HIV care. For example, avoidance of protease inhibitors could reduce risk [26], and 3-hydroxy-3-methylgutaryl-coenzyme A reductase inhibitors have shown promise in HIV-infected populations [27,28].


Funding: This study was funded by the National Institutes of Health (R21HL124712, K23MH099916, R56AI100765, R21AI078774, R01MH054907, P01AI027763, P01AI076174 and UM1 CA181255), the Harvard Center for AIDS Research, the Doris Duke Charitable Foundation, and the Sullivan Family Foundation. The authors also acknowledge salary support through K23MH096620. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author roles: Study design and data collection: M.J.S., J.H.K., R.S., L.H., V.A.T., J.E.H., J.N.M., Y.B., D.S.K., A.C.T., W.H., S.O., D.R.B. Data analysis and interpretation: M.J.S. Composed first draft of manuscript: M.J.S. Contributed significant editorial input to manuscript: J.H.K., R.S., L.H., V.A.T., J.E.H., J.N.M., Y.B., D.S.K., A.C.T., W.H., S.O., D.R.B. Approve of the final version of the manuscript: M.J.S., J.H.K., R.S., L.H., V.A.T., J.E.H., J.N.M., Y.B., D.S.K., A.C.T., W.H., S.O., D.R.B.

Presentation: This work was presented in part at the 2015 International AIDS Conference in Vancouver, Canada.

Conflicts of interest

There are no conflicts of interest.


