Cardiovascular disease and other non-AIDS defining events
Satyajit Das, University Hospital Coventry
Several studies at CROI 2013 looked at the pathogenesis and treatment of myocardial infarction and the outcomes of the treatment of cardiovascular disease (CVD) in HIV patients including an important oral presentation session. 
No evidence of premature ageing effect in HIV positive patients
Similar to some other conditions including diabetes, hyperlipidaemia and rheumatoid arthritis, HIV positive people are at higher risk of developing serious age-related co-morbidities including myocardial infarction and kidney and liver disease. It is still unclear whether HIV positive patients experience these conditions at similar or younger ages compared to HIV negative individuals and this is often discussed under the contentious concept of accelerated and premature ageing.
Keri Althoff and colleagues from the Veterans Ageing Cohort Study (VACS) compared mean age at diagnosis for myocardial infarction (MI), end stage renal disease (ESRD) and non AIDS defining cancers, and also compared their incidence by HIV status. 
Premature ageing was defined as differences in mean age at MI, ESRD and cancer diagnosis. All analysis were adjusted for race, sex and body mass index (BMI), alcohol use, cigarette smoking, hepatitis C infection, anaemia and diabetes. Myocardial infarction and end stage renal disease analysis only were adjusted for hyperlipidaemia, lipid lowering medication, hypertension, anti hypertensive medications and statin use.
The analysis was based on data collected from 2003 to 2008 on >100,000 patients with HIV positive cases matched by age, race and ethnicity 1:2 to HIV negative controls from the same cohort. HCV was more common in HIV positive people (35% vs 15%) but diabetes (17% vs 25%), hypertension (25% vs 38%) and dyslipidaemia (36% vs 44%) was more common in HIV negative people.
In the HIV positive group, 19% had a CD4 count <200 cells/mm3, 61% had undetectable viral load (<500 copies/mL) and 25% had an AIDS diagnosis. PI-based and NNRTI-based were each used by about 45% of people on ART. Mean age was 55 (+/- 8) years.
Mean age for each of the primary endpoints are detailed in Table 1 and although incidence rates remained higher for HIV positive vs. negative people, there were no differences in the adjusted analyses for age at diagnoses for MI and ESRD with the marginally lower age for cancers (0.7 years) unlikely to have clinical significance.
In conclusion HIV positive individuals had a greater rate of MI, ESRD and HIV associated cancers compared to HIV negative individuals.
There was no difference in mean age or adjusted mean age at MI and ESRD by HIV status. There was a modest difference at the age of non AIDS defining cancers in HIV patients (about 6 months younger in HIV positive groups). There was higher incidence of Hodgkin’s disease but over all no difference in the incidences of other HIV associated or non-AIDS defining cancer rates in HIV patients.
|HIV pos (yrs)||HIV neg (yrs)||adj. mean difference, years (95% CI)||aIRR vs HIV neg (95% CI)|
|HIV related cancer **||54.9||57.8||-0.57
** HIV-associated cancers were defined as anal, lung, liver and oral/pharynx cancers and Hodgkin lymphoma.
Even when a small age difference was found, the different risk factors and pathogenesis in HIV positive people are likely to explain this which is very different to the less scientific concept of premature ageing.
An analysis by Kathy Petoumenos from DAD group also found limited evidence of accelerated risk of cardiovascular disease (CVD) in HIV positive patients. 
The study hypothesised that accelerated ageing in HIV positive patients would mean an accelerating risk of CVD with older age, and that the increased risk per year older would be higher in D:A:D relative to the results from risk equations developed for the general population (Frammingham, CUORE, ASSIGN). The researchers included 24,323 men (man age 41 years) prospectively followed in the D:A:D study (approximately 139,000 patient years of follow up) who had data collected on conventional CVD risk factors but who had no prior CVD events.
Primary events included 474 MIs, 683 cases of coronary heart disease and 884 cases of cardiovascular disease events. Crude event rates for each of these endpoints was 2.29, 3.11 and 3.65 per 1000 PYFU at age 40-45 and 6.53, 11.91 and 15.89 at age 60-65 years. They showed that there was a slowly accelerating risk of cardiovascular disease for year older and which was somewhat raised compared to the general population based on the equations for cardiovascular disease. The relative risk with MI was not different between D:A:D and the general population. The researchers did not find evidence of accelerating risk of cardiovascular disease with age in their study population.
