Even when people living with HIV are on an effective antiretroviral (ARV) regimen and have a fully suppressed viral load, they still have a 50 to 100 percent greater risk of heart disease compared with the general population. Scientists reached this conclusion after factoring out other potential drivers of cardiovascular disease (CVD), such as smoking, diabetes, cholesterol and blood pressure.

In other words, ARV treatment notwithstanding, HIV itself appears to lead to heart disease.

Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), reflects that after two decades of the phenomenal life-extending success of combination ARV treatment, “We’re starting to see a disturbing increase in the risk for cardiovascular events, such as heart attacks and stroke in people with HIV.”

This increase in CVD rates will likely accelerate as the HIV population ages, a looming threat that adds urgency to the scientific community’s quest to come up with solutions to such a second-wave of HIV-related disease and mortality.

As it happens, a potent, readily available and relatively simple way of mitigating CVD risk among people with the virus may already be on the market. Statins, the commonly prescribed class of drugs used to lower cholesterol and reduce the risk of CVD and death among the general population, may have the power to strike at some of the root causes of heart disease in people with HIV.

Even when suppressed to undetectable levels by ARVs, HIV may lead to a state of chronic inflammation in the body, which scientists believe contributes to the increased rates of various diseases related to aging, including heart disease. Researchers know that chronic inflammation leads to plaque buildup in the veins and arteries, an unhealthy process known as atherosclerosis that can cause a heart attack or stroke. Such plaque accumulation may occur 10 to 15 years earlier among people who have HIV compared with those who don’t.

Research in HIV-positive individuals has found that statins don’t just lower cholesterol, they also reduce indicators, known as biomarkers, of inflammation. The drugs also have been shown to reduce plaque buildup and, of course, cholesterol, which tends to be higher in the HIV population.

Together, these findings might suggest that taking a statin is a no-brainer for HIV-positive individuals. But here’s the rub: The available body of research on statins’ effects among the HIV population hasn’t been able to provide gold-standard scientific proof that there is a direct cause and effect between statin use and actual reduced rates of heart disease, such as heart attack and stroke, as well as death rates among people with HIV.

“There’s some data on biomarkers, and there’s some data on plaque,” says Steven Grinspoon, MD, a professor of medicine at Harvard, where he studies cardiovascular disease among people with HIV. “But if you merge it all together and you ask, ‘Do we know for sure that statins will reduce [CVD] risk?’ we don’t know the answer to that.”

The major study of statins among people with HIV

There is considerable urgency in the HIV research and treatment community to answer questions definitively about the potential power of statins to help reduce HIV-associated health risks. Consequently, the NIAID and the National Heart, Lung, and Blood Institute have launched a massive, global randomized-controlled trial of statin use among people with HIV.

Called REPRIEVE, the trial started recruiting participants in April 2015 and thus far has enrolled about 2,600 out of a planned 6,500 HIV-positive participants at 100 research sites around the world, including in the United States. To qualify for the trial, participants must be 40 to 75 years old, on ARVs for at least six months, have no history of heart disease, including heart attack or stroke, not be taking a statin and have a low to moderate risk for developing heart disease. Women are strongly encouraged to participate to help researchers better tailor treatment guidelines specifically for this group.

The participants will be randomized to receive a placebo or the statin Livalo (pitavastatin), which those who designed the trial chose in part because it is considered safe for use with all ARVs and is very good at reducing inflammation.

By studying any differing health outcomes between the treatment and placebo groups, the researchers hope to learn whether statins can lower the risk of heart disease and death among people with HIV and whether Livalo’s effects on inflammation may yield other health benefits, such as lower rates of cancer and kidney disease. Additionally, they hope for new insights into the complex mechanisms involved in HIV’s contribution to heart disease risk and how exactly statins may combat this effect.

The REPRIEVE investigators also hope the data they gather can help them develop a heart-disease risk calculator specific to HIV-positive individuals. The treatment guidelines for statins released in 2013 made clear that there was not enough research available to make recommendations for people with HIV in particular. Additionally, researchers have found that standard CVD risk calculators tend to underestimate risk in the HIV population, leading clinicians with less effective guidance for reducing heart disease risk among their patients living with the virus.

