Can Statins Prevent CVD in HIV? Look to REPRIEVE

I wrote a year ago about the “new direction” that the NIH was planning for HIV/AIDS research.¹ In that blog posting, I quoted the Director of the National Institute of Allergy and Infectious Diseases (NIAID), Carl Dieffenbach, PhD, about plans for the end of NIH-funding of large-scale antiretroviral clinical trials. Director Dieffenbach stated that the Division of AIDS (DAIDS) would be focusing on smaller trials, including pilot trials of potential therapies for “curing” (ie, eradicating) HIV. I also quoted Director Dieffenbach as saying that the AIDS Clinical Trials Group (ACTG) would be trying to “partner” with other funders to continue to pursue research on other areas of relevance to HIV infection.

One of the “hottest” areas within HIV research over the last 5 years has been on cardiac complications of HIV. Accumulating data suggest that HIV-infected persons are at higher risk of myocardial infarction than HIV-negative persons, even when HIV is maximally suppressed on antiretroviral therapy. It is now estimated that cardiovascular disease (CVD)-related deaths are 1.5 to 2.0 times higher in HIV-infected persons than in HIV-negative persons.² While the reasons for the increased risks are not entirely known, it appears that pro-inflammatory markers of immune activation, which are elevated in HIV-infected persons, increase the rate and extent of atherosclerosis.³ Unfortunately, there are no proven ways to reverse this risk, although cigarette-smoking cessation would help, by removing one important independent risk factor for MI.

In addition to being at increased risk for CVD-related events as a result of being infected with HIV, HIV-infected persons are living longer, and increasingly not dying of “traditional” HIV-related complications. Furthermore, an HIV-infected person’s life expectancy on antiretroviral therapy still does not equal that of an HIV-negative person-in part because of the increased risk for CVD-related events. Consequently, it would be of tremendous public health benefit if it were shown that a pharmacologic intervention could significantly reduce the risk of MI and other CVD-related events in the HIV-infected population.

Importantly, though, twice the risk of a CVD-related event (compared to HIV-negative persons) still isn’t that great of a risk in the short-term (say 1 to 3 years). Consequently, to show any clinically relevant reduction in risk for CVD-related events, what is needed is a very large, long-term, multicenter, randomized trial. Such trials are inherently very expensive and time-intensive. It certainly did not seem likely to me, a year ago, that the ACTG, at a time of cost-cutting and budget reductions, would be able to undertake such an effort in the foreseeable future. And, of course, there would always be the need to find a product promising enough to study before investing the time and money in the project.

There actually is such a product, or at least class of products, that has that potential. And what is that class?

It is the statin class, comprised of drugs that are particularly effective at lowering low-density lipoprotein (LDL) cholesterol levels and reducing the risks of CVD-events by that mechanism. It turns out that the statins also are effective at lowering levels of various pro-inflammatory markers of immune activation. In a small study, among individuals in the general population with LDL cholesterol <130 mg/dL and moderate inflammation (defined as high sensitivity C-reactive protein >2 mg/L), statin therapy resulted in a 44% reduction in CVD events.⁴

To date, though, there have not been any large-scale randomized trials of statin therapy to prevent CVD events in HIV-infected persons. Until now: The NIH recently announced plans to fund REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV). The trial is jointly sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and the NIAID, with pharmaceutical industry support from Kowa Pharmaceuticals America. The trial will randomize 6500 HIV-1 infected men and women ≥40 and ≤75 years of age, with CD4+ T-cell counts >100 cells/mm³, who do not meet current guideline thresholds for recommended statin initiation (no known clinical CVD, LDL <190 mg/dL and 10-year CVD risk score estimated by Pooled Cohort Equations <7.5%) to therapy with pitavastatin (Kowa Pharmaceuticals America) versus placebo. Total duration of follow-up will be 6 years: the study will be powered to detect a 30% reduction in the time to first CVD event in the statin arm compared to the placebo arm. Approximately 100 to 130 sites are planning to participate, both within the ACTG and at “select” non-ACTG sites: majority will be in the United States. Enrollment is scheduled to start within the next couple of months. Participants will be seen and assessed, on average, every 4 months.

While there are a number of planned substudies (eg, intensive cardiovascular monitoring), the bottom line is that the NIAID is following through on its stated goal of partnering with other groups to pursue clinically relevant large-scale clinical trials that have the potential to positively impact public health and likely change the practice of medicine.

Personally, I can’t think of a better use of taxpayer-funded research dollars.

References:

• MacArthur RD. Whither HIV Clinical Research? ConsultantLive.com. February 24, 2014.
• Smith C, et al. Factors associated with specific causes of death amongst HIV-positive individuals in the D:A:D Study. AIDS. 2010;24(10):1537-1548.
• Hsue PY, Deeks SG, Hunt PW. Immunologic basis of cardiovascular disease in HIV-infected adults. J Infect Dis. 2012;205 (Suppl 3):S375-S382.
• Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207.