Protecting One’s Heart
The REPRIEVE study aims to prevent cardiovascular disease
by Chael Needle

heart3[dropcap]A[/dropcap]s people are living longer with HIV, researchers have been increasingly attending to questions surrounding the management of comorbidities, such as kidney disease, liver disease, and cardiovascular disease (CVD). Some of those questions have focused on treatment, of course, but some have focused on prevention, and, in a new study focused on cardiovascular disease (CVD), specifically who is at risk.

We know that individuals living with HIV on the whole are at greater risk than the non-HIV-infected population. However, that higher risk may fly under the clinical radar if physicians only look at traditional risk factors (think, smoking, high blood pressure, diabetes, high cholesterol), instead of also attending to non-traditional risk factors that come with living with the virus, such as plaque build-up and chronic inflammation, which may play a part in increasing the risk for CVD.

What if we could reduce the risk of CVD before patients progressed to something like a stroke or myocardial infarction with a prevention strategy that addressed non-traditional risk factors alongside traditional ones?

Seeking this answer, REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) holds the potential to significantly change long-term health outcomes in an aging HIV-positive patient population for the better.

A first-of-its-kind, landmark study, REPRIEVE is currently in the process of enrolling 6,500 participants across approximately 100 clinical research sites, mostly in the U.S. The primary endpoint of the randomized trial is to see if a daily dose of pitavastatin can reduce the risk of CVD and prevent vascular events in HIV-positive individuals with relatively low traditional risk factor scores and who would not otherwise be prescribed statins for high cholesterol and/or known heart disease. Participants will be counseled about reducing traditional risk factors, of course, but the spotlight will be on non-traditional ones.

Primarily funded by the NIH Heart Lung and Blood Institute (NHLBI) and supported by the NIH Division of AIDS (DAIDS), REPRIEVE is enrolling HIV-positive individuals who are between the ages of forty and seventy-five; on stable antiretroviral therapy for at least six months prior to entering the study; do not have a history of CVD (including heart attack or stroke); and have not been recommended for statin therapy or currently using a statin. The study is not excluding for viral load and accepting patients with a CD4 count over 100, thus seeking a broad study population that can produce generalizable results.

REPRIEVE’s co-principal investigator Steven Grinspoon, MD, a leading researcher, whose work has advanced our knowledge of HIV-related metabolic and cardiovascular complications as well as the treatment of lipodystrophy, talked with A&U about the impetus for the study, study eligibility, and the potential of pitavastatin as a preventative strategy for CVD.

“Prior studies done over the last few years suggest an increased risk in cardiovascular disease in patients living with HIV on the order of fifty to 100 percent in carefully constructed cohorts comparing HIV vs. non-HIV [patients], controlling for traditional risk factors. Traditional risk factors seem to account for about twenty-five percent of the excess risk but non-traditional risk factors may account for a preponderance of the risk,” said Dr. Grinspoon. “We want to be able to prevent the disease in those who do not know they have the [cardiovascular] disease and to prevent that excess risk by a strategy that attacks both traditional risk factors and, at the same time, non-traditional and potentially inflammatory risk factors.”

Previous research, including his own, brought these non-traditional risk factors, such as premature plaque build-up and chronic inflammation, to light.

Plaque can build up within the arteries and eventually harden and narrow them, reducing blood flow; and/or the plaque can erode and rupture, exposing its contents, cholesterol, calcium, inflammatory cells, and other material, to the bloodstream.

In an earlier study, whose results were published in AIDS in 2013, researchers, including Dr. Grinspoon, used coronary CTA (computed tomography angiography). Data “showed that the presence of plaque in HIV patients, carefully matched to non-HIV patients, is about twice as high, approximately sixty percent vs. thirty percent, with an atypical high-risk morphology,” noted Dr. Grinspoon about the variation and degree to which the plaque is vulnerable to rupture, which may be the culprit behind increased cardiovascular events.

“We may have a situation where relatively young patients are having this atypical plaque with vulnerable features in association with inflammatory markers. And these are people for whom the disease is sub-clinical—they don’t have known clinical disease; they’re not having symptoms. That’s exactly the kind of patient we want to recruit into REPRIEVE and try and prevent that sub-clinical disease from becoming clinical, from becoming an actual event like a myocardial infarction.”

ASCVD (atherosclerotic cardiovascular disease) risk scores, which are based on new 2013 American Heart Association guidelines for CVD, will be calculated for study candidates. The risk scores are based on traditional risk factors. “We are taking patients at less than ten percent—those in a low to moderate range for whom statins would not be clinically necessarily indicated, so there’s equipoise in the study to look at that group for whom there’s no definitive recommendation for statins, whose doctor may not prescribe them but for whom we think they may be useful [to prevent CVD].”

REPRIEVE is also focusing on the age range of forty to seventy-five in order to focus on those who would potentially maximally benefit from the preventative strategy. Noted Dr. Grinspoon: “Where the relative risk really ticks up strongly is in patients over forty, and particularly between forty and seventy is the greatest preponderance of excess risk in the HIV vs. non-HIV [patients]….”

Using pitavastatin is a strategy “designed to both lower traditional risk factors like lipids, etc., but also to simultaneously reduce inflammatory markers which we think are contributing to the excess risk,” said Dr. Grinspoon, explaining that pitavastain, the newest in the statin class, was selected for the trial because it is metabolized in such a way—glucoronidation as compared to CYP metabolism, to be specific—that its bioavailability is not affected by antiretroviral therapy. Neither does pitavastatin affect the bioavailability of antiretrovirals. Both can do their work in peace, in this regard.

Additionally, notes Dr. Grinspoon, much was learned about pitavastatin from the INTREPID trial that makes it a good candidate: It is highly efficacious when it comes to lowering cholesterol and does so very safely, without aggravating glucose like some of the earlier statins, which have been associated with increased blood sugar levels and thus increased risk for the development of Type 2 diabetes.

REPRIEVE is also tailoring its study to account for statins’ known effect on liver function. “Any statin can affect liver function but this is rare [as emphasized in new statin guidelines]. Once you exclude patients with significant liver disease, statins are unlikely to have a significant impact on liver function.” REPRIEVE is thus excluding participants with significant liver dysfunction. “By design patients entering REPRIEVE will have reasonably good liver function, minimizing the chance of adverse effect. Nonetheless, to be cautious, we are checking liver function at one month and twelve months. We have an algorithm in place to manage any liver toxicity that emerges in individual patients, but we think it is extremely unlikely. We have over 600 patients in the trial so far, and we have not seen any major impact on safety thus far, so we’re pleased.”

REPRIEVE is also looking beyond cardiovascular endpoints. “We have a hypothesis that statins, by reducing inflammation, will improve kidney function, liver function, and other non-cardiovascular endpoints.” Dr. Grinspoon continued: “In addition we have a substudy of 800 people out of 6,500 enrolled in REPRIEVE. Those 800 are getting CT angiography at baseline and two years and we’re hypothesizing that statins will reduce plaque in relation to events and also in relation to inflammatory biomarkers that we’re studying, including monocyte and T-cell activation. In this way, we hope we’ll be able to identify certain biomarkers that can help predict the response to statins, such that we can use those biomarkers to screen people in the future who might benefit from statin therapy.”


As mentioned, the trial is still enrolling and those interested in participating can log on to: The URL of the trial’s informational website is:


Chael Needle wrote about switching regimens in the November issue. Follow him on Twitter @ChaelNeedle.