1. World Health Organization. Global update on the health sector response to HIV. 2014. [Accessed 16 August 2015].
2. Greig J, Casas EC, O’Brien DP, Mills EJ, Ford N. Association between older age and adverse outcomes on antiretroviral therapy: a cohort analysis of programme data from nine countries. AIDS 2012; 26 (suppl 1):S31–S37.
3. Hontelez JA, de Vlas SJ, Baltussen R, Newell ML, Bakker R, Tanser F, et al. The impact of antiretroviral treatment on the age composition of the HIV epidemic in sub-Saharan Africa. AIDS 2012; 26 (suppl 1):S19–S30.
4. Lekakis J, Ikonomidis I, Palios J, Tsiodras S, Karatzis E, Poulakou G, et al. Association of highly active antiretroviral therapy with increased arterial stiffness in patients infected with human immunodeficiency virus. Am J Hypertens 2009; 22:828–834.
5. Schillaci G, Maggi P, Madeddu G, Pucci G, Mazzotta E, Penco G, et al. Symmetric ambulatory arterial stiffness index and 24-h pulse pressure in HIV infection: results of a nationwide cross-sectional study. J Hypertens 2013; 31:560–567.discussion 567.
6. Seaberg EC, Benning L, Sharrett AR, Lazar JM, Hodis HN, Mack WJ, et al. Association between human immunodeficiency virus infection and stiffness of the common carotid artery. Stroke 2010; 41:2163–2170.
7. O’Hare AM, Katz R, Shlipak MG, Cushman M, Newman AB. Mortality and cardiovascular risk across the ankle-arm index spectrum: results from the Cardiovascular Health Study. Circulation 2006; 113:388–393.
8. Allison MA, Hiatt WR, Hirsch AT, Coll JR, Criqui MH. A high ankle-brachial index is associated with increased cardiovascular disease morbidity and lower quality of life. J Am Coll Cardiol 2008; 51:1292–1298.
9. Mattace-Raso FU, van der Cammen TJ, Hofman A, van Popele NM, Bos ML, Schalekamp MA, et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 2006; 113:657–663.
10. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010; 55:1318–1327.
11. Peck RN, Shedafa R, Kalluvya S, Downs JA, Todd J, Suthanthiran M, et al. Hypertension, kidney disease, HIV and antiretroviral therapy among Tanzanian adults: a cross-sectional study. BMC Med 2014; 12:125.
12. Siedner MJ, Ng CK, Bassett IV, Katz IT, Bangsberg DR, Tsai AC. Trends in CD4 count at presentation to care and treatment initiation in sub-Saharan Africa, 2002-2013: a meta-analysis. Clin Infect Dis 2015; 60:1120–1127.
13. Ssinabulya I, Kayima J, Longenecker C, Luwedde M, Semitala F, Kambugu A, et al. Subclinical atherosclerosis among HIV-infected adults attending HIV/AIDS care at two large ambulatory HIV clinics in Uganda. PLoS One 2014; 9:e89537.
14. Fourie CM, Schutte AE, Smith W, Kruger A, van Rooyen JM. Endothelial activation and cardiometabolic profiles of treated and never-treated HIV infected Africans. Atherosclerosis 2015; 240:154–160.
15. Siedner MJ, Kim JH, Nakku RS, Bibangambah P, Hemphill L, Triant VA, et al. Persistent immune activation and carotid atherosclerosis in HIV-infected Ugandans receiving antiretroviral therapy. J Infect Dis 2015; [Epub ahead of print].
16. Hunt PW, Cao HL, Muzoora C, Ssewanyana I, Bennett J, Emenyonu N, et al. Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy. AIDS 2011; 25:2123–2131.
17. Siedner MJ, Lankowski A, Tsai AC, Muzoora C, Martin JN, Hunt PW, et al. GPS-measured distance to clinic, but not self-reported transportation factors, are associated with missed HIV clinic visits in rural Uganda. AIDS 2013; 27:1503–1508.
18. Resnick HE, Lindsay RS, McDermott MM, Devereux RB, Jones KL, Fabsitz RR, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004; 109:733–739.
19. Gerhard-Herman M, Gardin JM, Jaff M, Mohler E, Roman M, Naqvi TZ, et al. Guidelines for noninvasive vascular laboratory testing: a report from the American Society of Echocardiography and the Society of Vascular Medicine and Biology. J Am Soc Echocardiogr 2006; 19:955–972.
20. Arsenault BJ, Rana JS, Stroes ES, Despres JP, Shah PK, Kastelein JJ, et al. Beyond low-density lipoprotein cholesterol: respective contributions of nonhigh-density lipoprotein cholesterol levels, triglycerides, and the total cholesterol/high-density lipoprotein cholesterol ratio to coronary heart disease risk in apparently healthy men and women. J Am Coll Cardiol 2009; 55:35–41.
21. Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA 2012; 307:1302–1309.
22. Eugenin EA, Morgello S, Klotman ME, Mosoian A, Lento PA, Berman JW, et al. Human immunodeficiency virus (HIV) infects human arterial smooth muscle cells in vivo and in vitro: implications for the pathogenesis of HIV-mediated vascular disease. Am J Pathol 2008; 172:1100–1111.
23. Dube MP, Lipshultz SE, Fichtenbaum CJ, Greenberg R, Schecter AD, Fisher SD, et al. Effects of HIV infection and antiretroviral therapy on the heart and vasculature. Circulation 2008; 118:e36–40.
24. Ho JE, Deeks SG, Hecht FM, Xie Y, Schnell A, Martin JN, et al. Initiation of antiretroviral therapy at higher nadir CD4+ T-cell counts is associated with reduced arterial stiffness in HIV-infected individuals. AIDS 2010; 24:1897–1905.
25. Periard D, Cavassini M, Taffe P, Chevalley M, Senn L, Chapuis-Taillard C, et al. High prevalence of peripheral arterial disease in HIV-infected persons. Clin Infect Dis 2008; 46:761–767.
26. Schillaci G, De Socio GV, Pirro M, Savarese G, Mannarino MR, Baldelli F, et al. Impact of treatment with protease inhibitors on aortic stiffness in adult patients with human immunodeficiency virus infection. Arterioscler Thromb Vasc Biol 2005; 25:2381–2385.
27. Boccara F, Simon T, Lacombe K, Cohen A, Laloux B, Bozec E, et al. Influence of pravastatin on carotid artery structure and function in dyslipidemic HIV-infected patients receiving antiretroviral therapy. AIDS 2006; 20:2395–2398.
28. Lo J, Lu MT, Ihenachor EJ, Wei J, Looby SE, Fitch KV, et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV 2015.

Supplemental Digital Content

Copyright © 2016 Wolters Kluwer Health, Inc.