HIV and cardiovascular disease
This year at CROI, there were over 30 abstracts on cardiovascular disease and HIV, which is a noticeable increase from prior years.
This included a plenary session given by Dr. Steven Grinspoon, MGH, as well as three oral presentations, and a special presentation by Dr. Monica Shah, regarding the National Heart, Lung, and Blood Institute High-Impact AIDS Research.
Use of statins and other lipid lowering drugs in HIV positive people
Dr. Grinspoon’s plenary session highlighted the work that his group has done evaluating the role of monocyte/macrophage activation in HIV-related vascular inflammation. He discussed the upcoming clinical trial that he is leading in collaboration with ACTG and NHLBI entitled REPRIEVE, which will evaluate the impact of pitavastatin on clinical outcomes among HIV-infected individuals. 
Indeed, a major focus this year was on studies investigating the impact of statin intervention in HIV positive people. Dr. Janet Lo reported on results from a randomised double-blind placebo-controlled study of 40 HIV positive people with evidence of increased arterial inflammation using FDG-PET and LDL <130mg/dL. 
Individuals were treated with atorvastatin ranging from 20-40mg daily or placebo for one year. Change in FDG-PET uptake of the most diseased segment of the aorta was not different between the two groups, although adequate images could only be compared in 21 patients. In contrast, atorvastatin therapy reduced non-calcified plaque volume as compared to placebo with a median change of -19.4% vs. 20.4% (p=0.009). Overall plaque volume decreased 4.7% with atorvastatin compared to an 18.2% increase with placebo. Direct LDL and lipoprotein-associated phospholipase A2 decreased significantly in the atorvastatin treated individuals. This study has now been published in Lancet. 
Similar findings were reported by Dr. Chris Longenecker and Dr. Grace McComsey from the SATURN-HIV study (aka “JUPITER-HIV”). 
This was a 96 week double-blind randomised clinical trial of 10 mg rosuvastatin daily vs placebo among HIV positive individuals with LDL-C less than or equal to 130mg/dL and evidence of heightened T-cell activation or increased inflammation. While CCA (common carotid artery) intima media thickness in the placebo group progressed significantly, it was unchanged in the statin group, with a mean difference between groups of 0.014 mm/year, and a between group p-value of 0.074 (p<0.05). There was no difference between the development of new plaque among those without plaque at baseline between the two groups, while there was a trend toward more detectable CAC in the statin treated group among those without CAC at baseline, (15% statin vs. 6% placebo, p=0.19).
The impact of switching ART compared to statin therapy was evaluated in by Dr. Baker and colleagues. 
This was a 12 week study of 43 individuals on a ritonavir boosted regimen who had either a detectable HIV RNA level or total cholesterol less than or equal to 272 mg/dL. Within the switch group, most individuals were changed to raltegravir, rilpivirine or unboosted atazanavir. The rosuvastatin treated individuals had greater declines in total cholesterol, LDL cholesterol, and total/HDL ratio as compared to the ritonavir boosted individuals who switched regimens, and there were non-significant decreases in both the Framingham score and DAD score in the HIV positive individuals on rosuvastatin. In contrast, the people who switched ART had greater decreases in VLDL and triglycerides as compared to the rosuvastatin treated patients. Individuals who switched regimens had more drug-related adverse events. (See Table 1).
|Endpoint||Baseline mean (SD)All subjects (n=43)||Change at week 12mean (SD)||Difference(95%CI)||p value|
|rPI switch (n=20)||rosuvastatin (n=20)|
|TC||6.2 mmol/L (1.2)||–8.7% (10.8)||–21.4% (19.2)||12.7% (2.9 to 22.5)||0.003|
|LDL||4.0 mmol/L (0.9)||–1.0% (20.0)||–29.9% (27.3)||28.9% (14.0 to 43.8)||<0.001|
|VLDL||1.1 mmol/L (1.1)||–37.0% (25.3||–15.0% (26.6)||22.1% (6.0 to 18.1)||0.006|
|HDL||1.2 mmol/L (0.3)||+0.3% (15.0)||+2.4% (12.1)||2.2% (–10.5 to 6.2)||0.574|
|Total:HDL ratio||5.3 (1.4)||–7.6% (14.1)||–22/7% (18.3)||15.1% (5.0 to 25.3)||0.002|
|TG||2.2 mmol/L (1.3)||–34.1% (28.0)||–9.8% (31.7)||24.3% (5.7 to 42.8)||0.005|
|Framingham score (10 yr risk)||13.7% (5.1)||–2.1% (2.7)||–3.5% (5.9)||–1.4% (–1.4 to 4.3)||0.080|
|D:A:D score (5 yr risk)||8.4% (4.6)||–0.5% (3.1)||–1.6% (3.2)||1.1% (0.9 to 3.1)||0.098|
|Study drug-related side effects||11 (55%)||1 (4%)||10 (51%)||0.001|
CI: confidence interval; TC total cholesterol. LDL low density lipoprotein, VLDL very low density lipoprotein, HDL high density lipoprotein.
