Baffling Rift Between Patients With HIV and the Right Statin

MEXICO CITY — The Framingham score, used to evaluate risk for a cardiovascular event, is low-balling the threat in patients with HIV, and conflicting results on the success of statins is perplexing specialists.

The contribution of HIV itself to cardiovascular disease is not clear, and it is hard to assess risk when "we have imprecise tools to do so," acknowledged Judith Aberg, MD, from the Icahn School of Medicine at Mount Sinai in New York City.

Aberg encourages her patients with HIV and heart disease to quit smoking, and she monitors them. But should she start them on a statin?

Clearly, the risk is not the same for a 50-year-old person newly diagnosed with HIV and starting on new drugs as it is for a 50-year-old who has had HIV for 30 years and was on all those previous metabolically toxic drugs, she pointed out.

But sifting through all the data is not easy.

After a presentation of data from the Rosuvastatin and HIV Trial here at the International AIDS Society 2019 Conference on HIV Science, Aberg pointed out how far the research has yet to go to identify patients who will benefit from statins.

That is the issue that prompted Janine Trevillyan, MD, from the University of California, Los Angeles, and her colleagues to design their Rosuvastatin and HIV Trial using the Framingham risk score.

The measure has been shown to underestimate risk in people with HIV at risk for heart attack or stroke (Circulation. 2018;137:2203-2214), she said, but they used it because "it's a tool people already use for decision making."

In their study, Trevillyan's team used a Framingham risk score between 10% and 15%, which is lower than the threshold that would trigger statin use in the general population.

The participants had to meet strict criteria so that anyone eligible for preventive care would be excluded: HIV viral suppression (<200 copies/mL), no recent use of lipid-lowering drugs, no history of heart attack or type 2 diabetes, no family history of high cholesterol, no very high blood pressure, no high total cholesterol levels, and no high high-density-lipoprotein-to-total-cholesterol ratios.

In the study cohort of 87 Australian and Swiss adults, 97% of the participants were male and 87% were white. Half were randomized to receive rosuvastatin (Crestor, AstraZeneca) and half to receive placebo.

Adding a Statin

The researchers used carotid artery intima-media thickness to test the impact of the statin.

Cardiovascular events began to emerge during the study period. One participant was diagnosed with type 2 diabetes, one with cerebrovascular disease, three had heart attacks, two saw their creatinine kinase levels rise, and then, toward the end of the trial, one participant had a stroke.

"That's what you'd anticipate, given a Framingham score of 10% to 15% with 100 individuals," Trevillyan told Medscape Medical News. "So we thought the patient population was at the level of risk that we were expecting."

Because it was a randomized controlled double-blind trial, the researchers had to wait the full 96 weeks to examine the intima-media thickness images and to see which participants had received rosuvastatin.

That was when they found that the participants with diabetes and cerebrovascular disease, one of the participants who had a heart attack, and one with a worrying rise in creatinine kinase were all in the rosuvastatin group. In the placebo group, there was little change from baseline in intima-media thickness.

After adjustment for age, sex, and baseline Framingham risk score, there was "no difference across the arms or between the arms at any point," but there was an increase in grade 3 and 4 adverse events in the rosuvastatin group, Trevillyan reported.

On the basis of these data, "the benefit of this intervention in people with HIV at low to moderate risk may not justify the potential harms," she told the audience.

Understanding the Results

After the presentation, Turner Overton, MD, from the University of Alabama at Birmingham, said he was reminded of the Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV Infection (SATURN-HIV) study, which showed that progression of common carotid artery intima-media thickness was 0.019 mm less in the rosuvastatin group than in the placebo group (AIDS. 2016;30:2195-2203).

But he pointed out that the cohort in SATURN-HIV "had smokers, some people were viremic, and a significant number were African American."

"You're right," said Trevillyan, who acknowledged that the Australian and Swiss participants her team looked at "are clearly not at the same risk as African Americans."

"The story here is that we need to pick the person who's going to benefit from the therapy, and it probably isn't going to be a blanket approach across the clinic," she added.

But finding the right risk scores to identify the right patients for the right statin, and tracking progress using the right tools, is still very much a work in progress, said Aberg.

The "right tool" might have been developed by Stefan Esser, MD, from University Hospital Essen in Germany, and his colleagues from the ongoing prospective observational cohort HIV-Heart study.

In a poster presentation, Esser reported data showing that a combination of traditional cardiovascular risk factors, such as diabetes and smoking, and the ratio of CD4 to CD8 T cells, history of an AIDS-defining illness, HIV diagnosis prior to 1996, and a detectable viral load is a more accurate predictor of cardiovascular events than traditional risk scores for patients with HIV.

