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HIV and Cardiovascular Disease

June 2015

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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.1

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.2

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.3


Similar findings were reported by Dr. Chris Longenecker and Dr. Grace McComsey from the SATURN-HIV study (aka "JUPITER-HIV").4

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.5

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).

Table 1: Percent Changes in Primary and Secondary Endpoints at Week 12: rPI Switch vs Rosuvastatin
Endpoint Baseline Mean (SD) All Subjects (n=43) Change at Week 12 Mean (SD) Difference (95% CI) P Value
rPI switch (n=20) rosuvastatin (n=20)
Fasting lipids
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.6

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.7 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 study4 along with Janet Lo's atorvastatin study2 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%.

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This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.

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