Daily Statin Cuts Cardiovascular Risk in HIV

Statins should be considered for primary prevention in people living with HIV who are at low-to-moderate risk of cardiovascular disease, according to final data from the REPRIEVE trial that show pitavastatin therapy is associated with a significantly lower risk of cardiovascular events than placebo.

"There was a significant 35% lower risk of major adverse cardiovascular events after a median follow-up of 5.1 years " said Steven Grinspoon, MD, from Massachusetts General Hospital and Harvard Medical School in Boston, who presented the final analysis of data from the REPRIEVE trial on Monday at the International AIDS Society Conference on HIV Science (IAS) in Brisbane, Australia.

The results were simultaneously published in The New England Journal of Medicine. The primary endpoint of major adverse cardiovascular events included a composite of outcomes that included cardiovascular death, stroke, myocardial infarction, hospitalization for unstable angina, and transient ischemic attack among those treated with pitavastatin compared with placebo (95% CI, 0.48 - 0.90; P = .002).

The REPRIEVE trial was halted earlier this year for efficacy after an interim analysis pointed to a significantly lower rate of cardiovascular events in the treatment group.

The international double-blind, placebo-controlled trial randomly assigned 7769 people with HIV infection, who were at low-to-moderate risk of cardiovascular disease, to either 4 mg daily of pitavastatin calcium or placebo.

The secondary outcome — a composite of major cardiovascular events and all-cause mortality — also showed a significant 21% reduction in risk with pitavastatin treatment compared with placebo (95% CI, 0.65 - 0.96).

Cardiovascular Events in HIV

HIV infection is an independent risk factor for cardiovascular disease, Grinspoon pointed out, and those living with HIV have about double the risk of myocardial infarction and stroke compared to the general population.

"There's an unmet need for people living with HIV who have low to moderate traditional risk, for whom HIV is even considered a risk equivalent but for whom no primary prevention strategy has been tested in a large trial," Grinspoon said during an interview with Medscape Medical News.

Those enrolled in the study had a 10-year Atherosclerotic Cardiovascular Disease risk score ranging from 2.1% to 7%, with a median of 4.5%. While LDL cholesterol levels at baseline ranged from 87-128 mg/dL, the study showed a similar reduction in cardiovascular risk regardless of LDL.

"These are types of people who, if they came to the doctor's office right now before REPRIEVE, they would largely be told your risk score is not really making you eligible for a statin," Grinspoon said.

He explained that what is most interesting about the reduction in risk is that it was nearly twice what would be expected with LDL lowering, based on what has previously been seen in statin trials in non–HIV-positive populations.

"I think the data are suggesting that it's certainly in part due to the reduction in LDL — that is very important — but it's also due to other factors beyond changes in LDL," Grinspoon said. He speculated that the statin could be affecting anti-inflammatory and immune pathways, and that this could account for some of the reduction in cardiovascular risk, but "those data are cooking, and they're being analysed as we speak."

In a substudy analysis of REPRIEVE, Markella Zanni, MD, associate professor of medicine at Harvard Medical School and Massachusetts General Hospital, focused on the women in the clinical trial.

Women's Risk

In REPRIEVE, 31.1% of the study population were women. Zanni and her team investigated whether there are differences in the way HIV affects the risk of developing atherosclerotic cardiovascular disease in women compared with men.

They found that women have both higher levels of inflammatory markers, such as IL-6, C-reactive protein, and D-dimer, but a lower prevalence of coronary artery plaques than men.

"This finding represents an interesting paradox given that high levels of select inflammatory markers have been associated with coronary artery plaque, both among women living with HIV and among men living with HIV," Zanni explained.

She says the researchers were hoping to further explore whether inflammation is fueling the increased risk for atherosclerotic disease, and particularly the higher risk evident in women living with HIV compared to men.

"Women living with HIV should discuss with their treating clinicians heart risks and possible prevention strategies, including statin therapy coupled with healthy lifestyle changes addressing modifiable, traditional metabolic risk factors" she said.

Time for Primary Prevention?

All patients in the study were on antiretroviral therapy and investigators report that pitavastatin does not interact with these medications. The median CD4 cell count was 621 cells/mm³, and 87.5% of participants had an HIV viral load below the lower limit of quantification.

Participants were enrolled from 12 countries including the United States, Spain, Brazil, South Africa and Thailand, and around two thirds were non-White. Individuals of South Asian ethnicity showed the biggest reduction in cardiovascular risk with pitavastatin treatment.

There was a 74% higher rate of muscle pain and weakness in the pitavastatin group — affecting 91 people in the treatment arm and 53 in the placebo arm — but the majority were low grade. The rate of rhabdomyolysis of grade 3 or above was lower in the statin group, with three cases, compared with four cases in the placebo group.

Commenting on the findings, Laura Waters, MD, a genitourinary and HIV medicine consultant at CNWL's Mortimer Market Centre in London, UK, said that while HIV infection was considered a risk factor for cardiovascular disease, risk calculators don't specifically adjust for HIV infection.

"Now that we've got effective HIV drugs and people can enjoy normal life expectancy, cardiovascular disease is a particular issue for people with HIV," she said.

Waters, who was not involved with the study, suggested that people living with HIV should discuss the use of statins with their doctor, but she acknowledged there are some barriers to treatment in people living with HIV. "It's another pill and when it's a borderline [decision], it is easy to say, 'I have a think about it,' " she said, with the result that statin treatment is often deferred.

The REPRIEVE study was supported by grants from the National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare. Grinspoon declared institutional grants from National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare and consultancies unrelated to the study. Zanni reports no relevant financial relationships.

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