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Researchers anticipate results from REPRIEVE trial for CVD prevention in HIV patients
Although patients with HIV are living longer due to recent advances in treatment, other health issues in this population are becoming more evident.
Heart disease, in particular, has raised concerns among both cardiologists and infectious disease specialists. Prior research has demonstrated an increased risk for cardiovascular disease (CVD) in patients with HIV. In response, researchers launched the REPRIEVE trial to determine whether statins can reduce CV events in patients with HIV.
Two of these researchers recently spoke with Infectious Disease News about the possible association between CVD and HIV, and how the REPRIEVE trial may help physicians select the best care for their patients.
The following commentaries were excerpted from videos featured on Healio.com/ID. To watch the videos, scan the code below.
Carlos D. Malvestutto, MD, MPH, The Ohio State University College of Medicine
We know that patients with HIV have an increased risk for CVD. This is due not only to traditional risk factors, such as a higher prevalence of smoking, diabetes and hypertension, but also there is an excess risk independent of these traditional risk factors.
Several studies have shown that this increased risk in the HIV-infected population is somewhere between 75% and 100% higher than in uninfected people. This risk may be related to chronic immune activation. Chronic immune activation will lead to endothelial damage, [which] will eventually lead to CV events. In addition, we know that ART and specific classes are associated with an increased risk for dyslipidemias. For example, protease inhibitors in particular are strongly associated with an increase in [low-density lipoprotein] and triglycerides in HIV-infected participants.
How do we address this important issue in our patient population, particularly among those with normal lipids? There is a study that was done among the HIV-uninfected population called the JUPITER trial. Participants with normal lipids, but increased [C-reactive protein], a marker for inflammation, were randomized to receive either [Crestor (rosuvastatin, AstraZeneca)] or placebo. The study found a significant reduction in the risk of CV events and mortality among those who received rosuvastatin.
There is a new study currently enrolling patients. This is the REPRIEVE trial. This study is now trying to address a similar question in HIV-infected patients. The idea is to randomize HIV-infected participants with low-to-moderate CV risk using [the atherosclerotic CVD (ASCVD)] calculator risk estimator, [which predicts] CV events in the next 10 years. Participants with low risk will be randomized to receive either placebo or a statin. The statin medication selected for this trial is [Livalo (pitavastatin, Kowa Pharmaceuticals)]. This is a medication that was approved a few years ago and has been found to have minimal interactions with antiretrovirals because it is primarily metabolized through glucuronidation, and not through cytochrome P450. In addition, it has not been found to increase the risk of diabetes as much as other statins, and it seems to have good inflammatory reduction properties.
The trial is designed to enroll 6,500 participants who will be followed for a period of 6 years. The primary endpoints will be major adverse CV events as well as deaths. [Since] these events are rare, a very large trial is required. What we expect is that this trial will definitively answer the question of whether a statin used for its pleotropic properties, [or] anti-inflammatory properties, will cause a reduction in death and major CV events. There is also a mechanistic substudy that will include 800 participants to allow us to understand the mechanisms whereby CVDs are occurring and taking place in these participants.
We believe this is an important trial for our patients because they are living longer, and this is a major cause of death in our patient population.
Steven K. Grinspoon, MD, Harvard Medical School
[The REPRIEVE trial] is going to take 6 years to complete. [In the substudy], patients are going to have a coronary angiography performed or virtual angiogram, in which we’re going to look at the plaque. We’re going to determine whether this drug not only prevents events from happening, but whether it modulates and improves atherosclerotic indices, including the coronary plaque.
One interesting observation is the type of atherosclerotic disease in these patients. Typically, in non-HIV patients with CVDs, the plaque becomes calcified, or fibrotic. In HIV-infected patients, the plaque is usually not calcified. It’s typically fatty plaque that is vulnerable to rupture. This is a very, very distinct pattern that we aim to try and understand the etiology of, and whether it relates to inflammation, et cetera. This knowledge has led to studies investigating pathogenesis, which will hopefully lead to cure or prevention of this unique disease in HIV-infected patients.
Cardiologists have really worked over the years to forge collaborative links to infectious disease practitioners. I think there is an understanding among AIDS practitioners that with the use of highly active ART, AIDS is becoming a chronic, treatable condition. These practitioners are not so much exclusively focused on various infectious diseases, but are actually caring for the patient in toto, holistically, including for CV and other metabolic complications. Bringing cardiologists to the problem of CVD in HIV has really expanded our understanding of that problem and helping to treat the patients who are most at risk. It’s bringing a whole new toolset to investigations in this patient population. We’ve already had some great questions forged from these collaborations, and I suspect it will be a model for other diseases.
In general, we’ve had good success. The HIV community is behind us, which has been very gratifying to see. We’ve had some real positive uptake in the community. One potential problem is that some of the HIV patients already believe that statins work and may want to take them clinically as opposed to being in a trial. They do have a very good track record, but we emphasize that although the preliminary data suggest that they will work, there are no definitive data in HIV-infected patients. One has to be careful to always assess risk vs. benefit. There could be some side effects of these drugs in HIV patients on muscles and other things, so we have to work hard to convince the patients that the trial is perfectly placed with good equipoise and that we’re using a drug very likely to work, but one which has not been definitively proven to work yet.
One really good thing about the HIV-infected population is that they work really hard to participate in clinical trials. In fact, it is the very participation of that group in the seminal trials that has led to the eradication of infectious complications with the development of highly successful antiretroviral therapy. We are now working with the community and the HIV population to get them to also participate in this trial and again contribute to the eradication of this new complication in HIV. We are getting some positive feedback on our efforts in that regard.
Disclosures: Grinspoon reports being an investigator for the REPRIEVE trial and that his institution receives research funding from Kowa Pharmaceuticals. Malvestutto also is an investigator for the REPRIEVE trial.