Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents With HIV

Cardiovascular and Metabolic Complications in People With HIV

Cardiovascular Complications in People With HIV

Overview

Most people with HIV who are using continuous antiretroviral therapy (ART) and achieve viral suppression have a life expectancy that is approaching that of people without HIV.¹ However, a gap in mortality remains due to comorbidities, such as atherosclerotic cardiovascular disease (ASCVD). As mortality from AIDS events among people with HIV has declined, the proportion of ASCVD-related deaths has increased. When compared to people without HIV, people with HIV have an approximately twofold higher risk of developing ASCVD, even after accounting for traditional cardiometabolic risk factors,² with the age at incident ASCVD diagnosis among people with HIV younger than that of people without HIV. Factors influencing ASCVD risk among people with HIV include a higher prevalence of traditional cardiometabolic risk factors compared with the general population,³ ongoing systemic inflammation associated with HIV despite viral suppression,⁴ and cardiometabolic toxicity associated with certain antiretroviral (ARV) drugs.^5,6 In addition, differential access to screening and treatment of ASCVD risk factors also contributes to excess ASCVD risk among certain people with HIV in the United States.^7,8

Data also suggest that ASCVD risk relative to the general population is greater among women with HIV than among age-matched men with HIV.^9,10 Although data indicating the absolute risk of myocardial infarction (MI) is similar—12.71 versus 10.48 per 1,000 person-years for women and men with HIV, respectively—women with HIV have exhibited a nearly 3- to 4-fold increase in relative MI risk versus a 1.5- to 2-fold increase for men compared to sex-specific rates among people without HIV.^10-13 A substudy from The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) demonstrated the absence of an expected protective effect of female sex for the development of a major adverse cardiac event (MACE).³ For more information on REPRIEVE, see Rationale for Statin Therapy and the REPRIEVE Trial Results.

While there has been extensive focus on the epidemiology and pathogenesis of ASCVD among people with HIV, there are also data demonstrating increased risk of other cardiac and vascular diseases. People with HIV have an increased risk of developing stroke (including ischemic and hemorrhagic), heart failure, arrhythmia or sudden cardiac death, and thrombosis.^14-17 Risk factors for these outcomes are thought to be similar to those for ASCVD, with an etiologic role for both traditional risk factors and HIV-related factors. Currently, this section of the guidelines is focused on primary prevention strategies for people with HIV, with an emphasis on ASCVD. As data emerge concerning secondary prevention strategies for ASCVD and primary and secondary prevention strategies for other cardiovascular outcomes specific to people with HIV, this section may be expanded.

HIV-Related Risk Factors for Atherosclerotic Cardiovascular Disease

Factors related to HIV and its treatment have been shown to be important contributors to excess ASCVD risk. Specifically, HIV-related inflammation has been associated with elevated ASCVD risk. This inflammation is increased in the presence of active viremia and decreases with ART but still remains elevated when compared to those without HIV (see the Cardiovascular and Metabolic Complications Introduction). Data from the SMART trial demonstrated that continuous ART not only improves HIV-related outcomes but also significantly reduces non-AIDS events, including cardiovascular disease (CVD), an observation thought to be related to the beneficial effects of ART on inflammation.¹⁸ In the large Veterans Aging Cohort Study (VACS), MI risk was independently associated with detectable or increased HIV RNA; compared to people without HIV, MI risk was increased by 39% in those with HIV RNA <500 copies/mL and by 75% in those with HIV RNA ≥500 copies/mL.¹⁹ In REPRIEVE, even low-level HIV viremia (median 62 copies/mL) was linked to increased rates of MACE, as viremic individuals had a higher risk than those with viral load below the limit of detection (adjusted hazard ratio 1.4; 95% confidence interval, 1.00–1.97)^3,20; however, another recent study did not show an association between HIV viremia and CVD.²¹ Based on these findings, continuous ART is recommended for all people with HIV not only to maintain viral suppression but also to reduce ASCVD risk (AII). Immunomodulatory therapy as an intervention to reduce HIV-associated ASCVD risk is not recommended except in a clinical trial (AII). See Immune Activation and Inflammation Among People With HIV Receiving Antiretroviral Therapy for additional details.

