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

Cardiovascular and Metabolic Complications in People With HIV

Statin Therapy as Primary Prevention of Atherosclerotic Cardiovascular Disease in People With HIV

The above recommendations inform the use of statin therapy in primary prevention of atherosclerotic cardiovascular disease (ASCVD) in people with HIV receiving care in the United States. These recommendations were developed by the Panel for the Use of Antiretroviral Agents in Adults and Adolescents With HIV (the Panel) in collaboration with representatives from the American College of Cardiology (ACC), American Heart Association (AHA), and the HIV Medicine Association (HIVMA). The recommendations and supporting text have been endorsed by these organizations.

Background 

Traditional risk factor modification remains an important component of primary ASCVD prevention strategies for people with HIV, including modifications related to diet, exercise, smoking cessation, blood pressure control, and lipid lowering for those with hyperlipidemia. Hydroxymethylglutaryl‑‌coenzyme A reductase inhibitors (i.e., statins) may offer advantages for people with HIV over other prevention strategies, given that statin therapy is associated with a well-described reduction in ASCVD events, as well as treatment effects on inflammatory pathways.^1-3

Findings from the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) have provided evidence to support specific recommendations for statin therapy as primary ASCVD prevention in people with HIV aged 40 to 75 years in the United States. The 2018 AHA/ACC/Multisociety Guidelines for the general population recommend statin therapy for all people at high 10-year ASCVD risk (defined as ≥20%). For people at intermediate risk (i.e., ≥7.5% to <20%) or borderline risk (i.e., 5% to <7.5%), it is recommended to prescribe statin therapy based on shared decision-making. These recommendations are based on risk stratification that uses the pooled cohort risk equations to estimate 10-‍year ASCVD risk, along with clinician–patient discussions about risk, benefits, and patient preference.^4,5 Given that current ASCVD risk prediction tools typically underestimate risk among people with HIV, the AHA/ACC/Multisociety Guidelines identify HIV as a potential “risk enhancer” that should influence discussions on the use of statin therapy among those at borderline or intermediate risk.⁵ However, prior to the REPRIEVE trial, no formal recommendations had been issued for people with HIV at low-to-intermediate ASCVD risk (i.e., <20%). Results from REPRIEVE now provide clear evidence to inform the use of statin therapy as primary prevention among people with HIV who are aged ≥40 years, on continuous antiretroviral therapy (ART), and at low-to-intermediate ASCVD risk.

Primary Study Results From the REPRIEVE Trial

REPRIEVE was a Phase 3 global randomized controlled trial of oral daily pitavastatin 4 mg versus placebo to prevent ASCVD. The study enrolled a total of 7,769 people with HIV who were aged 40 to 75 years and at low-to-intermediate risk based on 10-year ASCVD risk estimates.^6,7 People with known ASCVD were excluded, and further eligibility criteria were based on low-density lipoprotein cholesterol (LDL-C) thresholds that varied based on 10-year risk estimates for ASCVD (up to a risk of 15%). The primary outcome was the occurrence of major adverse cardiovascular events (MACE), defined as a composite of cardiovascular disease death, myocardial infarction, 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, 53% from high-income countries, 41% Black, and 35% White, with a median age of 50 years (interquartile range [IQR] 45–‍55) and 10-year ASCVD risk of 4.5% (IQR 2.1–7.0). Additionally, median CD4 T lymphocyte (CD4) cell count was 621 cells/mm³ (IQR 448–827), with prior CD4 nadir <200 cells/mm³ in 49%, and HIV RNA below quantification in 88%.

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. A similar treatment effect was present across the individual components of MACE. In REPRIEVE, the absolute risk reduction was substantially greater for people with ASCVD risk estimates of ≥5% compared to those with risk of <5%, as discussed in the next section. Median LDL-C levels at baseline and 12 months were 107 mg/dL and 74 mg/dL, respectively, in the pitavastatin group, compared to 106 mg/dL and 105 mg/dL in the placebo group. During the study, a statin was initiated as part of clinical care in 5.7% of the pitavastatin group and 9.6% of the placebo group, leading to discontinuation of the blinded study drug. 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.

