2025 HHS建议：他汀类药物治疗作为 HIV 感染者的一级预防

Statin Therapy as Primary Prevention for Persons With HIV: A Synopsis of Recommendations From the U.S. Department of Health and Human Services Antiretroviral Treatment Guidelines Panel

Craig Beavers, PharmD; Alice K. Pau, PharmD; David Glidden, PhD; Emily Hyle, MD, MSc; Safia Kuriakose, PharmD; Seth S. Martin, MD, MHS; Grace McComsey, MD; Melanie Thompson, MD; Salim Virani, MD, PhD; and Jason V. Baker, MD, MS

Description: REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) showed bene fi ts of pitavastatin as preventive therapy for atherosclerotic cardiovascular disease (ASCVD) in people with HIV (PWH). In February 2024, the U.S. Department of Health and Human Services Panel for the Use of Antiretroviral Agents in Adults and Adolescents with HIV (ARV Guidelines Panel) developed statin therapy recommendations for PWH. These recommendations were issued in collaboration with representatives from the American College of Cardiology (ACC), the American Heart Association (AHA), and the HIV Medicine Association (HIVMA). This synopsis summarizes the development process, the recommendations, and how they supplement the AHA/ACC/multisociety cholesterol guidelines and outlines gaps in primary prevention of ASCVD for PWH.

Methods: The ARV Guidelines Panel convened a writing group of 10 members (6 members of the Panel with expertise in HIV-related comorbid conditions, biostatistics, and pharmacology and 4 consultants representing ACC, AHA, and HIVMA with cardiometabolic and HIV management expertise). The writing

A dvances in antiretroviral therapy (ART) for treatment of HIV have signi fi cantly improved life expectancy for people with HIV (PWH) over the past 3 decades. The causes of morbidity and mortality in PWH who achieve appropriate viral suppression are now dominated by conditions not related to AIDS (1, 2). Compared with people without HIV, PWH are at higher risk for many common aging-related diseases, such as atherosclerotic cardiovascular disease (ASCVD). This is likely due to increased prevalence of traditional ASCVD risk factors, prior immune depletion, in fl ammation caused by HIV viral persistence, toxicity from some antiretroviral (ARV) medications, higher rates of such risk factors as smoking than the general population, or some combination of these factors (1 – 3). Despite the clear increased risk for ASCVD, no de fi nitive clinical data are available to inform broader or earlier use of primary ASCVD prevention strategies among PWH, compared with what is recommended in the general population. The recently completed study REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) provided high-quality clinical outcomes data to inform the use of 3-hydroxy-3-methylglutaryl coenzyme A

group reviewed REPRIEVE trial data, other studies evaluating the use of statins in PWH, and the AHA/ ACC/multisociety cholesterol guidelines to devise recommendations. Recommendations were based on scienti fi c evidence with a rating scheme developed since the 1998 inception of the ARV guidelines. Proposed recommendations were presented to the full ARV Guidelines Panel, rated via vote, and approved by the Panel ’ s voting members. These recommendations were then endorsed by ACC, AHA, and HIVMA.

Recommendations: The ARV Guidelines Panel issued a strong recommendation for initiating statin therapy among PWH with a 10-year ASCVD risk score of $5\%$ or higher, whose absolute bene fi t from statins in REPRIEVE was greatest. For patients with a 10-year ASCVD risk score below $5\%,$ the Panel favored statins but recommended patient – clinician risk discussions considering additional HIV-related factors that can increase ASCVD risk.

Ann Intern Med. doi:10.7326/ANNALS-24-03564 For author, article, and disclosure information, see end of text. This article was published at Annals.org on 27 May 2025.

reductase inhibitor (that is, statin) therapy as primary prevention among PWH. In response to the evidence from REPRIEVE, in February 2024, the U.S. Department of Health and Human Services Panel for the Use of Antiretroviral Agents in Adults and Adolescents with HIV (ARV Guidelines Panel) developed recommendations for use of statin therapy among PWH in collaboration with representatives from the American College of Cardiology (ACC), the American Heart Association (AHA), and the HIV Medicine Association (HIVMA) (4). This article provides a synopsis of the ARV Guidelines Panel ’ s recommendations ( Table 1 ), the process and rationale for developing these recommendations, and how they supplement the AHA/ACC/multisociety guidelines for the general population.

See also:

Editorial comment Web-Only Supplement

Table 1.

ARV Guidelines Panel ’ s Recommendations for Statin Therapy for Primary Prevention for PWH\*

For PWH aged 40 – 75 y who have low to intermediate $(<\!\pmb{z}0\%)$ ) 10-y ASCVD risk estimates

When 10-y ASCVD risk estimates are $5\%$ to ${<}20\%$ , the ARV Guidelines Panel recommends initiating at least moderate-intensity statin therapy (AI). Recommended options for moderate-intensity statin therapy include the following: Pitavastatin, 4 mg once daily (AI) Atorvastatin, 20 mg once daily (AII) Rosuvastatin, 10 mg once daily (AII) When 10-y ASCVD risk estimates are ${\mathfrak{<}}5\%,$ , the Panel favors initiating at least moderate-intensity statin therapy (CI). The absolute bene fi t from statin therapy is modest in this population; therefore, the decision to initiate statin therapy should take into account the presence or absence of HIV-related factors that can increase ASCVD risk. Same options for moderate-intensity statin therapy as recommended for 10-y ASCVD risk estimates of $5\%$ to ${<}20\%$ (see above).