Additional factors related to HIV or common among people with HIV may further impact ASCVD risk. Lower CD4 T lymphocyte (CD4) cell count and nadir CD4 count have been shown to be associated with ASCVD events independent of traditional ASCVD risk factors or specific ART,^22,23 with the VACS cohort demonstrating CD4 <200 cells/mm³ as an independent predictor of MI with an increased risk of nearly 90%.^19,24 HIV-related ASCVD risk enhancers,²⁵ included in Table 11a below, may strengthen the rationale for ASCVD prevention strategies, including statin initiation in individuals <40 or >75 years (see Primary Prevention of ASCVD), and may be used to inform decisions to avoid certain ARV medications that have been associated with increased ASCVD risk.

Antiretroviral Therapy and Cardiometabolic Complications

Specific ARV medications and classes have been associated with potential cardiometabolic toxicity, which has informed the U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents (the Panel)’s recommendations on ART regimen selection to reduce risk for cardiometabolic complications. See Interactions Between ARV Drugs and Drugs for Treatment or Prevention of Cardiovascular Diseases below and Antiretroviral Regimen Considerations for Initial Therapy Based on Specific Clinical Scenarios for more information. Specifically, for individuals with elevated traditional ASCVD risk or known ASCVD, the selection of an ART regimen should consider options that minimize the introduction of new cardiometabolic adverse effects.

Antiretroviral Therapy and Atherosclerotic Cardiovascular Disease Risk

Individual ARV medications and classes have been linked to increased risk of ASCVD events. An association between abacavir (ABC) use and MI was first reported in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, with the increased risk noted only with recent/current ABC exposure (i.e., within 6 months) and particularly among participants with pre-existing cardiac risk factors.²⁶Since the D:A:D report, multiple studies, systematic reviews, and meta-analyses have evaluated the relationship between ABC therapy and cardiovascular events, with some confirming the initially observed association and others failing to identify an association.^26-31 Retrospective analyses from the REPRIEVE study corroborated the D:A:D results, showing an increased hazard of a first MACE with ART regimens, including ABC versus tenofovir-containing regimens,³² and an increased MACE hazard of 62% in participants with previous use and 41% with current use of ABC compared with participants who were never exposed.³³ An association between ABC and ASCVD risk reported in multiple large studies provides a rationale to consider underlying ASCVD risk when using ABC as a component of ART. Based on these data, the Panel recommends considering alternative ARV medications in place of ABC in people with HIV and higher underlying ASCVD risk or known ASCVD (AII).

An early study from the D:A:D cohort demonstrated a 16% increased risk of MI per year of cumulative protease inhibitor (PI) exposure,³⁴ specifically with older PIs (e.g., indinavir and ritonavir-boosted lopinavir [LPV/r]). A case-control study within the French HIV ANRS cohort CO4 FHDH also found a 33% increase in MI risk with LPV/r use.³⁵ A later study from the D:A:D cohort showed a 59% increased risk of ASCVD per 5 additional years of use with ritonavir-boosted darunavir (DRV/r) but not ritonavir-boosted atazanavir (ATV/r),³⁶ yet subsequent studies did not observe an association between boosted darunavir and increased ASCVD risk.^37-39 Based on these data, the Panel recommends considering alternative ARV medications in place of LPV/r in people with HIV and higher underlying ASCVD risk or known ASCVD (AII). If use of DRV/r is indicated, clinicians should weigh the potential benefits of therapy versus the potential cardiovascular risk.

The effect of integrase strand transfer inhibitors (INSTIs) on the risk of ASCVD is an area of active research, with recent studies showing inconsistent results. In a multicenter observational study of the international RESPOND consortium, INSTI exposure was associated with a nearly twofold greater incidence of a composite CVD endpoint within the first 6 months after exposure compared to no INSTI exposure,⁴⁰ and the increased risk persisted throughout the first 24 months. Subsequently, two target trial emulation studies found no association between INSTI use and a composite CVD outcome that included MI, stroke, or invasive cardiovascular procedures, regardless of previous ART experience.^41,42 Based on current data, there is insufficient evidence to recommend modifying suppressive INSTI-based ART regimens in people with weight gain, higher underlying ASCVD risk, or known ASCVD.

