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Cardiovascular Update CROI 2018
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by Priscilla Hsue MD
Professor of Medicine, UCSF
The 25th Conference on Retroviruses and Opportunistic Infections was held on March 4-7, 2018 in Boston, MA.
Cardiovascular complications in HIV infection continues to be a key clinical issue in HIV and many studies were presented at CROI which included descriptions of cardiovascular disease in HIV, mechanistic studies to evaluate inflammatory pathways and imaging, and also interventional studies designed to lower CV risk.
Use of inflammatory or novel biomarkers to identify HIV-associated cardiovascular risk continues to be an area of investigation.
To this end, using samples from the START study, Baker and colleagues demonstrated D-dimer, IL-6, CD8 and CD4:CD8 ratio were strongly predictive of subsequent AIDS and serious non-AIDS events and the impact of IL-6 and D-dimer were additive when combined with CD4/CD8 ratio (oral session, Abstract 74). This same ratio was predictive of worsening ankle brachial index which is an assessment of peripheral vascular disease in HIV-infected individuals age > 40 years on stable ART (Chow D et al, Abstract 707). In analysis again from individuals in the START trial, IL-6 was independently associated with worsened arterial elasticity after full adjustment (β=0.52, p=0.003). ABI were not significantly different in the setting of HIV or HCV infection as compared to uninfected controls in the WIHS cohort, although the high PAD prevalence overall was noted (29% in HIV/HCV group, 28% in the HCV group, 27% in the HIV+ and 29% in uninfected controls (Cedarbaum E et al Abstract 701). Plasma TMAO a metabolite produced by the gut was associated with carotid artery atherosclerosis in the MACS/WIHS cohort (Shan Z Abstract 708).
In the Canadian HIV and Aging Cohort Study, IL-32, which is a gene which has immunoregulatory and inflammatory functions, was demonstrated to be higher in treated HIV and a ratio of delta and beta isoforms in a subset of individuals was correlated with atherosclerotic plaque volume (El-Far M et al, Abstract 709). Lower Th17 cells in a small subset of this cohort were correlated with presence of coronary artery calcification in the setting of HIV (Salinas T et al Abstract 682).
In a retrospective study of acutely infected individuals, NT-proBNP and Troponin T decreased after attainment of virologic control; both these indices were correlated with humoral and cellullar inflammatory activation suggesting that subclinical cardiac injury as ascertained by biomarkers can be reversible with ART (Schuster C et al Abstract 699).
The role of immune activation/chronic inflammation in CV risk in HIV as well as strategies to reduce these indices were also the subject of several abstracts. In the general population, lowering inflammation using an IL-1β inhibitor was shown to reduce CV events (Ridker P NEJM 2017) as well as incident lung cancer and lung cancer mortality (Ridker PM Lancet 2017); these findings suggest that lowering inflammation not only has an impact on atherosclerosis but may impact other disease processes such as malignancy. In the A5314, low dose methotrexate (LDMTX) was associated with a significant decrease in CD8 T-cell activation, but no change in inflammatory markers or endothelial function suggesting that the immunomodulatory impact of this medication is mediated through CD8+ T-cells (Hsue P et al Abstract 79); in a substudy, LDMTX may reduce arterial inflammation using FDG-PET/CT (Tawakol A et al, Abstract 684LB).
Focus on the CV risk associated with antiretroviral therapy continued to be a dominant theme at CROI. Initiation of antiretroviral therapy was borderline associated with greater carotid artery intima media thickness (IMT) over time in the first 48 weeks after ART initiation (Hileman, C et al Abstract 671). ART initiation was also reported to increase Lp(a) and allele-specific apo(a) levels in HIV-infected women in the WIHS cohort (Byambaa E et al, Abstract 672). Atazanavir or abacavir containing regiments were associated with an increased risk of calcified plaque (OR 1.47 with atazanavir) and non-calcified/mixed plaque (OR 1.45 with abacavir) even after adjustment for traditional risk factors (Kovari H et al, Abstract 670).
Impact of ART on platelets was the feature of several studies. Using in vitro studies, abacavir enhanced expression of platelet activation markers which may underlie the increased risk of MI that has been described (Taylor K et al Abstract 673). Animal studies demonstrated that the pro-thrombotic impact of abacavir was dependent on leukocyte purinergic P2X7 signalling (Collado-Diaz V et al Abstract 674). Change from ABC/3tC to TAF/FTC was reported to increase soluble glycoprotein VI which is linked to increased CV risk in the literature but may be related to platelet dysfunction in HIV (Mallon P et al Abstract 677 LB). This switch was also associated with lower platelet reactivity (Mallon P et al Abstract 80). Change from abacavir to other ART may impact CV risk in a modeling study assuming that smoking cessation is not 100% successful (Hsue P et al Abstract 692).