For PWH aged ${\tt<}{\tt40}\,{\tt y}$

Data are insuf fi cient to recommend for or against statin therapy as primary prevention of ASCVD in PWH in this age group. In the general population, lifestyle modi fi cations are recommended, with statin therapy considered only in selected populations (see AHA)/ACC/multisociety guidelines).

Key recommendations for the general population (including PWH) based on AHA/ACC/multisociety guidelines

For people aged 40 – 75 y with high $({\geq}20\%)$ 10-y ASCVD risk estimates, initiate high-intensity statin therapy. For people aged 20 – 75 y with an LDL-C level ${\geq}4.92\;\mathsf{m m o l/L}$ $\scriptstyle\lambda\geq190\;{\mathsf{m g}}/{\mathsf{d L}})$ , initiate high-intensity statin therapy at maximum tolerated dose. For people aged 40 – 75 y with diabetes mellitus, initiate at least moderate-intensity statin therapy. Perform further risk assessment to consider using a high-intensity statin.

Key considerations

Coadministration of certain statins and antiretroviral drugs may result in signi fi cant drug – drug interactions (see Table 4). In some cases, the interaction may require statin dose adjustment, switching to another statin, or increased monitoring for statin-related adverse effects.

be discontinued if a person with HIV becomes pregnant. Breastfeeding is not recommended while a person is receiving statin therapy.

ACC $=$ American College of Cardiology; AHA $=$ American Heart Association; ARV Gu elines Panel $=0.5$ . Department of Health nd Human Services Panel for the Use of ntiretroviral Agents in Adults and Adolescents with HIV; ASCVD ¼ atherosclerotic cardiovascular disease; LDL-C ¼ low-density lipoprotein cholesterol; PWH $=$ ¼ people with HIV.

\* Modi fi ed from https://clinicalinfo.hiv.gov/sites/default/ fi les/guidelines/archive/adult-adolescent-arv-statin-therapy-2024-02-27.pdf. Rating of recommendations: $\mathsf{A}=$ strong, ${\mathsf{B}}=$ moderate, and ${\mathsf{C}}=$ weak. Rating of evidence: $|=$ data from randomized controlled trials; $||=$ data from welldesigned nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; and III ¼ expert opinion.

## CLINICAL SIGNIFICANCE OF ASCVD AMONGPWH

With continuous ART and viral suppression, the life expectancy of most PWH has become closer to that of people without HIV, with the estimated mortality gap now reduced to 10 years or less (1). However, compared with people without HIV, PWH have about a twofold higher risk for developing ASCVD, and their age at incident ASCVD diagnosis is about a decade younger (1, 2). Factors contributing to the development of early ASCVD include higher prevalence of traditional cardiometabolic risk factors, including obesity and smoking; incomplete immune recovery despite effective ART; toxicity of speci fi c ARV medications; and ongoing systemic in fl ammation associated with HIV (2 – 5). Risk prediction tools for ASCVD used for the general population tend to underestimate risk among PWH (5, 6), and this underperformance is likely due to HIV disease-speci fi c factors, such as systemic in fl ammation despite ART (7, 8).

Data from epidemiologic studies have established that ASCVD risk is associated with higher levels of biomarkers of in fl ammation among PWH than control participants without HIV (9 – 14). Recent data also suggest that the relative increase in ASCVD risk associated with HIV is greater among women than age-matched men, when comparing populations with and without HIV (8, 15). The mechanisms of gender- and sex-related differences in HIV-associated CVD risk broadly are an area

of active investigation that may also be in fl uenced by chronic immune activation (16, 17). Finally, structural barriers and health disparities in screening and treatment of ASCVD risk factors likely also contribute to excess ASCVD risk among PWH in the United States (18, 19).

Statins have long been posited to have advantages for PWH over other primary prevention strategies because they are associated with a well-described reduction in ASCVD events, as well as their treatment effects on in fl ammatory pathways (20 – 22). However, before the current ARV Guidelines Panel ’ s recommendations, there were no recommendations for statin therapy as primary ASCVD prevention speci fi cally among PWH (23 – 26).

AHA/ACC/M ULTISOCIETY S TATIN G UIDELINE FOR THE G ENERAL P OPULATION

The 2018 AHA/ACC/multisociety guideline on the management of blood cholesterol recommends a heart-healthy lifestyle across the spectrum of prevention, as well as using a risk-based approach to guide who should be considered for statin therapy (24). This risk-based approach allows clinicians to base the intensity of therapy on an individual ’ s absolute ASCVD risk, thereby providing preventive therapies to people who are likely to bene fi t the most. The guidelines recommend estimation of 10-year ASCVD risk as the fi rst

step and a patient – clinician risk discussion before initiation of statin therapy. To guide this discussion, the pooled cohort equations (PCEs) are used to estimate 10-year ASCVD risk, along with consideration of several risk enhancers not currently captured in the PCEs. Brie fl y, the PCEs are a validated sex- and race-speci fi c tool based on U.S. populations derived from 5 communitybased studies to estimate 10-year ASCVD risk (25). The PCEs perform well in risk estimation in a general U.S. population, with high con fi dence in non-Hispanic Black and White men and women. The performance of the PCEs in people from outside the United States or with varying degrees of chronic kidney disease or chronic in fl ammatory disease is highly variable because of the heterogeneous nature of the populations, differences in the prevalence of risk factors, and differences in population risk for ASCVD (25). Furthermore, the PCEs are not validated in those younger than 40 years.