Antiretroviral Therapy and Dyslipidemia

Higher levels of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglycerides have been observed with tenofovir alafenamide (TAF), efavirenz (EFV), all boosted PIs, and elvitegravir/cobicistat (EVG/c).^43,44 Among the PIs, similar lipid changes have been shown in participants from a randomized trial of ATV/r- and DRV/r-based regimens.⁴⁵ Importantly, differences in lipid levels between two ART regimens can be due to a lipid-raising effect of a given medication and/or a lipid-lowering effect of the other medication. For example, levels of total cholesterol, LDL, HDL, and triglycerides are higher in participants who received TAF when compared with those who received tenofovir disoproxil fumarate (TDF) in multiple randomized controlled trials.^46,47 However, data from a placebo-controlled pre-exposure prophylaxis trial support that TDF exposure has an independent lipid-lowering effect (for total cholesterol, LDL, and HDL).⁴⁸ Further, data support that total cholesterol–to-HDL ratios did not differ between participants receiving TAF and those receiving TDF,^49,50 and the clinical significance of ASCVD risk from increases across all lipid indices without changes in total to HDL ratios is uncertain.

Antiretroviral Therapy and Diabetes/Insulin Resistance

Direct effects on diabetes mellitus (DM) and insulin resistance have been observed with older ARVs, including ZDV and LPV/r.⁵¹ Several studies have demonstrated an increased risk of DM with INSTI use,^52-54 an association that may be mediated in part by weight gain.⁵⁵ An association between ART and DM has not been consistently observed with other contemporary ARVs, including those recommended as initial therapy in the guidelines.

Antiretroviral Therapy and Other Cardiac Complications

EFV, as well as higher-than-recommended doses of fostemsavir and rilpivirine, have been associated with QTc (QT corrected for heart rate) prolongation.^56-58 These ARV drugs should be used with caution in people with pre-existing heart disease, QTc prolongation, or concomitant use of medications that may increase drug concentration or prolong the QTc interval. Both ATV/r and LPV/r have been associated with PR prolongation, particularly among people with risk factors, including pre-existing heart disease and concomitant use of medications that may cause PR prolongation.^59,60

Strategies for Atherosclerotic Cardiovascular Disease Risk Estimation and Screening For People With HIV

Cardiovascular risk assessment strategies developed for the general population do not reflect HIV-specific factors, such as inflammation and immune activation or potential contributions from certain ARV drugs, which are key mechanistic contributors to HIV-associated ASCVD. This section will address lipid screening and ASCVD risk estimation for people with HIV. ASCVD prevention strategies specific to people with HIV are further discussed in the Cardiovascular and Metabolic Complications in People With HIV Introduction section and the Primary Prevention of ASCVD subsection below

Lipid Screening and Monitoring

Lipid screening should be performed in people with HIV (AIII), given the increased risk for ASCVD and the increased rate of dyslipidemia associated with certain ARV drugs. A fasting or random lipid profile should be obtained for all people with HIV at entry into care or at the time of ART initiation. If a random profile is abnormal, a fasting lipid profile should be obtained. Lipid levels should be rechecked 3 to 6 months after starting or modifying ART once viral suppression is achieved. Lipid levels measured after initiation of ART should then be used to calculate an ASCVD risk score and determine indications for statin therapy (see Primary Prevention of ASCVD). The 2026 American College of Cardiology (ACC)/American Heart Association (AHA)/Multisociety Dyslipidemia Management Guideline (2026 Dyslipidemia Guideline) additionally recommends checking lipoprotein(a) (Lp(a)) at least once for ASCVD risk assessment and considering testing for Apolipoprotein B (ApoB) in individuals on lipid-lowering therapy to guide decisions regarding further therapeutic intensification once LDL-C and/or non-HDL-C goals are achieved and in individuals not on lipid-lowering therapy to guide decisions about initiation of lipid-lowering therapy.

Among people with HIV who are receiving statin therapy, lipid monitoring should be performed annually to reassess ASCVD risk and inform decisions on statin management and/or other risk modification strategies. Further, specific to people on statin therapy, the approach to monitor lipids at least annually to assess adherence and the need for treatment intensification is consistent with recommendations by the 2026 Dyslipidemia Guideline.⁶¹ For people with HIV who are not receiving statin therapy, lipid levels should be monitored every 1 to 3 years to reassess ASCVD risk. For all people with HIV, more frequent lipid monitoring may be necessary based on lifestyle factors or clinical scenarios, including changes in traditional ASCVD risk factors (e.g., weight gain, new diagnosis of hypertension, concomitant medications that affect lipids) or a change to an ARV regimen with increased ASCVD risk.

