• Relative risks of various CVD manifestations are generally 1.5- to 2-fold greater for PLWH compared with uninfected individuals.4 Although the relative risk has decreased with effective ART, there is a large and rising absolute burden of CVD among PLWH
 
• PLWH have high rates of traditional risk factors, including dyslipidemia, metabolic disease, smoking, hypertension, and substance use, as described in the sections below. Aside from traditional risk factors, HIV-specific issues are implicated in CVD and include ART, chronic inflammation, and immune activation in the setting of treated and suppressed HIV disease. Imaging techniques have provided valuable insight into CVD onset and progression in HIV.
 
• HIV infection is associated with metabolic complications, including dyslipidemia, insulin resistance, and body composition changes, which can contribute to CVD. Initially, dyslipidemia in HIV was characterized by increased triglyceride levels, thought to be related to immunodeficiency in the pre-ART era.95 Later, specific ART medications, including several protease inhibitors (PIs) and efavirenz, a non-nucleoside reverse transcriptase inhibitor (NRTI), were associated with dyslipidemia (particularly elevated triglyceride levels). However, current first-line ART regimens have minimal lipid effects.
 
• Women with HIV may be at particularly elevated risk compared with uninfected women
 
• In the modern ART era, this phenotype has changed, and recent work has focused on dysfunctional subcutaneous fat, related in part to the effect of HIV on peroxisome proliferator-activated receptor-γ and Dicer, as well as other mechanisms. With increasingly effective ART, gains in both subcutaneous and visceral fat are often seen with the initiation of ART, regardless of regimen, and rates of generalized obesity are increasing among PLWH. Changes in body composition, including excess visceral adipose tissue, have been linked to overall mortality. These changes have been associated with increased coronary plaque, including both noncalcified and calcified plaque.
 
• Targeted attention and investment are needed. The quality of our care for HIV is further limited by shortcomings in the US healthcare reimbursement system. Healthcare providers are often unable to spend the time required to understand the problems facing the aging HIV population. PLWH who also have CVD often need longer visit times, care coordination, and multidisciplinary team engagement. There are many opportunities for implementation research aimed at leveraging the HIV care infrastructure to deliver integrated cardiovascular preventive and therapeutic care for PLWH. Such structures could include improving health insurance access to specialists, strengthening specialist referral pathways, nurse management, clinical pharmacist engagement,325 team-based approaches, electronic medical record-based approaches to targeting high-risk patients, colocated clinics, and other approaches that consider the specific vulnerabilities in this population.
 
• smoking may be the most important modifiable CVD risk factor among PLWH. Smoking is highly prevalent among PLWH (42% were current smokers and 20% were former smokers in a nationally representative US sample.
 
• Certain antiretroviral drugs and drug classes have been associated with elevated risk of ASCVD events, most notably among people with higher levels of traditional risk factors.
 
• cumulative PI use was associated with a 10% greater risk of MI, even after adjustment for cholesterol changes caused by PIs. Analyses from the D:A:D cohort of atazanavir and darunavir, 2 current-generation PIs in widespread clinical use, suggest that ritonavir-boosted or unboosted atazanavir is not associated with increased risk. It appears that the association of PIs with ASCVD events is a class effect, with atazanavir being the exception.
 
• Underlying mechanisms likely include an interplay among traditional risk factors, HIV-specific factors (eg, chronic immune activation/inflammation), ART-related dyslipidemia and other metabolic comorbidities, behavioral factors (eg, smoking), and disparities in access to or receipt of care.
 
• As in the general population, adherence to a healthy lifestyle is an essential first step for primary and secondary prevention of CVD among PLWH. Smoking cessation is of paramount importance given the high prevalence of smoking among PLWH and the clear role of smoking in atherosclerosis and MI. (An extensive library of resources for patients and providers to approach smoking cessation can be found online.) Limiting alcohol consumption is likewise important given the potential disproportionate contribution of alcohol to CVD in HIV. Although it is clear that heavy alcohol consumption has adverse effects on CVD and other disease end points, there is debate about whether a "healthy" level of alcohol consumption exists; some large analyses suggested a cardioprotective effect of light to moderate alcohol consumption (<100 g/wk [<7 drinks/wk]), whereas others found no benefit and perhaps elevated HF and stroke risks for light to moderate alcohol consumption. Regular physical activity is also an essential aspect of lifestyle optimization in HIV given the associations of physical inactivity with poor health and adherence in HIV and, conversely, the improvement in inflammation and cardiometabolic health with increasing physical activity in HIV. A randomized trial of sedentary PLWH at high risk for CVD demonstrated feasibility of a lifestyle-focused behavioral intervention to reduce sweetened beverage consumption and weight, although there was no significant effect of the intervention on physical activity levels. Absent HIV-specific data on optimal diets to prevent CVD, adherence to ACC/AHA dietary guidelines is recommended. This dietary approach emphasizes vegetables, fruits, legumes, healthy protein sources (fish/seafood, nuts, low-fat poultry, and low-fat dairy), whole grains, and nontropical vegetable oils while limiting intake of sweets, sugar-sweetened and artificially sweetened beverages (associated with coronary plaque burden in HIV), and red meats.
 
