Statins and HIV: how can the REPRIEVE findings be implemented in the real world?

Findings from the landmark REPRIEVE trial, which tested a daily statin medication for people living with HIV, were presented on Monday at the 12th International AIDS Society Conference on HIV Science (IAS 2023) and published in The New England Journal of Medicine. The results were presented at a symposium that also included a discussion of cardiovascular disease among people with HIV and the study’s implications for clinical practice.

As aidsmap reported, the study showed that participants randomly assigned to receive pitavastatin had a 35% lower risk of heart attacks, strokes and other major cardiovascular events compared with the placebo group. The demographics, comorbidities and laboratory values of the study participants reflected low to moderate cardiovascular risk – a group that normally would not be prescribed statins.

“This study offers a major step in addressing the unacceptable burden of heart disease among individuals living with HIV and an important opportunity to develop a cardiovascular disease prevention strategy uniquely tailored for this at-risk population,” lead investigator Professor Steven Grinspoon of Harvard Medical School and Massachusetts General Hospital said in a statement.

“I think we’ll look back on Brisbane 2023 as the conference at which we saw some truly guideline-changing data,” added former British HIV Association chair Dr Laura Waters of Mortimer Market Centre in London.

Following Grinspoon’s presentation of the data, a panel of experts discussed what the trial results mean for people living with HIV in high, middle and low-income countries, and whether a single prevention strategy would be appropriate worldwide.

A growing body of research shows that people with HIV are at greater risk for cardiovascular disease (CVD), and this risk is rising as they live longer thanks to effective antiretroviral therapy. But even those on consistent treatment can have persistent immune activation and inflammation that contribute to cardiovascular problems. What’s more, HIV-positive people experience a build-up of arterial plaque and ensuing complications at a younger age than their HIV negative peers. Yet CVD risk scores developed for the general population tend to underestimate the real risk for people with HIV. Statins reduce low-density lipoprotein (LDL) cholesterol levels and also have anti-inflammatory properties, so they could potentially address both traditional and non-traditional risk factors.

Dr Markella Zanni of Massachusetts General Hospital explained that among women living with HIV, traditional metabolic factors, immune factors and accelerated reproductive ageing all likely contribute to increased CVD risk. In a subset of REPRIEVE participants in the United States, women had higher levels of inflammatory biomarkers but less coronary artery plaque than men. Furthermore, standard CVD risk scores appear to underestimate actual risk “much more strongly” for HIV-positive women compared with men. It’s possible, Zanni, suggested, that these scores do not capture systemic immune activation.

Dr Gerald Bloomfield of Duke University in North Carolina, noted that the burden of CVD attributable to HIV is increasing worldwide, but “is not experienced equitably,” with a more rapid increase in low- and middle-income countries. While heart disease deaths are still more common in high-income countries, that is partly because these countries have older populations – in fact, lower and middle-income countries have higher age-standardised CVD mortality rates. The rise in CVD is particularly notable in countries that have experienced “recent social and epidemiological transition,” meaning a shift in mortality from infectious diseases to chronic non-communicable diseases (NCDs).

For example, in sub-Saharan Africa, the region with the highest burden of HIV, non-communicable disease prevalence is rising rapidly, and in other regions CVD accounts for the majority of NCD deaths, Dr Rosie Mngqibisa of the Enhancing Care Foundation in South Africa said.

Dr Beatriz Grinsztejn of Fundação Oswaldo Cruz in Rio de Janeiro noted that late diagnosis of HIV, with its associated burden of inflammation and immune activation, contributes to the CVD among people living with HIV in Latin America. She also raised a concern about CVD and statin use among transgender women who take hormone therapy, noting that many trans women with HIV in Latin American take large hormone doses without medical supervision. REPRIEVE enrolled 127 participants (2%) who identify as transgender, but this number was too small to draw meaningful conclusions.

Although HIV is a known risk factor for CVD, doctors haven’t known what to do with this information. Some have been hesitant to prescribe statins for HIV-positive people with low to moderate CVD risk because there were no data showing they would be effective for this population, according to Grinspoon. But now, “our data in low to moderate risk groups suggest that the guidelines should be amended to recommend that HIV patients, because they have this excess risk, [should] be offered statin therapy,” he said.

Pitavastatin is now available in many countries and it will be more broadly available when it goes off patent, likely in early 2024. This statin was chosen for REPRIEVE because it is generally well tolerated and does not interact with antiretrovirals. But if pitavastatin is not available, Grinspoon and Dr Anton Pozniak of London’s Chelsea and Westminster Hospital agreed that it would be reasonable to substitute another safe statin.

Statins “are not fancy drugs,” Grinspoon said. They are “really cheap” when off patent, which could potentially make them available to everyone.

But it remains to be determined whether every HIV-positive person at low to moderate risk for CVD should be offered a statin. The benefits were evident in REPRIEVE, and the effect was very consistent for men and women, across racial/ethnic groups, across most regions, and for people with any CD4 count and with high or low LDL levels at baseline.

But the benefits must be weighed against potential harms. In REPRIEVE, there were more cases of diabetes in the pitavastatin group, as seen in most statin studies. Although the rates were low – 5.3% in the pitavastatin group versus 4.0% in the placebo group – this could still mean a substantial number of additional cases if statins are offered to everyone with low to moderate CVD risk.

Dr Andrew Hill of the University of Liverpool told aidsmap that some African doctors are unsure whether pitavastatin will provide meaningful benefits when taking into account the added risk for diabetes, which is a leading cause of death in Africa.

Hill calculated that for every case of myocardial infarction prevented by pitavastatin in REPRIEVE, there were five additional cases of diabetes. In an African population with a higher rate of diabetes but a lower risk of heart attacks, this ratio could be even worse.

The REPRIEVE findings underscore the need for better risk-prediction tools specific to people living with HIV. “Predicting cardiovascular disease risk accurately is the first step to initiating appropriate primary prevention for those at elevated risk,” Bloomfield said.

The panellists also raised questions about who will manage CVD prevention and statin prescribing, as leaving it to HIV or infectious disease specialists rather than primary care or family practice providers could limit access. “It would be great if could be included in the primary care package,” Grinsztejn said.

“Let’s go back to the drawing board and see how best we can incorporate [the REPRIEVE findings] into a bag of preventative strategies that are already there,” said Mngqibisa. “We have to decide whether…to scale up addition of statins onto what we have, or we wait until later when we have to treat people with cardiovascular disease.”

Writing in an editorial accompanying the published REPRIEVE findings, Dr Matthew Freiberg of Vanderbilt University Medical Center in Tennessee called the trial “a necessary first step” toward a comprehensive preventive approach to reducing the risk of cardiovascular disease among people living with HIV.

“Although pitavastatin targets one and perhaps two important risk factors for atherosclerotic cardiovascular disease (i.e., LDL cholesterol and systemic inflammation), other risk factors merit attention for this preventive approach to be transformative,” he wrote.

“Hypertension and diabetes are often routinely addressed in clinical care, although behavioral risk factors such as cigarette smoking, unhealthy alcohol consumption, drug use, obesity and mental health conditions are often underassessed, under-addressed, or both, in part because these risk factors can be challenging to modify,” Freiberg continued. “Thus, targeting of these less traditional risk factors in this population could result in beneficial effects, either directly on the cardiovascular system or indirectly by reducing systemic inflammation.”

The panelists agreed that statin use should be part of a broader CVD prevention plan that emphasises a heart healthy lifestyle.

“We have to grasp this moment,” Pozniak said. “We have to change the way we practice hand-in-hand with the community and get that message out there so that we can improve the lives of persons living with HIV.”