Atherosclerotic Cardiovascular Disease Risk Estimation

ASCVD risk prediction algorithms enable clinicians to quantify the risk of a future cardiovascular event and are used in clinical practice to stratify risk and to guide the intensity of ASCVD preventive measures and risk factor management, including statin use and antihypertensive therapy. Yet established ASCVD risk prediction scores validated in the general population typically do not include risk factors specific to HIV, and they have been shown to systematically underestimate risk among people with HIV. Data from multiple studies and a meta-analysis have shown that the ACC/AHA Pooled Cohort Equations (PCEs)—the widely used U.S.-based CVD risk score since 2013—underpredict ASCVD risk in people with HIV in high-income countries.^62-67 Studies also suggest the accuracy of established ASCVD risk scores for people with HIV may vary by patient demographics and clinical characteristics, with underprediction of ASCVD risk demonstrated among women,^62,65,66 Black or African-American individuals,^62,66 and individuals with low or moderate predicted CVD risk versus high predicted risk.^62,64,65 ASCVD risk score accuracy may also differ by region globally, with a study of REPRIEVE data showing underprediction of risk in high-income countries yet overprediction in low- and middle-income countries.⁶⁶

In 2023, the AHA developed a new set of ASCVD risk equations for the general population. The Predicting Risk of CVD EVENTs (PREVENT) equations differ from the PCEs on several levels, including the inclusion of a new derivation dataset of more than 6 million individuals; new variables reflecting a broader cardiovascular-kidney-metabolic framework; new outcomes, including heart failure; and the removal of race from the models.⁶⁸ However, like the PCEs, the PREVENT equations were developed for the general population and consequently do not incorporate HIV-specific risk factors. Predicted ASCVD risk has been shown to be lower using PREVENT-ASCVD in the general population⁶⁹ and in people with HIV,⁷⁰ with 97% of people with HIV having lower predicted risk and 58% fewer strongly recommended for statins using PREVENT-ASCVD (vs. PCEs). Similar to prior risk prediction scores, the PREVENT-ASCVD equations have been shown to underestimate risk among people with HIV. In a U.S. cohort of more than 13,000 people with HIV, the PREVENT-ASCVD equations underestimated risk to a greater extent than the PCEs, with the degree of underprediction approximately twice as large with PREVENT.⁷¹ In an analysis of the placebo arm of the REPRIEVE trial, the PREVENT-ASCVD equations similarly underestimated risk of MACE, including CVD-related death, MI, or stroke.⁷² Importantly, the underestimation of ASCVD event risk by PREVENT, when compared to PCEs, is also present in the general population, and the 2026 Dyslipidemia Guideline provides risk categories that account for these differences in absolute risk between PREVENT and PCE scores.

The 2026 Dyslipidemia Guideline recommends using the PREVENT-ASCVD equations rather than the PCEs to estimate risk and guide lipid-lowering therapy for primary prevention in adults aged 30 to 79 years. For people with HIV aged 30 to 79 years, 10-year ASCVD risk should be estimated using the PREVENT-ASCVD equations whenever lipids are measured or in certain clinical scenarios that may affect ASCVD risk (e.g., changes in traditional CVD risk factors, such as weight gain, new diagnosis of hypertension, concomitant medications that affect lipids, or change to an ARV regimen with increased ASCVD risk) (BIII). Of note, although statin therapy is recommended for all people with HIV aged 40 to 75 years regardless of ASCVD risk estimate (see Primary Prevention of ASCVD below), routine estimation of ASCVD risk should be done when lipids are monitored among people with HIV (even outside of this age range) for statin intensification and/or additional lipid-lowering therapy, and for management of CVD risk factors other than dyslipidemia. Presently, there is insufficient evidence to recommend strategies to account for the underprediction of ASCVD risk by PREVENT-ASCVD and other established ASCVD risk scores among people with HIV, including the use of inflammatory biomarkers.