Grinspoon, who is the principal investigator of REPRIEVE, says the trial is progressing well so far and that researchers haven’t seen any major safety issues associated with statins among the study population.

Fauci in particular is bullish about the study, stating that his team thinks “there is a very good chance that” statins lower the risk of heart disease events such as heart attack and stroke. Nevertheless, like Grinspoon, he acknowledges that the results of major randomized-controlled trials have proved common medical assumptions wrong in the past. So as prudent scientists, the two of them eagerly await the results of this particular major study.

Weighing statins’ risks and benefits, known and theoretical

Results from REPRIVE likely won’t come until 2020, unless the benefits of statins among the study population become so clear so fast that it becomes unethical for the placebo arm to keep running because the study investigators would be denying participants a drug with a proven potential health benefit for them in particular.

In the meantime, people with HIV concerned about their risk of heart disease are left to weigh the risks and benefits, both known and theoretical, of statins among people with HIV. Should they go on a drug that U.S. treatment guidelines (written for those without HIV) may say is not for them and possibly experience side effects without any benefits? Or should they take it on faith that they’re protecting their health by taking a statin?

All drugs come with risks. But according to Grinspoon, the risks associated with statins “are relatively low.” Their main potential side effects are muscle pain and weakness, plus a smaller possibility of elevated liver enzymes (which indicate possible harm to the liver). Statins may also contribute to cognitive dysfunction (although the data are mixed on this) and increase glucose (sugar) in the body, which may cause diabetes (although the diabetes risk is apparently quite small, especially with Livalo). 

Statins also may clash with the body’s metabolism of some ARVs, in particular the so-called boosters, Tybost (cobicistat) and Norvir (ritonavir), which are included in various combination-tablet ARVs and which may raise the level of statins in the body.

Another potential drawback of statin use is that people who take them may become less motivated to make lifestyle changes to further prevent heart disease. Research suggests that as time passes, this mindset can lead people on statins more likely to become sedentary and obese, both of which are heart disease risk factors.

People with HIV commonly have other risk factors for CVD in addition to the virus, such as diabetes, high blood pressure and high cholesterol. The high rate of smoking among the HIV population is a critical risk factor. Research has found that people who have a fully suppressed virus thanks to ARVs double their risk of death by smoking and lose far more years of life to cigarettes than the virus.

Certain ARVs may contribute to heart disease risk; for example, for some, raised cholesterol is a potential side effect. Nevertheless, in 2015, definitive research from the global START trial found that there is in fact a net health benefit, including a lower risk of CVD, to starting HIV treatment early rather than waiting until the immune system begins to deteriorate.

Reassuringly, with the ever-expanding, ever-improving slate of approved ARV medications, health care providers have an increasing ability to prescribe regimens with the lowest associated increased risk of heart disease.

Take a statin? Join the trial and contribute to science?

“Many people, including me, give statins to patients who are on antiretroviral therapy or HIV infection because of the circumstantial and small-study data that indicate it’s beneficial,” says Fauci.

Joel Gallant, MD, who is the medical director of specialty services at Southwest CARE Center in Santa Fe, says some his HIV-positive patients are wary of the drugs because they’re concerned about side effects. So if he does prescribe statins to such anxious patients, he tends to start them on low doses. This easing-in allows them to acclimate to a statin and to process any misgivings they may have about the medication more gradually instead of simply jumping ship on a drug that may significantly benefit them.

“If a patient came to me really wanting a statin,” Gallant says, “I would give them a statin, discussing of course the modest risks and uncertain benefits. If they already had an elevated LDL cholesterol and/or a significant risk factor, I’d be even more positive about it.”

Appealing to the sense of altruism and community spirit among people with HIV in his recruiting pitch for the REPRIEVE trial, Grinspoon says, “We remind people that the HIV population, by jumping into clinical trials early and fast in the early part of the epidemic and participating in research, basically had the disease controlled. So we hope to be able to harness that enthusiasm in REPRIEVE.”

In the meantime, Grinspoon is chomping at the bit for the study’s data to pour in and give him and his research colleagues the opportunity to finally provide solid, HIV-specific guidelines about statin use. The ultimate goal is to make HIV an ever more manageable and less harmful infection.

For information on participating in the REPRIVE trial, click here. For a REPRIEVE information site geared specifically for women, who are strongly encouraged to participate, click here.

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