Adjustment for younger age of HIV cohorts compared to HIV negative general population controls appears to explain much of the difference seen in studies that previously reported younger age at diagnosis of non-AIDS events in HIV positive people.
Use of coronary CT angiography to detect early noncalcified plaque in asymptomatic patients
Two oral presentations reported on the incidence of coronary artery calcification in HIV patients.
Wendy Post and colleagues from the Multicenter AIDS Cohort Study (MACS) investigated the association of age with subclinical coronary atherosclerosis (Noncalcified Coronary artery Plaque (NCP) in a cross sectional observational study in 873 MSM (n=571 HIV positive and 302 HIV negative) enrolled in four US urban cohorts. 
NCP is an early stage of atherosclerosis but is more serious than established calcified plaque as it may be more prone to thrombus formation and plaque rupture. Gradual expansion of sub-clinical plaque are less associated with myocardial infarctions (MI) and sudden coronary deaths (SCD) than cute plaque rupture accounts for 75% of MI and 50% of SCD.
All men received non-contrast cardiac computed tomography (CT) scans with 660 eligible patients also receiving coronary CT angiography to detect NCP and mixed plaque, and stenosis. Plaques were graded and scored by degree of stenosis, size and composition. Participants were aged 40 to 70 years, without prior cardiac or coronary surgery and weighed less than 300 pounds (a limitation for CT scans). HIV positive patients were mostly (88.6%) on ART, 80% of whom had undetectable viral load, were younger (by about 30 months), with a lower BMI (26.1 vs 27.4). They were more likely to be current smokers (32% vs 21%), and have dyslipidaemia (lower LDL and HDL and higher trigylcerides).
Coronary plaque of any type was present in 77% of HIV positive vs 62% of negative men. This difference in this rate was significant after adjusting for CVD risk factors (OR 1.80; p=0.009). There was a similar association with NCP (p=0.002), and a trend for mixed plaque (p=0.053), but no association for either calcified plaque or stenosis >50%.
In both groups, any plaque was associated with older age [OR (95%CI) per year: 1.13 (1.09-1.17) vs 1.06 (1.03-1.09), respectively; both p<0.0001] but with NCP this was only significantly associated with age in HIV positive group (p=0.002). By contrast, associations between age and the presence of any type of plaque did not defer by HIV status.
These analysis however adjusted for age and race but not CVD risk factors. There was no association between the presence of plaque or NCP with traditional HIV risk factors including nadir CD4 count, viral load, a history of AIDS and duration of HAART exposure. Nadir CD4, detectable viral load, duration of ART were independently associated with stenosis >50%.
Although the degree of coronary calcium burden in the general population is predictive of CVD events, these people tend to also have high rates of non-calcified plaque. However, in the Q&A session, it was pointed out that while the prevalence of coronary calcium was higher in HIV positive patients, both groups in this study had similar rates of coronary calcium burden.
A second study, presented by Steven Grinspoon from Massachusetts General Hospital also used CTA to investigate morphologic features of coronary plaques in 102 HIV positive to 41 HIV negative controls, prospectively enrolled and matched for traditional CVD risk factors (but all asymptomatic for CVD disease), looking at the relationship with markers of immune dysregulation. 
Similar to the previous study, this group have also reported higher rates of subclinical plaque, mostly non-calcified, in HIV positive compared to HIV negative patients and that additionally this is associated with higher levels of circulating sCD163 (a marker of activated macrophages).
The study analysed more than 2500 coronary segments with previous identified plaque (out of a maximum 18 per patient). Duration of HIV infection was 13 years (+/- 6.5) and 95% were on antiretroviral therapy (80% undetectable), with a mean duration of 7 years (3-11) on ART.
The prevalence of high-risk attenuated or positively remodeled plaque was significantly higher for in the HIV positive group (7.9% vs zero for the highest risk three feature analysis, p=0.02), with HIV patients having higher numbers of plaques (0-4 plaques, p=0.01), with a significant association with HIV status in the adjusted analysis (p=0.02).