These guidelines recommend initiation of highintensity statin therapy for persons who are aged 40 to 75 years with a low-density lipoprotein cholesterol (LDL-C) level of at least 4.92 mmol/L $(\geq\!190\ \mathsf{m g}/\mathsf{d L})$ or a high $({\geq}20\%)$ 10-year ASCVD risk, and they recommend initiation of at least moderate-intensity statin therapy for those with diabetes mellitus ( Table 1 ). Among adults who are aged 40 to 75 years with intermediate $7.5\%$ to $19.9\%$ ) 10-year ASCVD risk, consideration of risk-enhancing factors (such as HIV infection) and patient – clinician discussion are recommended before initiating moderate-intensity statin therapy. The guidelines provide a comprehensive overview of all risk-enhancing factors, which are not within the scope of this review.

M ETHODS FOR U.S. D EPARTMENT OF H EALTH AND H UMAN S ERVICES A NTIRETROVIRAL T REATMENT G UIDELINES D EVELOPMENT AND I SSUANCE OF R ECOMMENDATIONS FOR S TATIN U SE IN PWH

The fi rst version, “ Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, ” was published in Morbidity and Mortality Weekly Report in 1998 (27). As advances in ART have continued to evolve over the ensuing 27 years, these guidelines have been maintained as a web-based “ living guideline ” with updates issued at least annually. The ARV Guidelines Panel includes a multidisciplinary team of members with expertise in HIV clinical practice and research, biostatistics, pharmacology, and related fi elds. All members provide a fi nancial disclosure annually, which is publicly available on the guidelines website. Supplement Table 1 (available at Annals. org) describes the guideline development process. Recommendations in these guidelines are based on scienti fi c evidence and expert opinion, with a rating scheme developed since the guidelines ’ inception in

1998. Panel members with expertise in the topics of interest review and assess scienti fi c evidence from published data. Each recommendation statement includes a letter (A, B, or C) that represents the strength of the recommendation and a Roman numeral (I, II, or III) that represents the quality of the evidence that supports the recommendation. Supplement Table 2 (available at Annals.org) provides a schema of the recommendation ratings in the guidelines. These guidelines traditionally focus on the use of ART in PWH. However, because the REPRIEVE trial established the bene fi t of pitavastatin among PWH at low to intermediate ASCVD risk, the Panel believed it was crucial for HIV providers to have a set of recommendations on the optimal use of statins in PWH. To broaden the expertise in CVD and statin use, the ARV Guidelines Panel also invited members from ACC, AHA, and HIVMA to form a writing group of 10 members (6 from the ARV Guidelines Panel, 1 from ACC, 2 from AHA, and 1 from HIVMA). The writing group reviewed data from the REPRIEVE study (28, 29) and other studies evaluating the use of statins in HIV (30 – 36), as well as the AHA/ACC/multisociety cholesterol guidelines (24), to draft the recommendations and ratings. The proposed recommendations were presented to the full ARV Guidelines Panel for discussion and further revision, and the Panel ’ s voting members ultimately voted on and approved each rated recommendation statement. These recommendations received formal endorsement from ACC, AHA, and HIVMA.

RECOMMENDATIONS FOR STATIN THERAPY ASPRIMARY PREVENTION AMONG PERSONS WITHHIV

Table 1 and the Figure summarize the ARV Guidelines Panel ’ s recommendations and considerations to inform the use of statin therapy for primary prevention of ASCVD in PWH receiving care in the United States. The recommendations should be considered in the context of appropriate viral suppression.

Results From the REPRIEVE Study

REPRIEVE was a phase 3, global, randomized controlled trial of oral pitavastatin, 4 mg daily, versus placebo for the prevention of ASCVD in PWH aged 40 to 75 years at low to intermediate risk based on 10-year ASCVD risk estimates, as determined by the score on the AHA and ACC 2013 PCE risk calculator. Low to intermediate risk was de fi ned as up to $15\%$ based on LDL-C level ( ≥ 1.81 mmol/L [ ≥ 70 mg/dL]) in conjunction with LDL-C levels below speci fi c thresholds (28, 29). People with known ASCVD were excluded, and further eligibility criteria were based on LDL-C thresholds that varied on the basis of 10-year risk estimates for ASCVD (up to a risk of $15\%$ ). The primary outcome was the occurrence of major adverse cardiac events (MACE), de fi ned as a composite of CVD death; myocardial infarction (MI);

 Figure. Recommendations for statin therapy as primary prevention among persons with HIV from the U.S. Department of Health and Human Services Panel for the Use of Antiretroviral Agents in Adults and Adolescents with HIV.

ASCVD $=$ atherosclerotic ca ovascular disease; ${\mathsf{D M}}=$ diabetes mellitus; LDL-C $=$ low-density lipoprotein cholesterol. Rating of recommendations: A = strong. Rating of evidence: I = data from randomized controlled trials; $||=$ data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies. (Adapted with modi fi cations from the ACC.org with permission from www.acc.org/Latest-in-Cardiology/Articles/2024/08/01/01/42/For-the-FITs-Closing-theMortality-Gap-For-People-Living-With-HIV-Updated-Recommendations-For-Statins-For-Primary-Prevention-of-ASCVD.)

hospitalization for unstable angina; stroke; transient ischemic attack; peripheral arterial ischemia; revascularization of coronary, carotid, or peripheral artery; or death of undetermined cause. A total of 7769 PWH receiving ART enrolled in the trial; $31\%$ were female, $53\%$ were from high-income countries (HICs), $4\,\uparrow\,\%$ were Black, and $35\%$ were White. Participants had a median age of 50 years (IQR, 45 to 55 years), a median 10-year ASCVD risk of $4.5\%$ (IQR, $2.1\%$ to $7.0\%)$ , and a median CD4 T lymphocyte (CD4) cell count of $0.621\times10^{9}$ cells/L (IQR, 0.448 to $0.827\times10^{9}$ cells/L); 49% had a prior CD4 count nadir below $0.200\times10^{9}\ {\sf c e l l s/L},$ and $88\%$ had an HIV RNA level below the lower limit of quanti fi cation.

