- People with HIV are at heightened risk for heart attack and stroke
- Researchers enrolled over 7,000 people with HIV who were given daily pitavastatin or placebo
- Analysis found that pitavastatin reduced the risk of cardiovascular disease by 35%
Multiple studies have found that people with HIV are at increased risk for cardiovascular disease, particularly heart attack and stroke. This increased risk is driven in part by chronic HIV, which causes excess activation of the immune system and inflammation. HIV also causes unfavourable changes to cholesterol levels. Some people with HIV may have additional risk factors for cardiovascular disease, such as smoking, diabetes, drug use, excess weight and insufficient physical activity.
When used as directed, HIV treatment (antiretroviral therapy or ART) can reduce the amount of HIV in the blood in the vast majority of people. With continued adherence, the viral load falls to very low levels that cannot be detected with routinely used lab tests; this is commonly called “undetectable.” One study has found that interrupting HIV treatment led to increased levels of HIV and, in particular, increased inflammation, which led to an increased risk for heart attack and stroke.
Although suppressing HIV by achieving and maintaining an undetectable viral load is beneficial for the health of people with HIV, it is not sufficient to normalize HIV-related inflammation and immune activation. Over the past decade, researchers have been testing many different interventions to try to reduce these two issues. However, none of these interventions has been proven to reduce the risk of heart attack and stroke in a large number of people with HIV.
Now, a study called Reprieve has changed that.
The Reprieve study
In Reprieve, nurses randomly assigned 7,769 people with HIV—all of whom had low-to-moderate levels of cardiovascular disease—to receive either pitavastatin (4 mg) or placebo once daily. All participants were taking ART and the majority (88%) had an undetectable viral load at the start of the study. Pitavastatin belongs to a group of drugs commonly called “statins” and helps to lower cholesterol levels.
After an average of five years of monitoring, the study was halted because pitavastatin was shown to have a beneficial effect—a 35% reduction in the risk of cardiovascular disease.
Reprieve shows the importance of viral suppression combined with a cholesterol-lowering medicine in HIV-positive people with low-to-moderate cardiovascular risk. Based on the results of Reprieve, it is very likely that doctors will offer more people with HIV a cholesterol-lowering medication of the type to which pitavastatin belongs; these are commonly called statins.
Researchers enrolled participants from Canada, the U.S., South America, parts of sub-Saharan Africa, India, Spain and Thailand between March 2015 and July 2019.
The average profile of participants at the start of the study was as follows:
- age – 50 years
- sex – 69% male, 31% female
- gender identity – 95% cisgender, 2% transgender (figures do not total 100 due to missing data)
- major ethno-racial groups: Black – 41%; White – 35%; Asian – 15%
- HIV viral load – in 88% of participants it was undetectable and in most other participants it was less than 400 copies/mL
- all participants had a risk of cardiovascular disease of 15% or less
After an average of five years, researchers found that pitavastatin significantly reduced the risk of heart attack and stroke by 35% compared to placebo. Pitavastatin was beneficial to a broad group of people with HIV regardless of gender, age, ethno-racial group, viral load or CD4+ cell count.
People who used pitavastatin had their cholesterol levels decrease compared to people on placebo.
Inflammation and immune activation
In Reprieve, the beneficial effect of pitavastatin was greater than expected. It is likely that this beneficial effect was not due solely to the cholesterol-lowering effects of pitavastatin. Statins have also been shown to reduce inflammation, which contributes to a reduced cardiovascular risk.
A previous study with more than 17,000 people without HIV who did not have elevated cholesterol levels (but who did have high levels of inflammation) found that another statin called rosuvastatin (Crestor) significantly reduced the risk of cardiovascular events compared to placebo. This study strongly suggested that the anti-inflammatory activity of rosuvastatin played a role in improving the health of participants.
Smaller placebo-controlled studies in people with HIV have found that pitavastatin can significantly reduce levels of proteins in the blood associated with inflammation and immune activation.
Detailed analyses of pitavastatin’s impact on immune activation and inflammation from Reprieve will be revealed in the future.
Overall, pitavastatin was safe and well tolerated. The main adverse events were as follows:
Type 2 diabetes
About 5% of people taking pitavastatin and 4% of people taking placebo developed type 2 diabetes during the study. The researchers stated that these proportions are similar to what is seen in the average person without HIV who is between 45 and 65 years in the U.S.
Muscle weakness and/or muscle pain
Overall, 2% of people who used pitavastatin and 1% of placebo users developed this issue. This problem was mild in most people. However, three people taking pitavastatin and one taking placebo had severe muscle weakness and/or pain.
Premature discontinuation from the study
Adverse events leading to premature departure from the study were uncommon and were distributed as follows:
- pitavastatin – 2%
- placebo – 1%
Importance of Reprieve
The Reprieve study breaks new ground. It has shown that people with HIV who are taking ART and who have low-to-moderate cardiovascular risk can benefit from using pitavastatin. As a result of Reprieve, it is likely that more doctors will offer statins to their patients with HIV.
Pitavastatin is approved in the European Union, the UK and the U.S., however, it is not approved in Canada and some other countries. The patent on pitavastatin expires in a few years. It is likely that after the patent has expired, the drug will be manufactured by generic companies and made more widely available.
Prior to the results from Reprieve, doctors in Canada and other countries prescribed statins such as rosuvastatin and atorvastatin (Lipitor) to their patients with HIV who had elevated cholesterol. As pitavastatin is not available in all countries, researchers with the Reprieve study encouraged doctors to consider prescribing another statin in such cases. They noted that an important consideration when prescribing statins is to choose one that does not interact with ART.
—Sean R. Hosein
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