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Ms. C*, a 53-year-old African American woman living with HIV for almost a decade, inquired about the for cardiovascular disease prevention among people with HIV (PWH). Her predicted 10-year atherosclerotic cardiovascular disease (ASCVD) risk score is not significantly increased at 5.3%, her LDL is only 100 mg/dL, but she smokes cigarettes and has a family history of early heart attack. Should she start a statin?

Before we evaluate the case using the new guidelines, let us set the stage.

Progress in Caring for People Living With HIV

Due to the remarkable strides in the management and support of PWH, life expectancy now almost parallels that of those without HIV, particularly in high-income regions. However, despite declining rates of AIDS-related illnesses and deaths, there's a concerning rise in non-AIDS-related conditions, such as CVD, among people living with HIV, leading to a stagnation in comorbidity-free years of life. Until recently, there were no established prevention and treatment recommendations for ASCVD in PWH.

Why Do We Need Recommendations for CVD Prevention in PWH?

Going back nearly two decades, began to show that PWH were 1.5 to 2 times more likely to experience a major adverse cardiovascular event (MACE) than people without HIV. Notably, rates were increased even when traditional CVD risk factors -- such as hypertension, cholesterol, and smoking status -- . Consequently, researchers sought to uncover what else in the setting of HIV might explain the increased risk of CVD.

Imaging studies provided valuable insights. These studies in more than half of PWH, a higher prevalence when compared to individuals without HIV but with similar traditional CVD risk factors. Furthermore, the studies found that coronary plaque in PWH had features suggesting . Together, these findings suggested a distinctive CVD phenotype characterized by vulnerable and inflamed plaque, with immune activation and inflammation likely contributing to this unique pathophysiology.

REPRIEVE: The Global, Multicenter, Endpoint Driven Trial

The known as REPRIEVE was initiated in collaboration with the Advancing Clinical Therapeutics Globally for HIV/AIDS Network. REPRIEVE was designed to address a key gap in knowledge and identify a successful primary CVD prevention strategy for PWH. Funded by the NIH with support from Kowa, Gilead, and ViiV, the trial tested a statin -- pitavastatin -- to prevent CVD.

The primary endpoint was MACE, a term that includes myocardial infarctions, strokes, cardiovascular death, and other ASCVD diagnoses. Because statins have both lipid-lowering and anti-inflammatory properties, the hope was that they would prevent MACE among PWH who would not otherwise be advised to take a statin under the existing guidelines.

REPRIEVE was a significant global effort involving enrollment of 7,769 individuals from 12 countries spanning five continents. Participants were diverse, with 65% being non-white and 31% female at birth. Notably, the baseline predicted 10-year risk of ASCVD was low, with a median of 4.5%, and the median LDL cholesterol level was 108 mg/dL.

An independent data and safety monitoring board halted REPRIEVE early after a planned interim analysis revealed a in the primary endpoint, MACE, among individuals randomized to pitavastatin compared to those randomized to placebo. This outcome was observed over a median follow-up of 5.1 years. Notably, individuals in the pitavastatin arm exhibited a 21% lower risk of experiencing MACE or death. The most common primary MACE recorded were strokes and myocardial infarctions.

Pitavastatin was effective across diverse participant subgroups of race, sex at birth, region of residence, and CD4 count. Of particular significance, a reduction in MACE occurrence with pitavastatin was observed among relatively young participants with relatively low 10-year ASCVD risk and LDL cholesterol levels.

As anticipated, individuals taking pitavastatin experienced more musculoskeletal adverse events. However, these occurrences were not common and mostly mild. There was a slightly increased occurrence of new-onset diabetes mellitus among participants taking pitavastatin, 5.3% versus 4% in the placebo arm. Nevertheless, in the subset of individuals with diabetes, the number of MACE was 12 -- four in the pitavastatin group versus eight in the placebo -- indicating that pitavastatin effectively reduced MACE among diabetics.

These findings, published in July 2023, underscore the favorable impact of pitavastatin in mitigating MACE risk, with manageable musculoskeletal side effects, thus illustrating its potential significance as an effective cardiovascular risk management strategy for PWH.

Enter the New Recommendations for Statin Therapy in People With HIV

Results from REPRIEVE demonstrated that statins can prevent MACE among PWH ages 40-75 with low-to-moderate traditional risk, and pitavastatin was safe and well tolerated. To facilitate the integration of these findings into clinical practice, HHS, in collaboration with the American Heart Association, American College of Cardiology, and HIV Medicine Association, issued recommendations for the utilization of statin therapy to prevent ASCVD in PWH.

The "Recommendations for the Use of Statin Therapy as Primary Prevention of ASCVD in People with HIV" establish three distinct categories designed to guide clinical decision-making. For PWH ages 40-75 with a 10-year ASCVD risk score ranging from 5% to <20%, the recommendations advocate for the initiation of a moderate-intensity statin, specifically pitavastatin, atorvastatin, or rosuvastatin. With a 10-year ASCVD risk above 5%, Ms. C fits into this category.

REPRIEVE showed good efficacy with prevention of one MACE for every 53 people treated with a risk score between 5 and 10%. Among the entire trial population, the overall number needed to treat to prevent one MACE was approximately 100.

The recommendations also endorse that statin therapy be considered even for PWH with a risk score <5%, but recognize that in this group, this decision should be informed by additional factors that influence ASCVD risk such as a history of smoking and family history of ASCVD. Remarkably, even among participants with a low ASCVD risk score (<5%), the number needed to treat remained below 200, outperforming other preventive interventions.

Conversely, for individuals below the age of 40, the available data is insufficient to recommend or discourage statin therapy as primary prevention, as REPRIEVE did not enroll participants below this age threshold. As a proactive measure, general lifestyle modifications are advised. Statin therapy should be contemplated selectively, considering ASCVD risk factors and other relevant indicators.

With these new recommendations, clinicians now have structured guidance to navigate primary prevention efforts. This signifies a critical step towards addressing cardiovascular risk among PWH.

The journey from inquiry to the formulation of comprehensive recommendations exemplifies the collaborative efforts aimed at enhancing the quality of care and extending healthy longevity for PWH. As we continue to refine our approach to HIV care, prioritizing cardiovascular health alongside viral suppression becomes imperative for achieving holistic well-being in this community.

is an associate principal in medicine at Harvard Medical School and Massachusetts General Hospital (MGH). She is the project manager of the REPRIEVE Trial and is a nurse practitioner in the Lipid and Metabolism Clinic at MGH. is a clinical research coordinator in the Metabolism Unit at Massachusetts General Hospital and Harvard Medical School. She is the study coordinator for the REPRIEVE Trial Clinical Coordinating Center. is a professor of medicine at Harvard Medical School. He is also chief of the MGH Metabolism Unit, and director of the Nutrition Obesity Research Center at Harvard.

*Patient's name has been changed.

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