Compared with placebo, pitavastatin was associated with a $36\%$ reduction in MACE (hazard ratio, 0.64 $[95\%$ CI, 0.48 to 0.84]), with event rates of 7.77 and 4.95 per 1000 person-years, respectively, over a median follow-up of 5.6 years. A similar treatment effect was present across the individual components of MACE. Median levels of LDL-C were 2.77 mmol/L (107 mg/dL) at baseline and 1.92 mmol/L (74 mg/dL) at month 12 in the pitavastatin group, compared with 2.75 mmol/L (106 mg/dL) at baseline and 2.72 mmol/L (105 mg/dL) at month 12 in the placebo group. Adverse events of grade 3 or higher and treatment-limiting, musclerelated symptoms occurred at higher rates in the pitavastatin group $(2.4\%)$ than in the placebo group $(1.5\%)_{r}$ , as did incident diabetes mellitus $6.0\%$ vs. $4.7\%;$ ; incidence rate ratio, 1.35 [CI, 1.09 to 1.66]).

Rationale for the ARV Guidelines Panel ’ s Recommendations According to ASCVD Risk Estimate

The overall fi ndings from REPRIEVE, combined with the observation that equations based on traditional risk factors underestimate ASCVD risk among PWH, informed the Panel ’ s decision to recommend the use of at least moderate-intensity statin therapy as primary prevention among PWH aged 40 to 75 years with low to intermediate 10-year ASCVD risk $(<\!20\%)$ . To inform whether some participants received greater bene fi t from pitavastatin, subgroup analyses were done in REPRIEVE (27, 28). Relative risk reductions across subgroups de fi ned by key demographic and clinical characteristics did not show a clear interaction with the treatment effect. When incident MACE was strati fi ed by 10-year ASCVD risk score, the absolute reduction in events was greatest for people with an ASCVD risk of at least $5\%$ . Table 2 reports the estimated number needed to treat over 5 years $({\sf N N T}_{5})$ to prevent incident MACE events with pitavastatin. Of note, the NNT 5 for people with an ASCVD risk of at least $5\%$ was one quarter to one third that for people with an ASCVD risk less than $5\%$ . These subgroup estimates of ${\mathsf{N N T}}_{5}$ motivated the Panel to issue separate recommendations for people with ASCVD risk above and below $5\%$ . These estimates are based on low numbers of events and should be interpreted with caution.

The relationship between a higher absolute benefi t from statin therapy (that is, lower ${\mathsf{N N T}}_{5}.$ ) and higher

|Table 2. NNT5 Based on REPRIEVE*||| |---|---|---| |10-Year ASCVD Risk Score, %|Participants, n (%)|nnts| |>10|563(7)|34| |5-10|2995 (39)|53| |2.5-|||

ASCVD $=$ atherosclerotic cardiov cular disease; ${\mathsf{N N T}}_{5}\mathrm{{=}}$ number needed to treat over 5 years; REPRIEVE $=$ ¼ Randomized Trial to Prevent Vascular Events in HIV. \* Modi fi ed from https://clinicalinfo.hiv.gov/sites/default/ fi les/guidelines/ archive/adult-adolescent-arv-statin-therapy-2024-02-27.pdf. Data from reference 29.

baseline ASCVD risk estimates is well described. This relationship should be used to inform shared decision-making discussions with PWH on the use of statins (24). Discussions on statin therapy should take into account the bene fi ts, along with adverse effects, costs, drug – drug interaction (DDI) potential, and other patient-centered factors. The discussion should also include the increased risk for diabetes and musclerelated symptoms reported in REPRIEVE and rates of other adverse events associated with statin therapy.

The fi ndings from REPRIEVE related to the higher absolute bene fi t of statin therapy among people with greater ASCVD risk motivated the Panel ’ s decision to issue a stronger recommendation (AI) for initiating statin therapy among people with a 10-year ASCVD risk score of $5\%$ or higher. Where the absolute bene fi t from statin therapy was more modest among participants with low estimated ASCVD risk $(<\!5\%),$ , the Panel issued a weaker recommendation (CI) and highlighted that HIV-related factors not considered by the PCEs are important to consider during patient – clinician risk discussions. Using a large body of observational data, the AHA identi fi ed HIV-related factors that enhance ASCVD risk, including the following: history of prolonged HIV viremia (whether due to delayed ART initiation, nonadherence, or treatment failure), low current or nadir CD4 count $(<\!0.350\times10^{9}$ cells/L), lipodystrophy or lipoatrophy, metabolic syndrome, fatty liver disease, and co-infection with hepatitis C (29). Additional HIV-related factors associated with greater ASCVD risk may include but are not limited to longer duration of HIV infection and exposure to older ARV drugs with cardiometabolic toxicity (such as zidovudine, protease inhibitors, or abacavir). Conversely, people diagnosed with HIV who initiated ART with contemporary regimens (for example, integrase inhibitors) at higher CD4 counts (for example, ${>}5{\bar{0}}\times10^{9}$ cells/L) are likely to be at lower absolute ASCVD risk.