Primary Prevention of ASCVD

Traditional Cardiovascular Disease Risk Factor Modification

Although HIV-specific factors influence CVD risk, traditional risk factors also play a critical role in the development and prevention of CVD among people with HIV. Many traditional risk factors both predict risk for CVD events and occur at higher rates among people with HIV when compared with the general population.^3,25,73 A 2025 global meta-analysis assessed common CVD risk factors among people with HIV and found higher odds of CVD incidence associated with DM, hypertension, dyslipidemia, smoking, and a prior history of CVD.⁷⁴ A U.S. population-based study among people with HIV found conventional risk factors, such as tobacco use, hypertension, and obesity, to be persistently associated with CVD incidence over follow-up periods of as long as 15 years.⁷⁵ Nontraditional CVD risk factors that are also more common in people with HIV, but are not specific to HIV disease itself, include alcohol use disorders, depression, and hepatitis C virus coinfection.

These data highlight the importance of traditional risk factor management among people with HIV. While CVD risk factors such as advancing age and other demographic characteristics are non-modifiable, many risk factors may be further optimized with behavioral and/or pharmaceutical interventions. A longitudinal study leveraging health system data found that associations between CVD risk and HIV status were attenuated when dyslipidemia and DM were well controlled.⁷⁶ For women with HIV, ensuring optimal CVD risk factor management is critical given the greater relative risk of ASCVD and underperformance of ASCVD risk score algorithms.

Optimal management of comorbidities (e.g., hypertension, diabetes, obesity, smoking) and lifestyle factors remains important to further reduce CVD risk among people with HIV. The AHA has further outlined “Life’s Essential Eight” as modifiable risk factors that can be targeted to improve cardiovascular health for everyone (regardless of HIV infection), and these include: healthy diet; participation in physical activity; smoking cessation; healthy sleep; healthy weight; and healthy levels of blood lipids, blood glucose, and blood pressure.⁷⁷ Management strategies and treatment goals for optimizing traditional risk factor profiles are outlined in guidelines established for the general population.^61,78,79

Rationale for Statin Therapy and the REPRIEVE Trial Results

The increased ASCVD risk associated with HIV disease and/or ARV exposure, despite viral suppression and optimizing traditional risk factor management, has motivated research on lower thresholds for use of primary CVD prevention strategies. Statins may offer advantages for people with HIV over other prevention pharmacotherapy, given that statin therapy is associated with a well-described reduction in ASCVD events as well as treatment effects on inflammatory pathways.^80-82 

REPRIEVE provided evidence that the use of statin therapy as primary prevention for people with HIV who otherwise did not have an indication for statin reduced risk of ASCVD events. REPRIEVE was a Phase 3 global randomized placebo-controlled trial of oral daily pitavastatin 4 mg that enrolled 7,769 people with HIV who were aged 40 to 75 years and at low-to-intermediate risk based on 10­year ASCVD risk estimates (using PCEs) and LDL cholesterol levels.²⁰ People with known ASCVD were excluded. The primary outcome was the occurrence of MACE, defined as a composite of cardiovascular disease death; MI; hospitalization for unstable angina; stroke; transient ischemic attack; peripheral arterial ischemia; revascularization of coronary, carotid, or peripheral artery; or death of undetermined cause. Study participants were 31% female, had a median age of 50 years, had a median CD4 T cell count of 621 cells/mm³, and 88% had an undetectable HIV RNA level. Compared to placebo, pitavastatin was associated with a 36% reduction in MACE (hazard ratio 0.64; 95% confidence interval [CI], 0.48–0.84), with event rates of 7.77 and 4.95 per 1,000 person-years, respectively, over a median follow-up of 5.6 years. In REPRIEVE, the absolute risk reduction was substantially greater for people with ASCVD risk estimates of ≥5% compared to those with risk of <5% (estimated using PCEs). Finally, incident diabetes (incident rate ratio [IRR] 1.29; 95% CI, 1.07–‍1.57) and Grade ≥3 or treatment-limiting muscle-related symptoms (IRR 1.58; 95% CI, 1.14–‍2.19) were also higher in the pitavastatin group.