Several inflammatory and immune markers were higher in the HIV positive group including IL-6 (p=0.01), LPS (p=0.0004) and sCD163 (p=0.0007) but not d-dimer (p=0.93), CRP (p=0.49) or MCP-1 (p=0.13), with a trend for sCD14 (p=0.08) but in the multivariate model, only sCD163 retained a strong association with risk of vulnerable plaque (p=0.009).
In the question session, the non-prediction of age and smoking was explained by these traditional factors having a close association with calcified but not non-calcified plaque and that these are relatively young patients (mean age 44) who have had little time to build up coronary calcium.
This group also studied a small group of elite controllers, compared to HIV positive suppressed patients and HIV negative controls, but reported few differences, perhaps to low numbers under-powering comparisons. 
It is also notable that a late breaker poster from the same group reported similarly higher plaque (34.7 vs 12.0%, p = 0.04) and correlation to increased sCD163 (p=0.006) in 60 HIV positive women (median age 47, HIV duration 15 years, 84% undetectable), compared to 30 HIV negative controls. 
These studies were important for their focus on patients with sub-clinical atherosclerosis. The highlight specific potential risks for HIV positive patients related to immune activation that are additional to traditional risks seen in general population studies and which occur even with suppressed viral load.
Coranry calcium burden, which may be the most predictive for future events was not different by HIV status in the MACS cohort.
While coronary artery calcification score is important in the general population non-calcified plaques have been found to be important as well.
Non-calcified plaques appear to be more vulnerable for getting dislodged from the arterial wall and get thrombus in the distal places. These finding may have implications for the risk of myocardial infarctions and optimal timing for CVD screening for ageing in HIV positive patients.
Post-MI survival in HIV positive patients
Several posters also looked at clinical responses in HIV positive people who experienced MI.
The D:A:D study reported dramatic improvements in short-term mortality outcomes post-MI over time in this important HIV cardiovascular study, that appeared to be related to a higher use of invasive CVD procedures (ICP). 
The study included 844 people with an MI, 84% of who were on ART and 61% had viral load <50 copies/mL. This group was 91% male, median age 50, median CD4 count 444 cells/mm3 (IQR 297, 666) and 66 (8%) had had a prior MI.
Over a median follow-up of 33 months, 88 (10%) patients experienced a further MI, and 281 (33%) patients died. There were 172 deaths during the first month after the MI (short-term mortality rate: 20.4%). At least one ICP in the first month was used by 419 patients (60% of those surviving >1 day) (31 bypass, 402 angioplasty, 1 carotid endarterectomy).
Over time, mortality rates in the first month dropped from 26.4% in 1999-2002 to 8.2% in 2009-2011 with use of early ICP increasing from 43% to 73% in the earlier vs later periods respectively.
A US study concerned that HIV positive people might have poorer access to the emergency services that are essential in ensuring rapid responses to MIs reported similarly positive outcomes irrespective of HIV status, though the numbers of HV positive patients was relatively low. 
In this registry 30/646 patients (4.5%) were HIV positive, with HIV positive patients being younger (50 vs. 62 years,p<0.01), significantly more likely to use illegal drugs (43% vs 13%,p<0.01) and with a trend towards fewer traditional cardiovascular risk factors (hypertension, 34% vs 53%,p= 0.06 and dyslipidaemia, 14% vs. 30%,p= 0.09).
There were no differences in the rates of angioplasty, stent placement or in-hospital mortality between the two groups and after multivariate adjustment, HIV positive patients were significantly more likely to use emergency services (OR 3.03, 95% CI: 1.16 – 7.88).
A second multivariate analysis from the VACS study reported that HIV positive people had higher rates of heart failure compared to HIV negative patients, and that this resulted in significantly higher hazard ratios, there was no difference in outcomes related to whether ejection fraction was preserved or reduced. 
The improved immediate survival over time after MI in HIV patients is helpful and encouraging for both health workers and HIV positive patients.
