People with HIV are more likely to develop cardiovascular conditions, including atherosclerosis and peripheral artery disease, than their HIV-negative counterparts, researchers reported at the recent 25th Conference on Retroviruses and Opportunistic Infections (CROI 2018) in Boston. The mechanisms underlying increased cardiovascular risk related to HIV are not fully understood, but chronic immune activation and inflammation appear to play a role.
Atherosclerosis refers to narrowing and “hardening” of arteries due to the build-up of plaque on blood vessel walls. Over time the artery walls thicken, interfering with blood flow and forcing the heart to work harder. Plaque may damage blood vessel linings and leads to the formation of blood clots, which can break off and cause blockages.
Coronary artery disease affects the large arteries that supply the heart. In severe cases blockage can deprive the heart muscle of oxygen, leading to a myocardial infarction, or heart attack. Blockages in the arteries supplying the brain can lead to strokes. Peripheral artery disease affects vessels further away from the heart, especially in the legs.
Wendy Post of Johns Hopkins University and colleagues looked at the link between HIV and the development and composition of coronary plaque among participants in the Multicentre AIDS Cohort Study (MACS), a long-running observational study of gay and bisexual men living with and at risk for HIV in four US cities.
This cardiovascular sub-study included 313 HIV-positive and 235 HIV-negative men age 40 to 70 years (mean 54 years) who had not previously undergone cardiovascular procedures. In the HIV-positive group about a third were African American and 27% were current smokers. In the HIV-negative group 26% were black and 18% were smokers. About 40% were being treated for hypertension (high blood pressure) and nearly half were taking statins or other medications for elevated blood lipids. Almost all were on antiretroviral therapy (ART), 81% had an undetectable viral load, the median CD4 count was 652 cells/mm3 and 9% had a history of Aids.
The researchers used computed tomography scans with coronary angiography, an imaging technique that uses dye to visualise blood vessels, to analyse both calcium-containing plaque (a type more easily detected by scans) and non-calcified plaque at baseline and a median of about five years later.
At baseline, 30% of the men had no apparent plaque. Over time, 2% saw their plaque volume decrease, 20% stayed the same and 78% had worsening plaque. One third of the group without baseline plaque developed it during follow-up.
Overall, HIV-positive men had a greater increase in plaque volume compared with HIV-negative men. This was the case for both calcified plaque and non-calcified plaque. After adjusting for other factors, the association between HIV status and plaque progression was statistically significant for white men but not for black men. There was no significant difference in plaque progression between HIV-positive men with and without detectable viral load, showing that ART did not abolish the risk, Post said.
Post said that it is important to focus on the mechanisms that lead to plaque development and progression, which may include co-infections, inflammation and immune activation. Further studies should also look at reasons for the observed racial differences, as well as plaque progression in women.
Asked whether HIV-positive people might benefit from starting statins earlier than HIV-negative people, Post noted that the large REPRIEVE trial is currently looking at this question. Until then, people with HIV should follow statin use guidelines for the general population and make lifestyle changes such as smoking cessation.
In a related study, David Hanna of Albert Einstein College of Medicine in the Bronx, New York, and colleagues looked at the association between carotid artery atherosclerosis and mortality among HIV-positive and at-risk women in the Women’s Interagency HIV Study (WIHS) and men in MACS.
This analysis included 1,722 women and 1,304 men. In the WIHS group, 71% were HIV positive, the median age was about 40 years, 60% were black and about 45% were smokers. In the MACS group, 62% had HIV, the median age was about 50, about 30% were black and about 30% were smokers. About two-thirds of the women and the quarters of the men with HIV were on ART.
The researchers used ultrasound to measure carotid artery plaque in six different locations and common carotid artery intima-media thickness, or the thickness of the artery wall. They also measured arterial elasticity, or stiffness. At baseline, carotid plaque was more common in both HIV-positive and HIV-negative men (27% and 29%, respectively) than in their female counterparts (10% and 7%). Men also had higher arterial stiffness scores than women, but carotid intima-media thickness was similar regardless of sex or HIV status.