Recommendations for Use of Statin Therapy Among People With HIV

The 2026 Dyslipidemia Guideline for the general population issues recommendations for people with HIV based on data from REPRIEVE.⁶¹

For People With HIV Aged 40–75 Years

Among all people with HIV aged 40–75 on stable ART, the Panel concurs with the strong recommendation from the 2026 Dyslipidemia Guideline (section 4.2.8.9) to initiate statin therapy regardless of LDL-C or estimated ASCVD risk to reduce the risk of a first ASCVD event and reduce the rate of coronary atherosclerosis progression. For these patients, additional testing is not specifically recommended for risk stratification for statin initiation. The full 2026 Dyslipidemia Guideline should be referenced for additional details, including LDL-C goals and thresholds for statin intensification.

For People With HIV Aged <40 or >75 Years

The REPRIEVE trial did not enroll people with HIV aged <40 years or >75 years. In this context, the 2026 Dyslipidemia Guideline does not issue a recommendation for statins specific to people with HIV aged <40 or >75 years and instead references additional sections that provide guidance on primary prevention for adults aged 19–39 years and adults with LDL-C <190 mg/dL (aged 30–‍79 years) regardless of HIV status. The Panel has also determined there is insufficient evidence to issue a recommendation for or against statin therapy as primary prevention for people with HIV aged <40 or >75 years. For these patients, decisions on use of statin therapy should be informed by benefit–risk discussions with patients and apply decision algorithms based on 10-year risk estimates (using PREVENT-ASCVD), as outlined in the 2026 Dyslipidemia Guideline. For these decisions, HIV is an ASCVD risk enhancer that can help support the use of statin therapy if a statin is not already recommended (e.g., for those with a borderline 10-year risk as defined by PREVENT-ASCVD 3–‍5%), in addition to the ASCVD risk enhancers in the 2026 Dyslipidemia Guideline (see Table 11b below).

The 2026 Dyslipidemia Guideline recommends using the presence of coronary artery calcium (CAC) to improve risk assessment among those with “borderline” or “intermediate” risk (as estimated by PREVENT-ASCVD). There is no HIV-specific recommendation for using CAC scoring for risk stratification, beyond guidance provided for the general population within the 2026 Dyslipidemia Guideline. In people without HIV, the assessment of CAC is generally recommended for use in men aged ≥40 years and women aged ≥45 years; people with HIV in these age groups are already recommended to initiate statin therapy, making assessment of CAC to guide decision-making less relevant. Additionally, given the predominance of noncalcified plaque in people with HIV, it should be noted that the absence of CAC may not reflect lower risk in this context.

Additional Considerations for Decisions on Use of Statin Therapy

Statin therapy should be avoided for women with HIV who are pregnant or are planning to become pregnant. Specifically, initiation of statin therapy should be deferred until after pregnancy for those with HIV where statin therapy is recommended and should be discontinued if pregnancy occurs for those on statin therapy. As in the general population, breastfeeding is not recommended while taking statin therapy.

Some patients may be hesitant to start statin therapy despite recommendations and/or clinical scenarios in which statin therapy is favored. In these cases, clinicians should work to identify factors underlying a patient’s concern and provide education or support to alleviate these concerns when feasible. In addition, the presence or absence of additional ASCVD risk enhancers may help inform and/or strengthen the rationale for statin therapy when discussing with patients through shared decision-making. Table 11a lists HIV-related factors that further increase ASCVD risk,25 such as prolonged HIV viremia or low nadir CD4 count.

Table 11b lists additional risk enhancers identified within the 2026 Dyslipidemia Guideline. For example, factors that are not specific to HIV, including clinical measurement of Lp(a), ApoB, and high-sensitivity C-reactive protein (hsCRP), may be helpful to further inform decisions on statin therapy in this context. Risk enhancers can help support initiation of statin therapy when decisions are based on risk assessments (e.g., for people <40 years old) and/or for people who are hesitant to start statin therapy.