Use of Statins Among PWH Younger Than 40 Years

REPRIEVE did not enroll PWH younger than 40 years, and the PCEs do not provide 10-year ASCVD risk estimates for persons under 40. In the general population,

lifestyle modi fi cations to address traditional risk factors (such as diet, exercise, smoking cessation, and blood pressure control) are recommended for people younger than 40 years (24). Still, some younger persons would likely bene fi t from statin therapy, such as those with familial hypercholesterolemia or LDL-C levels of 4.92 mmol/L $\scriptstyle(\geq190^{\circ}\,{\mathsf{m g}}/{\mathsf{d L}})$ or higher (in whom high-intensity statin therapy is recommended) or adults with a family history of premature ASCVD (which may also favor statin therapy) (24). Data are insuf fi cient to inform whether risk enhancers, such as HIV-related factors, would favor statin therapy among people younger than 40 years. However, some younger PWH may be at increased ASCVD risk in the intermediate term or over their lifetime — particularly those with a very long duration of HIV infection (for example, due to perinatal exposure). Decisions on statin therapy should be individualized among this population.

C ONSIDERATIONS ON C HOICE OF S TATIN T HERAPY FOR PWH

In REPRIEVE, pitavastatin was chosen in part because of less DDI potential with certain ARV medications than other statins (30, 31). Although no comparative effectiveness trials have studied various statins among PWH, studies support the treatment effect of other moderateintensity statins for lipid lowering, reducing in fl ammation and immune activation, and alleviating surrogate measures of ASCVD ( Table 3 ). Pitavastatin, atorvastatin, and rosuvastatin are all associated with greater reductions in LDL-C among PWH than pravastatin. In addition, pitavastatin (4 mg daily), rosuvastatin (10 mg daily), and highdose atorvastatin (80 mg daily) all have shown reductions in in fl ammatory, monocyte, and T-cell immune activation biomarkers among PWH (32 – 34). Finally, in 2 separate phase 2, placebo-controlled randomized trials of statin therapy for PWH, atorvastatin (initiated at 20 mg daily) was associated with reductions in coronary noncalci fi ed plaque by computed tomography angiography, and rosuvastatin, 10 mg daily, was associated with slower progression of common carotid artery intima – media thickness (35, 36). Cumulatively, these data motivated the ARV Guidelines Panel ’ s recommendation for use of at least moderate-intensity statins, including pitavastatin, 4 mg daily (AI); atorvastatin, 20 mg daily (AII); or rosuvastatin, 10 mg daily (AII).

C ONSIDERATIONS FOR D OSING OF S TATIN T HERAPY

Statin intensity consists of 3 categories — high, moderate, and low — based on the LDL-C lowering effect (24). Table 3 outlines the statin agents and doses that qualify for each intensity based on their anticipated LDL-C lowering effects. Speci fi cally, every reduction of 1 mmol/L (39 mg/dL) in LDL-C leads to an approximate reduction of greater than $20\%$ in ASCVD events and $10\%$ in all-cause mortality (36, 37).

Table 3. Intensity of Statin Therapy\*

|Variable|High Intensity|Moderate Intensity|Low Intensity| |---|---|---|---| |Estimated LDL-C lowering|≥50%|30% to 49%||

-C $=$ low-density lipoprotein cholesterol. Rating of recommendations: A = strong. Rating of evidence: $|=$ data from randomized controlled trials; II = data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies. \* Modi fi ed from https://clinicalinfo.hiv.gov/sites/default/ fi les/guidelines/archive/adult-adolescent-arv-statin-therapy-2024-02-27.pdf. Data from references 28 and 29. † Atorvastatin and rosuvastatin have drug – drug interactions with ritonavir- and cobicistat-boosted antiretroviral medications; see Table 4. ‡ These statins are included in the Panel ’ s recommendations. § Simvastatin and lovastatin are contraindicated with ritonavir- and cobicistat-boosted antiretroviral medications.

However, the magnitude of LDL-C lowering varies in clinical practice.

C ONSIDERATIONS ON D RUG – D RUG I NTERACTIONS B ETWEEN S TATIN T HERAPIES AND ARV

M EDICATIONS

In current clinical practice, ART is recommended for all PWH and most commonly consists of a secondgeneration integrase inhibitor (such as bictegravir or dolutegravir) in combination with 2 nucleoside reverse transcriptase inhibitors (27). These medications are not expected to have signi fi cant pharmacokinetic interactions with statins. However, interactions between statins and some other ARV drugs may occur and may lead to an increase or decrease in statin drug exposure. Before having a patient start statin therapy, clinicians should consult resources to screen for DDIs and to determine which ARV drugs and which statin can be safely taken together or if dosage adjustment is necessary. Some resources with a focus on interactions between ARV drugs and statins are the Liverpool HIV Drug Interactions Checker (www.hiv-druginteractions.org/checker) (38) and the U.S. Department of Health and Human Services antiretroviral treatment guidelines (27). Because PWH may have multiple comorbid conditions and may take multiple medications, clinicians are advised to carefully review a patient ’ s medication pro fi le before having them start statin treatment to assess for signi fi cant interactions.

The potential for DDIs varies among the statins on the basis of their susceptibility to cytochrome P450 (CYP) enzymatic and transporter-mediated interactions. Pitavastatin, pravastatin, and rosuvastatin are not signi fi - cantly metabolized by CYP enzymes. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4, whereas fl uvastatin is a major substrate of CYP2C9. All statins are susceptible to interactions related to drug transporters (for example, OAT1B1 [organic anion-transporting polypeptide 1B1]) (39).