Over a median 10 years of follow-up, mortality rates per 1,000 person-years were 19.9 for HIV-positive women, 14.7 for HIV-negative women, 15.3 for HIV-positive men and 7.9 for HIV-negative men.
In an adjusted analysis, the presence of carotid artery plaque was associated with a 46% greater risk of death overall. The association was most pronounced for the men, with more than double the risk (hazard ratio [HR] 2.28), but it did not reach statistical significance for the women (HR 1.06).
People with the greatest arterial stiffness scores had a 45% greater overall risk of death than those with the least stiffness. In this case, the association was stronger for the women (HR 1.71) but not significant for the men (HR 1.11). Carotid intima-media thickness was not associated with mortality in either group.
Interestingly, the association between carotid plaque and mortality was stronger among HIV-negative women and men combined (HR 3.84) than it was among HIV-positive people (HR 1.37), as was the association between arterial stiffness and death, potentially owing to non-cardiovascular-related Aids deaths in the latter group.
In another study, Andreas Knudsen of Rigshospitalet in Copenhagen compared the risk of peripheral artery disease (PAD) in HIV-positive and HIV-negative people. PAD in the lower extremities starts as asymptomatic narrowing of the arteries but over time can lead to ulceration, gangrene and amputation, he noted.
This cross-sectional (single point in time) study included 908 people with HIV from the Copenhagen COCOMO cohort and 11,106 matched HIV-negative control subjects. About 85% were men, the median age was about 53 years and almost all were of European ethnicity. People in the HIV-positive group were less likely to have hypertension (48% vs 61%) but were twice as likely to smoke (28% vs 13%). Almost all HIV-positive people were on ART and 95% had viral suppression.
The researchers measured PAD using the ankle-brachial index (ABI), a ratio of blood pressure in the ankles and upper arms. In healthy adults, ABI is between 1 and 1.4, but gradually drops as PAD develops, Knudsen said. This study used an ABI cut-off of 0.9, which correlates with 50% blood vessel stenosis or narrowing. Symptomatic PAD was defined as pain when walking that stopped when standing still.
PAD was twice as common in the HIV-positive group compared with the HIV-negative group (12% vs 6%); 2% and 1%, respectively, had symptomatic PAD. However, the mean ABI score did not differ between the two groups (1.1 in each). After adjusting for other factors, having HIV increased the risk of PAD by about the same amount as smoking.
Older age, female sex, hypertension, diabetes and decreased kidney function were also associated with increased PAD risk in both the HIV-negative and HIV-positive groups. However, each 10-year increment in age doubled the risk of PAD in the HIV-positive group, while raising it by just 36% in the HIV-negative group.
Like Post, Knudsen said that the mechanism for increased PAD in people with HIV needs to be further explored, but in the meantime, management should focus on traditional modifiable risk factors such as smoking.
Abstract 1
HIV infection is associated with coronary atherosclerosis, especially non-calcified plaque (NCP) and mixed plaque; however, development and progression of atherosclerosis associated with HIV has only been shown with coronary artery calcium scanning, which cannot detect more potentially unstable plaques. We prospectively evaluated the association between HIV serostatus and the progression and composition of coronary plaque among men in the Multicenter AIDS Cohort Study (MACS).
We performed baseline and follow-up coronary CT angiography in 409 men (253 HIV+, 156 HIV-; median interscan interval=4.5 yrs). Calcified and NCP volumes, including lipid-rich low attenuation plaque (LAP), were measured in each coronary segment. We used Poisson regression to test the association between HIV serostatus and incident plaque among men without baseline plaque, and generalized gamma regression to test the association with progression among men with baseline plaque, adjusting for time between scans, demographics and CVD risk factors. We also evaluated plaque progression differences between HIV- men and HIV+ men with suppressed viral load (<50 copies/mL, ≤ 1 'blip' <500 copies/mL) and those with viremia during the inter-scan interval.