Rationale for the Panel’s Recommendation on Choice and Dose of Statin

Although there are no clinical outcome comparative effectiveness trials of different statins among people with HIV, additional studies beyond REPRIEVE support the treatment effect of certain other statins (other than pitavastatin) for lipid lowering, reductions in inflammation, and improvements in surrogate imaging measures. Pitavastatin, atorvastatin, and rosuvastatin are all associated with greater reductions in LDL-‍C among people with HIV than pravastatin. In addition, pitavastatin (4 mg daily), rosuvastatin (10 mg daily), and high-dose atorvastatin (80 mg daily) have each demonstrated reductions in inflammation among people with HIV.^83-85 Finally, in two separate Phase 2 placebo-controlled randomized trials among people with HIV, atorvastatin (20 mg daily) was associated with reductions in coronary noncalcified plaque, and rosuvastatin (10 mg daily) was associated with slower progression of carotid artery intima-media thickness.^86,87 Cumulatively, these data motivated the Panel’s recommendation that moderate-intensity statin therapy include either pitavastatin 4 mg daily, atorvastatin 20 mg daily, or rosuvastatin 10 mg daily, with the level of evidence differing between statins (see Table 11c).

The 2026 Dyslipidemia Guideline classifies statin intensity as high, moderate, and low intensity.⁶¹ Table 11c below outlines the statin agent and dose that qualify for each intensity, as well as the anticipated LDL­C lowering effect. Specifically, for every 39 mg/dL reduction in LDL­C, there is approximately a >20% reduction in ASCVD events and a 10% reduction in all-cause mortality.⁸⁸ However, it should also be noted that the magnitude of LDL­C lowering varies in clinical practice.

Common Adverse Effects of Statins

Statin therapy is well tolerated and safe; however, some side effects have been observed. The most frequent adverse events are statin-associated muscle symptoms, with reported occurrence in 5% to 25% of people who receive statins.⁸⁹

All statins have been implicated in small increases in both relative and absolute risk of diabetes. The increased risk of diabetes with statin use has been associated with older age and the presence of at least two risk factors, such as elevated baseline fasting glucose level, elevated fasting triglycerides, elevated body mass index, or history of hypertension.^90,91 Mild increases in liver enzymes are seen in some individuals, although these are usually transient without clinical complications. 

Interactions Between Antiretroviral Drugs and Drugs for Treatment or Prevention of Cardiovascular Diseases

People with HIV may receive medications for the treatment or prevention of CVD. Some of these drugs (especially antiarrhythmics, anticoagulants, calcium channel blockers, beta blockers, and statins) may have clinically significant interactions with some ARV drugs. Before initiating or changing these medications, clinicians should carefully assess for potential interactions (AIII). The Liverpool HIV Drug Interaction Checker provides guidance for managing these interactions. Major mechanisms of pharmacokinetic interactions between ARV drugs and cardiac drugs are noted below.

For the prevention of ASCVD, among the statins, pitavastatin, pravastatin, and rosuvastatin are not significantly metabolized by cytochrome P450 (CYP) enzymes. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4, whereas fluvastatin is a major substrate of CYP2C9. Lovastatin and simvastatin are contraindicated when coadministered with cobicistat- or ritonavir-boosted ARVs. All statins are susceptible to interactions related to drug transporters (e.g., OATP1B1).⁹²

Other Management Considerations and Unanswered Questions

Estrogen, Progestins, or Testosterone Therapy and Cardiovascular Risk

Studies have produced conflicting results on associations between estrogen, progestins, or testosterone therapy and CVD risk, varying by study design, study population, duration and timing of therapy, and other clinical factors.^93-96 Research on relationships between these drugs and CVD among people with HIV is even more limited.^97-100 Data on testosterone use among people with HIV have been limited to the treatment of testosterone deficiency and lack longitudinal information on CVD-related outcomes.^101,102 Studies of estrogen use suggest a potential increase in CVD risk; however, this association may vary by dose, mode of delivery, and underlying physiological stress.^95-‍97,103 A longitudinal study of combined estrogen and progestin use for oral contraception among people with HIV suggested increased CVD risk, although the association was not statistically significant.¹⁰⁴

As the population with HIV ages, a growing number of women with HIV are entering menopause. CVD is the leading cause of morbidity and mortality in menopausal women, and this risk is increased in women with HIV.^105,106 Studies of the cardiovascular risk associated with menopausal hormone therapy have led to changes in guidelines over the years.¹⁰⁶ Systemic hormone therapy is not currently recommended for CVD prevention or treatment.¹⁰⁷ However, hormone therapy remains the most effective treatment for vasomotor symptoms.¹⁰⁸ Some research suggests that women with HIV are undertreated for menopausal symptoms.¹⁰⁹ However, data are lacking on menopause and hormone therapy in women with HIV, including whether menopause amplifies the effects of HIV on CVD risk.¹¹⁰ Current HIV primary care guidelines recommend that menopause-related hormone therapy for women with HIV should not differ from the care of women without HIV.¹¹¹