In general, DDIs are expected between certain statins and cobicistat- or ritonavir-containing regimens, as

well as the recently approved long-acting injectable medication lenacapavir. Ritonavir and cobicistat are potent inhibitors of CYP3A4 enzymes and are used as pharmacokinetic boosters to increase the drug concentrations and half-lives of some ART. The magnitude of the interaction and management strategy vary on the basis of the individual statin and ARV drugs. Lovastatin and simvastatin are contraindicated with cobicistat- or ritonavir-boosted ARV drugs, whereas no dosage adjustment is needed when these ARV drugs are used with pitavastatin. Statin dose reduction, a switch to an alternative statin, or increased monitoring for statin-related adverse effects may be necessary with atorvastatin or rosuvastatin, depending on the concomitant ARV drug ( Table 4 ) (38).

A DVERSE E FFECTS W ITH S TATIN T HERAPY

Statin therapy is generally well tolerated and safe; however, some adverse effects have been observed. The 2018 AHA/ACC/multisociety guidelines introduced the terminology statin-associated side effects , as opposed to statin intolerance , when these adverse effects occur (24). This nomenclature was changed because most people can tolerate statin rechallenge with an alternative statin. The most frequent adverse events are statin-associated muscle symptoms, as reported in $5\%$ to $25\%$ of patients (40). Further, there has been no evidence of tendonitis or tendon rupture associated with statins (40).

All statins have been implicated in small increases in the risk for diabetes. The increased risk has been associated with older age and the presence of 2 or more risk factors, such as hypertension or an elevated fasting glucose level, fasting triglyceride level, or body mass index (41, 42). Pitavastatin has previously been shown to have a neutral effect on glucose levels among people with metabolic syndrome. This effect was consistent in REPRIEVE, where no treatment effect on glucose levels was observed (28, 43). However, in REPRIEVE, there was a small increase in new-onset

| Table 4. Concomitant Use of ARV Drugs and Statins Recommended by the ARV Guidelines Panel as Primary ASCVD Prevention* || |---|---| ||| | Panel-Recommended Statins and Doses; ARV Drugs |Recommendations| |Pitavastatin, 4 mg once daily|| |INSTI: BIC, CAB, DTG, RAL|No dosage adjustment.| |NNRTI: DOR, EFV, ETR, RPV|| |NRTI: 3TC, ABC, FTC, TAF, TDF|| |PI/r: ATV/r, DRV/r|| |Other: LEN, MVC|| | INSTI: EVG/c PI/c: ATV/c, DRV/C |No data; use standard dose and| |Other: FTR|monitor for AEs.| ||| | Atorvastatin, 20 mg once daily INSTI: BIC, CAB, DTG, RAL NNRTI: DOR, RPV |No dosage adjustment.| | NNRTI: DOR, RPV NRTI: 3TC, ABC, FTC, TAF, TDFNRTI: 3TC, ABC, FTC, TAF, TDF Other: LEN, MVC || | INSTI: EVG/c PI: DRV/c, DRV/r |Increase atorvastatin concentra-| || tions observed. Do not exceed 20 mg/dt;: monitor for AEs. Decrease atorvastatin concentra- | |NNRTI: EFV, ETR|| | PI: ATV/c PI: ATV, ATV/r |Do not coadminister.| || Increase atorvastatin concentra- tions observed or possible. | || tions observed or possible. Monitor for AEs. | |Rosuvastatin, 10 mg once daily|| | INSTI: BIC, CAB, DTG, RAL NNRTI: DOR, EFV, ETR, RPV NRTI: 3TC, ABC, FTC, TAF, TDF Other: LEN, MVC |No dosage adjustment.| ||| |INSTI: EVG/c|Increase rosuvastatin concentra-| | PI: DRV/r Other: FTR |tions observed. Monitor for AEs.| ||| |PI: DRV/c|Increase rosuvastatin concentra-| || tions observed. Do not exceed 20 mg/dt: monitor for AEs. | |PI: ATV, ATV/r, ATV/c|Increase rosuvastatin concentra-| ||tions observed or expected. Do| || not exceed 10 mg/dt; monitor for AEs. |

3TC ¼ lamivudine; ABC $=$ abacavir adverse effect; ARV ¼ antiretroviral; ARV Guidelines Panel ¼ $=\cup.S$ U.S. Department of Health and Human Services Panel for the Use of Antiretroviral Agents in Adults and Adolescents with HIV; ASCVD $=$ atheroscleroti vascular disease; V ¼ atazanavir; ATV/c ¼ ATV – cobici $\mathsf{A T V/r}=$ ¼ DRV ATV – ritonavir; BIC ¼ darunavir ¼ – co bictegravir; CA cistat; DRV $=$ ¼ cabotegravir; DO ritonavir; DTG ¼ $=$ dolutegravir; ¼ doravirine; EFV ¼ efavirenz; ETR ¼ etravirine; EVG/c ¼ elvitegravir – cobicistat; FTC ¼ emtricitabine FTR ¼ fostemsavi INSTI ¼ integras trand transfer inhibitor; LEN ¼ lenacapavir; MVC ¼ araviroc; NNRTI ¼ nonnucleoside reverse tr iptase inhibitor; NRT $= $ cleoside reverse transc inhibitor; PI ${\mathsf{P}}{\mathsf{I}}=$ ¼ protease hibitor; PI/c ${\sf P I/c=}$ ¼ cobicistat-boosted PI; PI/r ${\mathsf{P}}{\mathsf{I}}/{\mathsf{r}}=$ ¼ ritonavir-boosted PI; RAL ¼ raltegravir; RPV ¼ rilpivirine; TAF ¼ tenofovir alafenamide; TDF ¼ tenofovir disoproxil fumarate.