Mean age was 54 yrs (53 HIV+, 57 HIV-) and 32% were black (35% HIV+, 27% HIV-). 70% of HIV+ men were aviremic during the interval. There were 118 men (74 HIV+, 44 HIV-) with no baseline plaque. Incident plaque was seen in 36 (30%) men; 24 developed both NCP and calcified plaque (mixed plaque) and 12 developed only NCP. LAP developed in 27 men. HIV+ men had a greater adjusted incidence of NCP (IRR 2.13, p=0.03), LAP (IRR 2.84, p=0.05) and mixed plaque (IRR 3.09, P=0.01) than HIV- men. In addition, compared to HIV- men, the incidence of LAP was greatest among HIV+ men with viremia (IRR 5.4, p=0.009; aviremic men IRR 2.4, p=0.096). There were 291 men with baseline plaque (179 HIV+, 112 HIV-). Among men with the greatest NCP volume change, the adjusted increases were significantly greater among HIV+ compared to HIV- men (e.g. 80th %tile of change in NCP was 175 mm3 for HIV+ compared to 112 mm3 for HIV-, P=0.03), with similar trends for total plaque and LAP.
This is the first study to demonstrate that HIV infection is associated with an elevated incidence and progression of high risk coronary plaque and suggests the need for additional studies to determine the importance of controlling viremia to limit the excess burden of CVD events in this population.
Authors
Wendy Post, Sabina Haberlen, Long Zhang2, Mallory Witt, Lisa Jacobson, Todd T Brown, Frank J Palella, Lawrence Kingsley, Matthew Budoff
Abstract 2
Using carotid artery intima-media thickness (cIMT) measured by ultrasound as a surrogate marker for cardiovascular disease is standard, yet long-term studies of carotid artery ultrasound parameters predicting major health events in persons with HIV are lacking. We evaluated associations of carotid artery measurements with all-cause mortality in the Women's Interagency HIV Study (WIHS) and the Multicenter AIDS Cohort Study (MACS).
Participants without self-reported coronary heart disease underwent B-mode carotid artery ultrasound in 2004-2006, with measurement of 1) cIMT at the common carotid artery; 2) plaque (focal cIMT >1.5 mm) at the common or internal carotid arteries or carotid bifurcation; and 3) Young's modulus of elasticity, a measure of arterial stiffness. Participants were followed for a median 9 years (total 22,432 person-years), and death was ascertained by active surveillance and the National Death Index. Cox models estimated the association of each measure at baseline with time to death, controlling for HIV status and demographic, behavioral, cardiometabolic, and HIV-related factors. We tested interactions by cohort and HIV status.
Among 1,722 women (median age 40 years, 88% black or Hispanic, 71% HIV+, 62% on ART at baseline) and 880 men (median age 49, 35% black or Hispanic, 66% HIV+, 72% on ART), 10% (206 women, 83 men) died during follow-up. In adjusted analyses, cIMT was not associated with mortality. Presence of carotid artery plaque was associated with 56% greater mortality risk (95% CI 1.13-2.15) and varied by cohort (HR 1.25 among women, 95% CI 0.83-1.89; HR 2.48 among men, 95% CI 1.35-4.38; p for interaction 0.045). The highest quartile of Young's modulus, indicating greatest stiffness, was associated with 58% greater mortality risk compared with the lowest quartile (95% CI 1.05-2.38, p for interaction by cohort 0.29). While the association of plaque with mortality was more pronounced in HIV- vs. HIV+ participants (p for interaction=0.01), potentially owing to AIDS deaths in the HIV+ group, the relationship was statistically significant in each group (Table). The association of Young's modulus showed a similar pattern, but the interaction by HIV status was marginally significant (p=0.08).
Carotid artery measurements were independently associated with all-cause mortality in both HIV+ and HIV- persons. To our knowledge our study is the first to show that carotid artery plaque is predictive of major health events in HIV+ adults.