Measuring Risk, Choosing to Treat

"A cardiovascular event is a multifactorial," Esser told Medscape Medical News, so detecting its risk in people with HIV is too. If you can do that, it could lead to "great success, because our patients are used to taking meds and they are used to understanding the importance of taking something when you are healthy."

And then there's the matter of finding the right statin for the right population.

Researchers assessed rosuvastatin in both SATURN-HIV and the Rosuvastatin and HIV Trial. Aberg and her colleagues tested the cardiovascular effects of a different statin, atorvastatin, in patients with HIV (J Clin Lipidol. 2017;11:61-69). And Aberg was also involved in a trial that looked at pitavastatin (Livalo, Kowa Pharmaceuticals) (Lancet HIV. 2017;4:e284-e294).

Pitavastatin is a newer drug, still under patent, and "the cleanest drug as far as drug interactions," she said. Like atorvastatin and rosuvastatin, pitavastatin is clinically effective at reducing low-density-lipoprotein cholesterol, said Aberg, who has been involved in writing statin guidelines for the HIV Medical Association, the National Lipid Association, and the Infectious Disease Society of America.

Rosuvastatin and atorvastatin are still first-line drugs for lowering lipids in people with HIV. Although they are both associated with some drug interactions, "they are the cheapest and most widely available on formularies," she pointed out.

But the approach to measuring cardiovascular risk in the scientific world has shifted since Trevillyan and her colleagues started the Rosuvastatin and HIV Trial.

SATURN-HIV and the Rosuvastatin and HIV Trial used coronary intima-media thickness to assess the effectiveness of statins, but coronary noncalcified plaque identified with coronary CT angiography has also been used (Conference on Retroviruses and Opportunistic Infections 2015, Abstract 136), as have surrogate measures of inflammation, such as interleukin-6 and CD4 and CD8 T-cells (J Clin Lipidol. 2017;11:61-69).

"If you read the newest guidelines, measurement of carotid intima-media thickness is not among the tools to assess CVD risk," said Aberg. The new standard is coronary CT angiography.

Specifically, a group of organizations — including the American Heart Association, the American College of Cardiology, the American Association of Cardiovascular and Pulmonary Rehabilitation, the Association of Black Cardiologists, and the American Diabetes Association — came together to issue comprehensive guidelines for the management of cholesterol (Circulation. 2018;139:e1082-e1143).

The guidelines list HIV as one of the chronic inflammatory disorders that indicate that a person at intermediate risk for heart disease might be at risk for a premature cardiovascular event. And they suggest that HIV enhances the chance that such patients could benefit from statins. But the guidelines do not mention carotid intima-media thickness.

The bigger issue, Aberg said, is that we don't know what we're looking for in patients with HIV.

In the past, HIV–heart disease research has focused on the lipid-laden plaques that build up in the arteries and eventually lead to a rupture that causes a heart attack or stroke.

"But when you have a plaque rupture, you form a clot," which is made up of platelets. The role of those platelets seems to be equal to the role of lipids, Aberg explained. "We've been focusing on the pathophysiology on one side" but not the other.

"Before deciding whether we need different thresholds for the institution of primary prevention and whether statin therapy in people with HIV can be recommended," we need to see data from the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) trial (NCT02344290), said Trevillyan.

The 7500 REPRIEVE participants have been randomized to receive either pitavastatin or placebo, and one-third of those participants are women.

The 96-month trial is ongoing because the number of cardiovascular events required to arrive at any conclusions has not yet been reached, said Aberg, who is a REPRIEVE investigator. In addition, a planned substudy on the mechanics of the progression of cardiovascular disease in patients with HIV will track the biomarkers most strongly associated with HIV risk.

"The thing about REPRIEVE is that it may actually show that statins aren't beneficial at certain risks," Aberg explained. "We're just missing a lot of the pathophysiology and understanding. What we really need now are the outcomes from that study."

The Rosuvastatin and HIV Trial was funded by the Swiss National Foundation and the Australian National Health and Medical Research Council, among others. Trevillyan reports receiving speaker fees from Gilead Sciences. Aberg reports serving on advisory boards for Janssen, Merck, and ViiV Healthcare. Esser reports no relevant financial relationships.

International AIDS Society (IAS) 2019 Conference on HIV Science: Abstract MOAB0201 (Trevillyan), presented July 22, 2019; abstracts TUPEB202 and TUPEB203 (Esser), presented July 23, 2019.

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