Cardiovascular Risks of Adults Who Acquired HIV Perinatally or During Adolescence

An increasing number of adults acquired HIV perinatally or during adolescence, but the cardiovascular effects of perinatal or adolescent HIV acquisition and long-term ART use are unclear. For individuals who acquired HIV perinatally, it is hypothesized that exposure to HIV and ART in utero while the cardiovascular system is developing, use of older ART drugs with cardiometabolic and mitochondrial toxicity, lifelong duration of infection, and a longer period of chronic inflammation may further exacerbate the already heightened CVD risk observed in people with HIV. Investigation of the cardiovascular complications of perinatal HIV infection has largely focused on youth and adolescents. Abnormalities in cardiac structure and function have been well documented and include systolic and diastolic dysfunction, left ventricular hypertrophy and dilatation, and myocardial fibrosis.^112-117 Studies of perinatally acquired HIV have also demonstrated elevated rates of surrogate markers of atherosclerosis (including carotid intima-media thickness, arterial stiffness, and endothelial dysfunction),^118,119 impaired glucose metabolism and insulin resistance,¹²⁰ lipodystrophy and metabolic syndrome,¹²¹ and increased Pathobiological Determinants of Atherosclerosis in Youth (or PDAY) cardiovascular risk scores.^122,123 Adults with perinatally acquired HIV also appear to be at risk for cardiometabolic comorbidities, with a large North American study of young adults aged 18–‍30 years demonstrating a high incidence of DM, hypercholesterolemia, hypertriglyceridemia, hypertension, and chronic kidney disease.¹²⁴ Current gaps in knowledge regarding CVD risk among those who acquired HIV perinatally or during adolescence include (1) the clinical significance of cardiac structural and functional abnormalities and surrogate markers of atherosclerosis with respect to coronary plaque and cardiac endpoints; (2) whether the epidemiology and pathophysiology of CVD differ for people with similar durations of perinatally versus horizontally acquired HIV, including HIV acquired during adolescence; (3) whether the epidemiology and pathophysiology of CVD differ for people in low- and middle-income versus high-income countries; (4) the optimal approach to estimate ASCVD risk and frequency of monitoring in adults who acquired HIV perinatally or during adolescence; and (5) whether primary prevention approaches (e.g., statins) for adults with HIV aged 40 and older apply to younger adults who acquired HIV perinatally or during adolescence.

Knowledge Gaps

• More research is needed on strategies to improve ASCVD risk stratification among people with HIV, including the utility of using inflammatory biomarkers, other non-traditional risk factors, Lp(a) and ApoB levels, and CAC estimates.
• More research is needed on recommended strategies for primary prevention of ASCVD among people with HIV aged <40 or >75 years.
• More research is needed on the role of immunomodulatory therapy to reduce HIV-associated ASCVD risk.
• More research is needed on the epidemiology, pathophysiology, risk estimation, prevention, and management strategies for ASCVD in key subgroups, including—
  • Women with HIV
  • People who acquired HIV perinatally or during adolescence (see Cardiovascular Risks of Adults Who Acquired HIV Perinatally or During Adolescence above for current knowledge gaps)
  • People with HIV across different geographic regions globally 
• More research is needed on the role of HIV in non-ASCVD manifestations, including stroke, heart failure, arrhythmia, sudden cardiac death, and thrombosis.
• More research is needed on the association of CVD risk with INSTI-based ART, as well as newer regimens entering clinical practice.
• More research is needed on HIV-specific recommendations for pharmacotherapy targeting traditional risk factors (e.g., dyslipidemia, hypertension, diabetes, chronic kidney disease), such as lower thresholds for primary prevention, treatment goals and medication intensification, non-statin lipid-lowering therapy (including PCSK-9 inhibitors), and secondary prevention.
• More research is needed on implementation strategies for primary prevention of ASCVD among people with HIV.

References

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