Authors
David B Hanna, Jee-Young Moon, Kathryn Anastos, Sabina Haberlen, Audrey French, Frank J Palella, Stephen J Gange, Mallory Witt, Seble Kassaye, Jason Lazar, Phyllis Tien, Lawrence Kingsley, Wendy Post, Robert C Kaplan, Howard Hodis
Abstract 3
Risk of cardiovascular disease (CVD) is higher among persons living with HIV (PLWH) than among the background population. Peripheral artery disease (PAD) is a manifestation of CVD that is less well-explored in PLWH with conflicting reports on prevalence and risk factors. Ankle-brachial index (ABI) is an excellent diagnostic tool for diagnosing PAD. In this study, we aimed to determine the prevalence and risk factors for PAD in PLWH compared to uninfected controls. We hypothesized that prevalence of PAD would be higher among PLWH than among controls and that HIV is an independent predictor of PAD.
PLWH aged ≥40 were recruited from the Copenhagen comorbidity in HIV infection (COCOMO) study. Sex and age matched uninfected controls were recruited from the Copenhagen General Population Study. Blood pressure, lipids, glucose, eGFR and hsCRP were measured. Questionnaires were used to obtain data on smoking history and medication. ABI was measured with the Doppler method. We defined PAD as ABI ≤ 0.9 and non-compressibility as ABI ≥ 1.4 and excluded the latter from PAD analyses. We assessed predictors of PAD using a logistic regression model adjusted for age, sex, smoking status, dyslipidemia, diabetes, hsCRP and hypertension.
Among 908 PLWH and 11,106 controls, the PLWH were slightly younger (median 52 vs 53 p=0.0010), had a lower prevalence of hypertension (48 % vs 61% p<.0001), but higher proportions of current smokers (28% vs 13% p<.0001) and persons with intermittent claudication (4 % vs 2 % p<.0001) than controls. PAD was detected in 112 (12% [95% 10-14]) and 623 (6% [95% 5-6]), respectively (p<0.0001); odds ratio (OR)=2.4 [95% 1.9-2.9], adjusted OR=1.7 [95% 1.3-2.3, p=.0002]. Furthermore, age, female sex, smoking status, hypertension, intermittent claudication, and kidney function were independently associated with risk of PAD, irrespective of HIV status (Fig 1). In PLWH, neither previous AIDS, CD4 nadir, CD4 count, CD4:CD8-ratio, HCV coinfection, cART nor duration of infection were associated with PAD. Interaction of HIV with age was borderline significant (p=0.0517).
Prevalence of PAD was higher among PLWH compared to healthy controls, and remained so after adjusting for common CVD risk factors. Our findings expand the evidence base that PLWH have excess arterial disease to also include PAD. The exact biological mechanisms causing this excess risk remain to be elucidated. Until then, focus on management of modifiable traditional risk factors is important.
Authors
Andreas D Knudsen, Jens D Lundgren, Marco Gelpi, Ashley Roen, Amanda Mocroft, Shoaib Afzal, Børge Nordestgaard, Henrik Sillesen, Andreas Ronit, Anne-Mette Lebech, Lars Køber, Klaus F Kofoed, Susanne D Nielsen
Aidsmap material
www.aidsmap.com/Research-sheds-more-light-on-cardiovascular-risk-in-people-with-HIV/page/3248843/
[link url="http://www.croiconference.org/sessions/hiv-infection-associated-progression-high-risk-coronary-plaque-macs"]CROI 2018 abstract 1[/link]
[link url="http://www.croiconference.org/sessions/carotid-artery-atherosclerosis-associated-mortality-hiv-women-and-men"]CROI 2018 abstract 2[/link]
[link url="http://www.croiconference.org/sessions/increased-risk-peripheral-artery-disease-persons-hiv-compared-controls"]CROI 2018 abstract 3[/link]