Use of imaging to ascertain the mechanism of HIV-associated cardiovascular disease was evaluated using CTA, IMT, and cardiac MRI. In the MACS cohort, lipid rich low attenuation plaque (LAP) was highest among HIV-infected individuals with viremia and non-calcified plaque volume increased more in the HIV infected group compared to uninfected (175mm3 for HIV+ vs. 112mm3 for HIV-, p=0.03, Post W et al Abstract 77). In the WIHS/MACS cohort, carotid IMT was not associated with mortality; however carotid artery plaque was associated with a 56% greater mortality risk (95%CI 1.13-2.15) ; this finding was more pronounced in HIV- individuals (Hanna D et al Abstract 78). Using cardiac MRI and CTA demonstrated increased coronary vessel wall thickness and impaired relaxation in the setting of HIV (Purdy J et al Abstract 700). Using cardiac MRI, women with HIV had more intramyocardial triglyeride content compared to controls (Toribio M et al Abstract 694), along with impaired strain and strain rate (Awadalla M et al, abstract 695). Among vertically infected individuals, median age of 24 years, decreased LV global longitudinal strain and global area strain were present even in the setting of normal LV ejection fractions as compared to uninfected controls (Capotosto, L et al, abstract 698).
Among individuals with reduced ejection fraction and heart failure, HIV infection was associated with a higher 30 day readmission rate along with all-cause mortality (Alvi R et al Abstract 696) and obstructive sleep apnea was common in HIV (Alvi R et al Abstract 697). In the HIV Heart Study, HIV-infected men had higher rates of CV events which included MI and SCD as compared to population matched controls (Esser S et al Abstract 691).
Cholesterol, lipid lowering, and HIV: Levels of proprotein convertase subtilisin/kexin 9 were elevated in HIV as compared to uninfected individuals (p=0.05) but did not relate to atherosclerotic plaque (Zanni M et al Abstract 681). Twelve weeks of pitavastatin therapy at 2mg/day was found to reduce proportions of patrolling monocyte and PD1+CD4+ T cells in a study of 24 suppressed individuals (Phuphuakrat A et al Abstract 689). Among HIV-infected individuals in the DC Cohort Study, using ATP III, ACC/AHA, and NLA guidelines, approximately half of HIV-infected participants were eligible for statins but actual statin prescriptions and achievement of treatment goals were substantially lower (Levy M et al Abstract 690). In the US Military HIV natural History Study, only 55% of individuals eligible for statin therapy were currently prescribed a statin, including only 58% of diabetics (Larson D et al Abstract 705). A randomized controlled study of dietary intervention using a Mediterranean diet (containing nuts, plant stanols, soy, beans and oats) was associated with reduced in LDL and BP as compared to standard guidelines to reduce saturated fat in a study of 60 HIV-infected individuals (Stradling C et al Abstract 703). In a trial of young HIV-infected individuals, ART naïve who were heavy drinkers, zinc supplementation for 18 months did not change Reynolds CVD risk score (Freiberg M et al Abstract 693).
Studies on HIV and CVD and CV risk in resource limited settings were the topic of several studies at CROI. In a cohort of young adolescents, echocardiographic imaging showed that ejection fraction and diastolic function appeared to be similar among HIV+ on ART and uninfected controls in Cape Town, South Africa (Mahtab S et al Abstract 702). Comparing integrated vs. referred traditional risk factor management for HIV-infected adults on ART in Swaziland both demonstrate suboptimal retention but both strategies demonstrated improvement in risk factor control (Rabkin M et al Abstract 710). Hypertension was common in HIV-infected adults in Botswana (Mosepele M et al Abstract 711) and individuals who are treated and suppressed have better blood pressure and diabetes control (Manne-Goehler J et al Abstract 712). Screening for hypertension may be integrated as part of HIV testing (Drain P et al Abstract 715). The Pan African Pulmonary Hypertension Cohort had 134 cases of pulmonary hypertension overall; HIV-infected individuals had better exercise tolerance at presentation but had excess mortality compared to uninfected individuals (Thienemann F et al Abstract 714). Arterial stiffness was more common in HIV vs. controls in a rural African cohort (Vos A et al Abstract 716); similarly, 46.8% of treated and suppressed HIV-infected Thai individuals had evidence of detectable coronary calcium (Chattranukulchai P et al Abstract 718). Using modeling techniques, the prevalence of hypertension among individuals living with HIV in South Africa is estimated to be 46% (Osetinsky B et al Abstract 717).
The spectrum of cardiovascular disease in HIV continues to play a key role among individuals on ART and among HIV-infected individuals in resource limited settings - an issue that is predicted to continue as well as increase in the future. The underlying mechanism of HIV-associated cardiovascular disease along with biomarkers of risk, and treatment strategies (both traditional risk factor along with HIV-related or other) are being evaluated with purpose of identifying individuals at risk, reducing risk and optimal therapy that may be unique in the setting of HIV.
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