Aspirin use in HIV positive patients
While there is increased risk of CVD in HIV positive patients, aspirin use has not been studied in this group. Sujit Suchindran and colleagues from Massachusetts General Hospital presented results from a retrospective a cohort analysis of around 3,700 HIV positive patients and 33,000 HIV negative controls without known baseline coronary heart disease, followed from 2000 to 2009 in a US healthcare cohort. 
They investigated use of aspirin whether it reduced incidence of cardiovascular disease. They found that aspirin use was lower in HIV patients, particularly men and those with highest cardiovascular disease risk. However, aspirin use had no obvious effect in reducing myocardial infarction in HIV positive patients compared to the HIV negative individuals.
Aspirin use was recorded as being slightly but significantly lower among HIV positive people compared to HIV negative controls (12.4% vs 15.3%, p <0.001) although the difference was driven by lower use by HIV positive men rather than women. It was more almost 50% lower amongst higher risk patients with two or more coronary heart disease risk factors (22.1% vs 42.4%, p <0.001), with similarly reduced use byt both HIV positive men and women.
In multivariate analyses, aspirin use was only associated with reduced risk of myocardial infarction amongst HIV negative patients with no association of protection in overall HIV group or any subgroup.
Aspirin use was lower amongst HIV positive patients compared to HIV negative patients with a greater relative difference amongst those with significant cardiovascular risk. Although benefit was not demonstrated in HIV positive patients, this was an observational study with potential for selection bias especially with data dependent on hospital inpatient and outpatient prescription registries.
In the absence of evidence from randomised studies, aspirin use should probably be considered in HIV positive patients for similar indications as the general population.
Unless stated otherwise, all references are to the Programme and Abstracts of the 20th Conference on Retroviruses and Opportunistic Infections, 3-6 March 2013, Altanta, GA.
- Cardiovascular Disease and Other Non-AIDS Events: Epidemiology and Pathogenesis. Monday 4 March, 4-6pm. Webcast:
- Keri Althoff et al. for Veterans Aging Cohort Study HIV+ adults are at greater risk for myocardial infarction, non-AIDS cancer, and end-stage renal disease, but events occur at similar ages compared to HIV– adults. 20th CROI, 2013 Atlanta, USA, Abstract 59. Atlanta, USA. First presentation.
- Petoumenos K et al. Increased risk of cardiovascular disease with age in men: a comparison of D:A:D with HIV– cardiovascular disease risk equations. 20th CROI, Atlanta, 2013. Oral abstract 61. Third presentation.
- Post W et al. Age and noncalcified coronary plaque in the Multicenter AIDS Cohort Study. 20th CROI, 3-6 March 2013, Atlanta. Oral abstract 62. Fourth webcast.
- M Zanni et al. Increased coronary atherosclerotic plaque vulnerability features on computed tomography angiography among HIV+ subjects vs matched HIV– controls. 20th CROI, 3-6 March 2013, Atlanta. Oral abstract 63. Fifth webcast.
- Post W et al. Elite controllers and coronary plaque in the Multicenter AIDS Cohort Study. 20th CROI, 3-6 March 2013, Atlanta. Poster abstract 758.
- Fitch K et al. Non-calcified coronary plaque and macrophage activation markers are increased in HIV+ women. 20th CROI, 3-6 March 2013, Atlanta. Late breaker poster abstract 185LB.
- Sabin C et al. Improvements in short-term mortality following myocardial infarction: the Data Collection on Adverse events of Anti-HIV Drugs Study. 20th CROI, 2013, Atlanta. Poster abstract 748.
- Cruz MD et al. Emergency medical service utilization and reperfusion times among HIV+ individuals presenting with ST-elevation myocardial infarction. 20th CROI, 2013, Atlanta. Poster abstract 751.
- Freiberg M et al. The risk of and survival with preserved vs reduced ejection fraction heart failure by HIV status. 20th CROI, 2013, Atlanta. Poster abstract 750.
- Suchindran SG et al. Comparison of aspirin use and incident myocardial infarction rates in HIV+ and HIV– patients in a large US healthcare system. 20th CROI, Atlanta, 2013. Oral abstract 65. Seventh presentation.