• Expanding the HIV treatment cascade for the prevention of non-AIDS comorbidities is a necessary extension of the treatment cascade paradigm. PLWH who also have CVD often need longer visit times, care coordination, and multidisciplinary team engagement. There are many opportunities for implementation research aimed at leveraging the HIV care infrastructure to deliver integrated cardiovascular preventive and therapeutic care for PLWH. Such structures could include improving health insurance access to specialists, strengthening specialist referral pathways, nurse management, clinical pharmacist engagement, team-based approaches, electronic medical record-based approaches to targeting high-risk patients, colocated clinics, and other approaches that consider the specific vulnerabilities in this population
 
• Pharmaco-Prevention of Coronary Artery Disease in HIV: Primary prevention to reduce the risk of ASCVD is an important goal for PLWH. Statins significantly reduce CVD events in patients without HIV with increased inflammation and low levels of LDL-C. In a randomized study among hypercholesterolemic PLWH, pitavastatin lowered LDL more than pravastatin, and neither was associated with increases in glucose, an important consideration for PLWH. As discussed, PLWH often present with normal LDL but increased systemic and arterial inflammation72 and persistent immune activation despite successful ART. Traditional CVD risk factors, particularly smoking, are also more common and should be targeted in HIV. Statin use in HIV is complicated by potential drug interactions, although newer statin and ART therapies appear to have more benign drug-drug interaction profiles.
 
• In terms of clinical adverse events, observational cohorts have shown that most statins (simvastatin and lovastatin excluded) can be safely prescribed for PLWH with lipid-lowering effects similar to those for people without HIV. A caveat to this may be people >75 years of age, for whom there are conflicting data on net statin benefits in the general population.
 
• a randomized controlled trial of rosuvastatin 10 mg versus placebo among PLWH demonstrated a reduction in some markers of inflammation, monocyte activation markers, and vascular inflammation with rosuvastatin. There was a significant increase relative to placebo in insulin resistance but no significant difference in fasting glucose, hemoglobin A1c, or the incidence of diabetes mellitus. However, other studies have not shown effects on specific inflammatory indexes, including IL-6, hsCRP, and D-dimer. Efficacy data for the primary prevention of ASCVD are not yet available, and statins may be underused in HIV.
 
• To address this knowledge gap, the National Institutes of Health launched REPRIEVE, a randomized, placebo-controlled, 7,500-person global trial to test a primary prevention strategy in HIV. REPRIEVE includes patients at low to moderate risk and assesses whether treatment with pitavastatin will prevent adjudicated major adverse cardiovascular events. REPRIEVE will also assess the degree to which changes in lipids, immune activation, and inflammation contribute to this effect. Furthermore, little is known about the differential effects of statins in women with HIV, but immune activation is higher among women.159 This knowledge gap is being investigated in REPRIEVE, which has enrolled a high percentage of female PLWH.
 
• Given the prothrombotic milieu common in HIV, inconsistent findings related to aspirin effects on inflammation and endothelial dysfunction in HIV, and the tradeoff seen between reduced vascular events and increased bleeding with aspirin for primary ASCVD prevention in non-HIV populations
 
• In recent years, several studies of lipid-lowering therapies added to a background of statin therapy have demonstrated that aggressive LDL-C lowering in populations at high ASCVD risk reduces cardiovascular events. The benefit of aggressive LDL-C lowering is demonstrated by data from 14 large statin studies in the non-HIV population (Cholesterol Treatment Trialists' Collaborators) in which each 38.6-mg/dL reduction in LDL-C translated to a reduction in cardiovascular events by 22% PCSK9 (proprotein convertase subtilsin-kexin type 9) binds and degrades LDL receptors, leading to an increase in LDL-C.
 
• PCSK9 inhibitors are monoclonal antibodies with minimal significant drug-drug interactions identified thus far that reduce LDL-C by ≈60% even in the setting of high-intensity statin therapy. Two PCSK9 inhibitors are approved by the US Food and Drug Administration for individuals with heterozygous familial cholesterolemia or clinical ASCVD on maximally tolerated statins who require additional LDL-C lowering. Among uninfected people with ASCVD, PCSK9 inhibitor therapy in addition to statin therapy reduced clinical events by 15% (P<0.001). A longer study demonstrated that PCSK9 inhibitor therapy reduced rates of major adverse cardiovascular events significantly overall and reduced mortality among individuals with an LDL-C ≥100 mg/dL. PCSK9 levels are higher in PLWH than in uninfected person, particularly in the setting of hepatitis C virus coinfection, and are increased in parallel with inflammatory markers such as IL-6