Statin reduces fat deposits in arteries in people with HIV

As well as lowering levels of harmful cholesterol, statin treatment in people with HIV may cut the risk of heart disease by reducing the size and instability of fat deposits in arteries, according to a sub-study of the REPRIEVE trial published in the journal JAMA Cardiology.

The REPRIEVE study randomised 7769 people with HIV to receive 4mg of pitavastatin or a placebo once a day. Over a median follow-up period of five years, pitavastatin treatment reduced the risk of experiencing a heart attack, stroke or other major cardiovascular event by 35%.

The effect of statin treatment in the REPRIEVE study was larger than would be predicted from the change in LDL cholesterol in people taking pitavastatin, leading researchers to ask what additional mechanisms explain the effect, and whether they are specific to people with HIV.

People with HIV have a higher risk of cardiovascular disease than other people of a similar age. REPRIEVE recruited people at low-to-moderate risk of a major cardiovascular event who would not ordinarily be prescribed a statin. The study tested pitavastatin, a moderate-intensity statin, using the highest recommended dose. As a result of the study findings, the British HIV Association recommended that all people with HIV aged 40 and over should be offered a statin. This week, US guidelines recommended the same (further details below).

Statins appear to reduce the risk of cardiovascular disease in two ways. They reduce levels of LDL cholesterol, the harmful form that is deposited in blood vessels in clusters called plaques. They also reduce inflammation, which contributes to the rupture of plaques. When a plaque ruptures, this leads to blood clots, heart attack or stroke.

Dr Michael Lu of Harvard University and colleagues carried out a sub-study of the REPRIEVE trial to examine the impact of treatment assignment on the progression of coronary artery plaque and inflammation. The sub-study enrolled 804 trial participants at 31 trial sites in the United States (whereas the full REPRIEVE trial recruited participants in five continents).

Sub-study participants underwent computed tomographic angiography (CTA) scans of the coronary artery on recruitment to the sub-study and two years later. In a CTA scan, iodine-containing liquid is injected into a vein and the scan creates three-dimensional pictures of the coronary artery to show up blockages.

Participants also provided blood samples at study entry, four months later and two years later to measure cholesterol levels and markers of inflammation.

The median age of study participants was 51, 84% were male, 35% were Black or African American, 25% were current smokers, 20% were taking medication to control their blood pressure and 25% had a family history of premature development of cardiovascular disease.

At study entry, the median 10-year cardiovascular risk score was 4.5% (low-to-moderate risk with no indication for statin treatment under existing guidelines). Nine per cent of participants had a coronary artery calcium score between 101 and 400, indicating moderate plaque formation. One per cent had a score of 400 or higher, indicating extensive plaque deposits.

Participants had been living with HIV for a median of 15 years and 59% had been taking antiretroviral treatment for at least 10 years. The median CD4 count was 609 cells at study entry and 98% had viral load below 400 cpies/ml.

The primary outcome under investigation in the sub-study was the change in non-calcified plaque and progression of non-calcified plaque. Non-calcified plaque is less stable and more likely to rupture, leading to a blood clot that can cause a heart attack. There is a higher risk of heart attack and stroke when the volume of non-calcified plaque is greater.

Of those enrolled into the study, 611 had complete data for non-calcified plaque and 587 had complete data for non-calcified plaque volume.

At study entry, the mean non-calcified plaque volume was 52.3 mm³ in the pitavastatin arm and 57.7 mm³ in the placebo arm. After two years, non-calcified plaque volume had decreased by 1.7 mm³ in the pitavastatin arm and increased by 2.6 mm³ in the placebo arm, representing a 7% greater reduction in non-calcified plaque volume in the pitavastatin group (p=0.02). Pitavastatin recipients were 33% less likely to show progression of noncalcified plaque (p=0.003).

A secondary analysis showed a non-significant trend towards a smaller increase in total plaque volume in people receiving pitavastatin, as well as significant reductions in the percentage of non-calcified plaque and the volume of low-attenuated plaque, the most unstable form of plaque.

LDL cholesterol levels declined from 105mg/dL to 75 mg /dL (2.71 mmol/L to 1.93 mmol/L) in the pitavastatin group after two years but remained almost unchanged in the placebo group.

Pitavastatin recipients experienced significantly greater reductions in two inflammatory markers (oxidised LDL cholesterol and lipoprotein-associated phospholipase A₂, or LpPLA2) but no change in a third inflammatory marker, hsCRP.

There was no significant change in immune activation as measured by MCP-1, soluble CD14, soluble CD163, IL-6, IL1-neta or IL-18 in either study arm.

In an accompanying commentary, Dr Matthew Feinstein of Northwestern University, Chicago, says that in people with HIV, statins do not appear to deliver their benefit through reducing systemic inflammation. But if they are not having a systemic effect on inflammation, why was the treatment effect of statins in people with HIV substantially greater than would be predicted from their cholesterol-lowering effect?

He asks whether statins are exerting an anti-inflammatory effect within plaques in people with HIV, acting against “uniquely dysregulated, hyperinflammatory macrophage and T-cell responses” in plaques. Further research to understand what is taking place in arterial plaques will be needed to understand how people with HIV with low-to-moderate cardiovascular risk derive a substantial benefit from statin treatment, he concludes.

The study investigators say that as well as lowering LDL cholesterol levels, statins also reduced plaque volume and non-calcified plaque. Small changes in plaque volume have been associated with substantial reductions in cardiovascular events in previous clinical trials in the general population, a 2023 meta-analysis showed.

Although LDL cholesterol reduction below 70mg/dL was associated with a 38% reduced risk of plaque progression, the magnitude of LDL cholesterol reduction ceased to be significantly associated with plaque progression after adjusting for non-calcified plaque levels at study entry. The researchers say that further research is needed to understand how statins reduce non-calcified plaque volumes in people with HIV.

New US guidance on statins for people with HIV

On February 27, the US Health and Human Services department issued new guidance on statin use in people with HIV. The guidance recommends that everyone aged 40 and over with a 10-year cardiovascular risk between 5% and 20% should receive at least a moderate-intensity statin. For people with HIV aged 40 and over who have a 10-year cardiovascular risk below 5%, the guidance recommends that moderate-intensity statin treatment should be initiated. However the guidance cautions that “the absolute benefit from statin therapy is modest in this population; therefore, the decision to initiate a statin should take into account the presence or absence of HIV-related factors that can increase ASCVD risk.”