\* Modi fi ed from https://clinicalinfo.hiv.gov/sites/default/ fi les/guidelines/ archive/adult-adolescent-arv-statin-therapy-2024-02-27.pdf. This table includes recommendations for pitavastatin, atorvastatin, and rosuvastatin when used with various ARV drugs based on potential drug – drug interactions.

† Based on recommendations from the U.S. Food and Drug Administration product label.

diabetes $6.0\%$ in the pitavastatin group; $4.7\%$ in the placebo group). Data are lacking on risk for new-onset diabetes with other statins among PWH, but a randomized controlled trial in PWH did show increases in insulin resistance and impaired fasting glucose levels with rosuvastatin use (44). The speci fi c mechanisms leading to statin-associated diabetes mellitus remain unclear. Rather, it seems that a few patients with diabetic susceptibility cross the threshold to incident diabetes mellitus after statin therapy. Thus, the 2018 AHA/ACC/ multisociety guidelines note that the bene fi ts of statin therapy are shown to outweigh the risks for new-onset diabetes mellitus, and the possibility of incident diabetes mellitus should not be a contraindication to statin therapy or indication for withdrawal of statins (24).

Mild increases in liver enzyme levels are seen in some patients who receive statins; these are usually transient without clinical complications (45). Data related to any concerns about cognitive decline have been weak or contradictory and, as such, do not warrant statin avoidance or cessation (24). Before having a patient start statin therapy, clinicians should do a comprehensive evaluation of musculoskeletal symptoms; assess risk factors for diabetes; and have a clinician – patient shared decision-making discussion focused on indications, bene fi ts, risks, and patient concerns and preferences.

I MPLICATIONS FOR P RACTICE IN O THER S ETTINGS G LOBALLY

Differences in ASCVD risk and the validity of risk prediction tools have implications when considering the application of the ARV Guidelines Panel ’ s recommendations on use of statin therapy in other settings globally. Although most PWH live in sub-Saharan Africa and other low- to middle-income countries (LMICs), risk prediction tools and prevention strategies for ASCVD have typically been validated in HICs, such as the United States and western European countries. This creates uncertainty about whether the risk for ASCVD and benefi ts from statin therapy that have been established in HICs can be applied in LMICs. Of note, the REPRIEVE population re fl ected global enrollment (although $52.7\%$ was from HICs), with $18.3\%$ from Latin America or the Caribbean, $7.6\%$ from Southeast or East Asia, and $14.9\%$ from sub-Saharan Africa (27).

The relative contribution of ASCVD as the primary manifestation of CVD, or as a major cause of morbidity and mortality among PWH, may also differ between LMICs and HICs. A systematic review describing causes of morbidity and mortality within sub-Saharan Africa during the era of ART (2008 to 2018) found that tuberculosis was the most common cause of hospitalization or death, with infectious diseases still outnumbering other noncommunicable diseases as a group (46). When the speci fi c manifestations of CVD among PWH are considered, nonischemic causes of heart failure

account for a large proportion of CVD illness in LMICs (47, 48). Speci fi c to HIV endemic regions within subSaharan Africa, important factors in fl uencing the spectrum of individual CVD manifestations among PWH include the younger age distribution of the population (49), the higher burden of infectious diseases with CVD complications (such as tuberculosis) (50), the lower burden of dyslipidemia (51, 52), and the high prevalence of hypertension and associated hypertensive heart disease and heart failure (53). Consistent with this, data from REPRIEVE show that the rate of ASCVD events (MACE) among the placebo group was lowest in sub-Saharan Africa (1.8 per 1000 person-years) compared with other regions in the trial.

In this context, there are limitations in applying ASCVD risk scores across regions globally. A recent study compared predicted ASCVD risk using the Framingham risk score (used commonly in the United States and Canada), the PCEs (used by the AHA/ACC/ multisociety cholesterol guidelines in the United States), and 4 versions of the Systematic Coronary Risk Evaluation 2 (SCORE2; recommended by the European Society of Cardiology and European Atherosclerosis Society within Europe, and the only score that considers geographic risk region) (54). This study used a simulated cohort that varied risk factor prevalence, such that this theoretical population would not directly re fl ect the populations used to derive or validate the risk equations. The concordance across these risk algorithms ranged between $19\%$ and $85\%,$ , and the proportion of the population strati fi ed speci fi cally to moderate risk was $32\%$ by the Framingham risk score, $39\%$ by the PCEs, $45\%$ by the SCORE2 version for low-risk regions, and $25\%$ by the SCORE2 version for very-high-risk regions. The lack of validated risk scores for sub-Saharan Africa and other LMIC regions where most PWH reside greatly limits the ability to identify those who may bene fi t most from primary prevention strategies, such as statin therapy. Finally, recommendations on statin use in LMICs is further complicated by public health priorities competing for a smaller pool of health care resources, both in absolute dollars and when measured by the proportion of gross domestic product spent on health care.