The impact of the new ACC/AHA Cholesterol guidelines which were released in autumn 2013 was evaluated in two studies in the setting of HIV. Dr. Clement and colleagues used the Veterans Affairs (VA Clinical Case Registry, CCR), to evaluate the impact of the new guidelines among HIV positive veterans. 
She found that overall, 11.6% of HIV-positive adults (n=13,293 males) not previously eligible for statin therapy using the prior guidelines (ATP-III) would now be recommended for statin treatment using the new ACC/AHA guidelines (representing an increase from 53.3% previously eligible to 64.9% eligible).
Most of the increase was from individuals meeting criteria for primary prevention with 9.1% newly recommended based on the revised ASCVD risk score, 1.7% recommended base on diabetes, and 0.8% recommended due to CVD.
A similar study was performed by Dr. Susan Regan and colleagues in the Partners HealthCare System HIV longitudinal cohort of 2239 HIV positive adults.  In this Boston cohort, 41.8% were recommended for statin therapy using the new ACC/AHA guidelines as compared to 25.7% using the 2008 ATPIII guidelines and similar to the prior abstract, the most common indication for statin use was CVD risk of 7.5% using the new risk prediction algorithm.
Among individuals with a CVD event, statin therapy was recommended for 44% of individuals using ATPIII and 62% using ACC/AHA. Interestingly, despite more individuals being recommended for statin therapy, around 40% of patients with CVD events would not qualify for statin treatment using the ACC/AHA guidelines. This study underlies the issue that even among individuals with HIV, traditional risk factors only account for approximately 20% of cad and unknown factors which may be more prominent in HIV infection are likely not captured using traditional risk calculators.
So, should we as doctors prescribe statins for all HIV patients? Will statin target the inflammatory pathways of interest in HIV?
The data on clinical outcomes and statin intervention are largely mixed and will be the focus of the REPRIEVE study. Data from the SATURN study  along with Janet Lo’s atorvastatin study  suggest that inflammatory markers and immune activation are largely not reduced by statin therapy. New drugs for lipid lowering and inflammatory interventions are being evaluated by other ongoing clinical trials.
Payal Kohli and colleagues presented a post on PCSK9, a promising new target of pharmacologic inhibition that has had impressive results for lowering low-density lipoprotein-cholesterol (LDL-C) in the general population – and may prove to be a valuable therapy in HIV positive people. Patients with HIV are at high risk for CVD and tend to be difficult to treat due to drug-drug interactions with antiretroviral therapies and limited efficacy of stains. This group aimed to collect preliminary data on PCSK9 levels and its homeostasis in this small cohort study. They found that PCSK9 is elevated in HIV infection, with high levels of PCSK9 that was not been previously observed in studies with >20,000 patients. PCSK9 elevation was not related to HIV-specific parameters, such as viral load or CD4 count. They also showed, in a pilot study of six patients inadvertently enrolled into clinical trials of PCSK9 inhibitors, that PCSK9 inhibition with a monoclonal antibody was highly effective and appeared to be safe, with reductions in LDL-C of around 60%.
Predicting CVD risk in HIV positive people
To further investigate the issue of CVD risk prediction in HIV, investigators in Boston calculated the Framingham risk scores and ACC/AHA risk scores in the Partner’s Cohort (n=2270 patients) in a 3 year interval ending in 2009.  Risk scores were discordant in 17% of individuals with the ACC/AHA risk calculator predicting risk in 10% of patients and FRS predicting high risk in 7% of individuals. Both the ACC/AHA risk score and the FRS underestimated CVD risk in HIV patients, comparing 5-year observed to predicted event rates.
Four different risk calculators were compared in the HIV Outpatient Study which represents 2,392 individuals receiving care at 10 US clinic sites as of September 2013 and had a year of follow up, one assessment of cholesterol and two measurements of blood pressure. 