O NGOING C LINICAL Q UESTIONS AND P RIORITIES

Given the limitations of the PCEs both domestically and internationally, as outlined above, there have been efforts to continue to re fi ne CVD risk estimates across all populations, including PWH. The 2018 AHA/ACC/ multisociety guidelines note that other markers can help inform individual risk, including in fl ammatory markers, such as high-sensitivity C-reactive protein (24). Additional analyses in REPRIEVE will inform whether in fl ammatory biomarkers (high-sensitivity C-reactive protein and interleukin-6) measured at entry can identify participants who had a greater treatment effect from pitavastatin. In this context, it should be

noted that the REPREIVE population had relatively low ASCVD risk by traditional risk factors and limited changes in high-sensitivity C-reactive protein with pitavastatin (55). One additional biomarker that may re fl ect residual in fl ammatory risk is lipoprotein(a), which has been associated with greater pericoronary in fl ammation among PWH than among people without HIV (56). Further analyses and additional research are needed to inform whether lipoprotein(a) or other novel in fl ammatory markers have a role in risk strati fi cation for PWH.

Work is also ongoing to develop novel algorithms that will improve risk prediction. As mentioned above, several risk scores have been designed to re fi ne estimates on the basis of global region, such as the SCORE2. Any risk score would ideally be independent of sex and race and include a younger demographic, which would allow broader generalizability. Through a science advisory group, the AHA recently developed the PREVENT (Predicting Risk of CVD EVENTs) equation to improve the estimated risk for ASCVD and heart failure separately, as well as a total CVD composite. Using more contemporary epidemiologic data, the PREVENT equation has been validated and enables 10- and 30-year risk estimates for total CVD, including heart failure, for a U.S. cohort aged 30 to 79 years, independent of race (57, 58). The score includes the variables of sex, age, cholesterol level and treatment, body mass index, systolic blood pressure and treatment, renal function, diabetes, and smoking, as well as optional models that also incorporate urinary albumin – creatinine ratio and social deprivation index as a marker of social determinants of health. Further research is needed to understand how this tool performs among PWH. In addition, research into implementation strategies, including those with a focus on removing barriers to care, will be needed.

Other future research questions to be addressed in the prevention of ASCVD among PWH include the use of lipid-modifying agents beyond statins, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, ezetimibe, inclisiran, bempedoic acid, and other agents under investigation. A recent study examined the use of evolocumab, a PCSK9 inhibitor, in PWH and dyslipidemia, which reduced LDL-C by $56.9\%$ compared with placebo at 24 weeks (59). Although this is promising, additional con fi rmatory studies and clinical outcome data are needed for PCSK9 inhibitors and other novel classes of treatment.

Another important area needing further evidence and guidance is the role of type II versus type I MI in PWH younger than 40 years given the high prevalence of type II MI in this subset and the fact that statins may have a limited role in prevention of type II MI (60).

C ONCLUSION

REPREIVE was a practice-changing clinical trial that, when combined with guidelines for the general

population, informed recommendations on use of statin therapy as primary prevention among PWH at low to intermediate ASCVD risk. The ARV Guidelines Panel issued a strong recommendation for initiating statin therapy among people with a 10-year ASCVD risk score of $5\%$ or higher, whose absolute bene fi t from statins in REPRIEVE was greater. For PWH with a 10-year ASCVD risk score below $5\%,$ the ARV Guidelines Panel favored statin therapy but also recommended that patient – clinician risk discussions consider the presence or absence of additional HIV-related factors that can increase ASCVD risk but are not included in traditional risk assessment equations. There remain important clinical questions in the management of CVD risk among PWH, including further improvements in risk strati fi cation, as well as additional ASCVD prevention strategies focused on reducing residual risk associated with in fl ammation. It is important to remember that optimizing lifestyle factors (including smoking cessation, diet, and exercise) remains paramount regardless of statin use. Finally, future research is needed to better understand the absolute risk for ASCVD and other nonischemic CVD manifestations among PWH speci fi cally within regions where most of the HIV epidemic exists globally.

From University of Kentucky College of Pharmacy, Lexington, Kentucky (C.B.); National Institutes of Health, Bethesda, Maryland (A.K.P.); University of California, San Francisco, San Francisco, California (D.G.); Massachusetts General Hospital, Boston, Massachusetts (E.H.); Frederick National Laboratory, Bethesda, Maryland (S.K.); The John Hopkins University School of Medicine, Baltimore, Maryland (S.S.M.); Case Western Reserve University, Cleveland, Ohio (G.M.); Thacker and Thompson, Atlanta, Georgia (M.T.); The Aga Khan University, Karachi, Pakistan (S.V.); and University of Minnesota, Minneapolis, Minnesota (J.V.B.).

Acknowledgment: The authors thank Ms. Marylu Schaffhauser for her support in the coordination of the work of the writing team and the U.S. Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents.

Disclosures: Disclosure forms are available with the article online.

Corresponding Author: Craig Beavers, PharmD, Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, 783 South Limestone, Lexington, KY 40508; e-mail, cjbeav2@uky.edu.

Author contributions are available at Annals.org.

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Virani, J.V. Baker. Analysis and interpretation of the data: C. Beavers, D. Glidden, S.S. Martin, M. Thompson, J.V. Baker. Drafting of the article: C. Beavers, A.K. Pau, S. Kuriakose, G. McComsey, M. Thompson, J.V. Baker. Critical revision for important intellectual content: C. Beavers, A.K. Pau, E. Hyle, S. Kuriakose, S.S. Martin, G. McComsey, M. Thompson, S. Virani, J.V. Baker. Final approval of the article: C. Beavers, A.K. Pau, D. Glidden, E. Hyle, S. Kuriakose, S.S. Martin, G. McComsey, M. Thompson, S. Virani, J.V. Baker. Administrative, technical, or logistic support: C. Beavers. Collection and assembly of data: C. Beavers, G. McComsey, J.V. Baker.