The Framingham point score, pooled cohort equation, systematic coronary risk evaluation and DAD equations were compared as shown in Table 2.
|HOPS participants (n=2,392)||10 years CVD risk estimation|
|Framingham point score (FPS)||Pooled cohort equations (PCE)||Systemeic coronary risk evaluation (SCORE)||D:A:D equation|
|Harrell’s C-statistic *||0.71||0.71||0.57||0.72|
|Expected events (E)||126||147||19||193|
|Observed events (O)||149||178||19||256|
* Harrell’s C-statistic assessed the ability of each prediction model to discriminate patients who did or did not experience incident CVD events.
Overall all four risk prediction equations underestimated the 10 year risk of CVD in this HOPS cohort of HIV positive adults in the U.S. The FPS, PCE, and D:A:D equations had moderate discrimination with a c-statistic ranging from 0.68 to 0.72 and SCORE had poor discrimination (c-statistic = 0.57).
The Veterans Aging Cohort Study Virtual Cohort (VACS VC) was used to evaluate the role of copy years of viraemia, CD4 years, and VACS index years (age, HIV-1 RNA, CD4, LFTs, Hg, platelet, creatinine, and known HCV infection). 
Among 12,131 individuals included in the analysis, three cumulative measures provided added information about risk of acute myocardial infarction: HIV viral load copy years (VCY), CD4 count years (CD4Y), and the VACS index years (VISI).
While all three cumulative measures predicted the studied outcome, VCY ≥63,000 copy years/mL (HR=4.17; 95%CI=3.59-4.85) and CD4Y3 (HR=5.61; 95%CI=4.56-6.90); patients with higher VACS Index score-years had the highest risk of AMI (VISY ≥250; HR=40.56; 95%CI=33.25-49.47).
The authors concluded that participants with the highest cumulative viraemia (in the upper quartile of viraemia copy-years) ran a 2.6-fold increased risk of MIs. Cumulative CD4 counts were not statistically significantly associated with an increase of MI incidence.
Participants in the highest quartile of VACS index score years ran a 4 times higher risk of MI incidence during the study.
These results showing that risk predictor algorithms developed in non-HIV populations do not apply to HIV infected individuals is not surprising. They do not take into account HIV-related features that likely contribute including ART, chronic inflammation, and immune activation. Interestingly, even the D:A:D calculator which was developed in HIV performed similarly to the other calculators demonstrating that even in HIV, one size does not fit all – suggesting perhaps differences in the HOPS patient populations as compared to the DAD individuals. Validation of HIV-specific risk calculators in different HIV cohorts will be needed in the future.
Further support for abacavir link to MI
Two studies from NA-ACCORD were also featured. Frank Palella and colleagues looked at recent abacavir use and incident MIs using MESA criteria in the North American Cohort (NA-ACCORD). 
There were a total of 301 incident MIs in 16,733 adults and 64,607 person-years of follow up. Recent abacavir use (defined as prescription within 6 months) was associated with an increased risk of MI (aHR 1.71; 95%CI 1.11 to 2.64) in an adjusted models that were analogous to ones used in DAD, and the results linking current abacavir use to MI risk is similar to the original DAD result reported in 2009. In the full study population in the adjusted analysis, the significance was lost. However, in the restricted population, the finding remained significant even after adjustment. Of note, this is the first study to show risk of ABC present among ART naive individuals initiating ART, which is a new contribution to the field. The controversy over abacavir seems to ebb and tide but has not gone away.
Daniel Drozd and colleagues from NA-ACCORD determined the incidence of adjudicated primary MIs distinct from secondary MIs and examined baseline risk factors for primary MIs. The Universal Definition of MI, includes primary (type 1) MIs due to atherothrombotic plaque, and secondary (type 2) MIs due to a mismatch in supply/demand – for example, troponin leak in the setting of sepsis. Seven NA-ACCORD cohorts were included in the study between 1996-2010, resulting in 24,919 individuals with 262 type 1 MIs and 205 type 2 MIs. Traditional risk factors, along with lower CD4 counts were associated with type 1 MIs. In contrast, sepsis, cocaine, respiratory failure, and hypertensive emergency were responsible for 50% of type 2 MIs.
This study is an important contribution as it is the first to acknowledge the differences in MI definitions which impact treatment and conclusions drawn from studies. For example, type 2 MIs are not usually treated with aspirin, beta blockers, statins etc but typically by addressing the primary issue – ie drug use, sepsis which is in contrast to type 1 MIs. The distinction between type 1 and type 2 MIs in HIV cohorts thus is a critical one and may underlie some of the contrasting data that has been previously reported in different cohort studies.
Impact of intestinal microbiota on CVD risks
Suman Srinivasa and colleagues described the association between a microbiota-derived precursor of TMAO, namely TMA, and coronary plaque. 
The study included 155 HIV positive individuals along with 67 HIV negative controls. Serum choline trimethylamine (TMA) and trimethylamine-N-oxide (TMAO) were assessed using mass-spectometry and cardiac CT angiography was used to assess coronary plaque. Among HIV positive patients, TMA was associated with number of plaques, calcified plaques, calcium score, plaque volume and mass and LPS. After adjustment for Framingham risk score, TMA remained significantly associated with total, calcified, calcium score, plaque volume and mass. After additional adjustment for LPS, TMA remained associated with total plaque segments, calcium score, and plaque mass. There was no association of TMAO to plaque in contrast.
Trimethylamine-N-oxide (TMAO) is metabolised by intestinal microbiota from dietary lipids. In HIV negative people, TMAO levels are associated with cardiovascular events.
Arjun Sinha and colleagues evaluated TMAO levels and carotid IMT in a small study from UCSF. 
The median TMAO levels were similar among HIV patients and controls; however, TMAO levels between HIV patients were similar to HIV negative patients with CAD. Traditional risk factors along with current ARV were associated with higher TMAO levels and TMAO was weakly associated with carotid IMT.
In summary, HIV and cardiovascular diseases were an expanding arena of investigation at CROI 2015.
The emphasis this year was on statin interventions, evaluation of the new ACC/AHA cholesterol guidelines in HIV, abacavir and risk of MI, comparison of risk calculators in HIV, and new markers of CV risk such as TMAO.
New event driven studies such as REPRIEVE and other smaller proof of concept studies designed to target inflammation in HIV are ongoing and NHLBI along with NIAID is committed to supporting studies in HIV with dedicated funding for HIV-related investigations.
Hsue P. HIV and Cardiovascular Disease: Report from 2015 CROI. natap.org. The full report includes additional slides and tables. This article in HTB was lightly edited for a print format.
Unless stated otherwise, all references are to the Programme and Abstracts of the 2015 Conference on Retroviruses and Opportunistic Infections (CROI 2015), 23-26 February 2015, Seattle.
- Grinspoon S. Cardiovascular disease in HIV patients: an emerging paradigm and call to action.
- Lo J et al. Statin therapy reduces coronary noncalcified plaque volume in HIV patients: a randomized controlled trial. Oral sbstract 136.
- Lo J et al. 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; (published online Jan 9)
- Longenecker C et al. Rosuvastatin arrests progression of carotid intima-media thickness in treated HIV. Oral abstract 137.
- Baker D et al. Rosuvastatin vs. protease inhibitor switch for hypercholesterolaemia: a randomised trial – the statin or switch (SoS) study. Poster abstract 733.
- Clement M et al. HIV-infected veterans and the new ACC/AHA cholesterol guidelines: got statins? Poster abstract 750.
- Regan S et al. Application of new ACC/AHA cholesterol guidelines to an HIV clinical care cohort. Poster abstract 734.
- Kohli P et al. PCSK9 Is elevated in HIV+ patients and may mediate HIV-associated dyslipidemia. Poster abstract 731.
- Regen S et al. Evaluation of the ACC/AHA CVD risk prediction algorithm among HIV-infected patients. Poster abstract 751.
- Thompson-Paul A et a. Cardiovascular disease risk prediction in the HIV Outpatient Study (HOPS). Poster abstract 747.
- Salinas J et al. Cumulative HIV care measures highly associated with acute myocardial infarction. Poster abstract 746.
- Palella F et al. Abacavir use and risk for myocardial infarction in the NA-ACCORD. Late breaker poster abstract 749LB.
- Drozd D et al. Incidence and risk of myocardial infarction (MI) by type in the NA-ACCORD. Poster abstract 748.
- Suman Srinivasa S et al. Calcified plaque burden Is associated with serum gut microbiota-generated TMA in HIV. Oral abstract 138.
- Sinha A et al, TMAO and HIV-associated atherosclerosis. Poster abstract 755.