Rationale for the Panel’s Recommendations for People With HIV at Low-to-Intermediate (<20%) 10-Year ASCVD Risk 

The overall findings from REPRIEVE, combined with the observation that equations based on traditional risk factors underestimate ASCVD risk among people with HIV, informed the Panel’s decision to recommend the use of at least moderate-intensity statin therapy as primary prevention among people with HIV aged 40 to 75 years.^8,9

To determine whether some participants demonstrated greater benefit from pitavastatin, subgroup analyses were performed in REPRIEVE.⁶ Relative risk reductions across subgroups defined by key demographic and clinical characteristics did not demonstrate a clear interaction with the treatment effect. However, when incident MACE was stratified by 10-year ASCVD risk score, the absolute reduction in events was greatest for people with a 10-year ASCVD risk ≥5%. The estimated number needed to treat over 5 years (NNT₅) to avoid incident MACE events with pitavastatin treatment is reported below (Table 11a). Of note, the NNT₅ for people with ASCVD risk ≥5% was one-quarter to one-third that for those with ASCVD risk <5%. These data motivated the Panel’s decision to issue a strong recommendation for initiating statin therapy among those with ASCVD risk ≥5%. It should be noted that some of these NNT₅ for subgroups defined by ASCVD risk are estimated based on low numbers of events and should be interpreted with caution.

The relationship between a higher absolute benefit from statin therapy (i.e., lower NNT₅) with higher baseline ASCVD risk estimates is well described and should be used to inform shared decision-making discussions on the use of statins.⁵ These discussions should take into account the benefits along with side effects (see Common Adverse Effects of Statin Therapy below), costs, drug–drug interaction potential, and other patient-centered factors. For people at low (<5%) 10-year ASCVD risk who may experience a more modest absolute benefit from statin therapy, it is particularly important to weigh potential benefits for the individual against risks.

The findings from REPRIEVE reporting higher absolute benefit of statin therapy among people with HIV aged 40 to 75 years with greater ASCVD risk informed the Panel’s decision to recommend the use of at least moderate-intensity statin therapy with a strong recommendation for those with a 10-‍year ASCVD risk score ≥5% to <20% (AI). Among participants aged 40 to 75 years with low estimated ASCVD risk (<5%), additional HIV-related factors may be important to consider. Using a large body of observational data, the AHA identified HIV-related ASCVD risk-enhancing factors that include the following: history of prolonged HIV viremia and/or delayed ART initiation, low current or nadir CD4 count (<350 cells/mm³), HIV treatment failure or nonadherence, and lipodystrophy/lipoatrophy, as well as metabolic syndrome, fatty liver disease, and coinfection with hepatitis C.¹⁰ Additional HIV-related factors associated with greater ASCVD risk that may be considered include, but are not limited to, a longer total duration of HIV infection and prior or current exposure to certain antiretroviral (ARV) drugs with cardiometabolic toxicity (e.g., abacavir, ritonavir-boosted lopinavir, ritonavir-boosted darunavir, and older protease inhibitors [PIs] no longer in use) (see Cardiovascular Complications for more detailed discussion). Conversely, people with HIV who initiated ART with contemporary regimens at higher CD4 counts (e.g., >500 cells/mm³) are likely to be at lower absolute ASCVD risk. Finally, non-HIV risk factors that may favor initiating statin therapy are discussed within the AHA/ACC/Multisociety Guidelines.⁵ In this context, clinician–patient discussions that weigh individual HIV-related factors along with the potential benefits and risks of statins are particularly important for people with HIV at low (<5%) 10-year ASCVD risk, where the NNT₅ for benefit is substantially higher. In summary, the Panel favors initiating at least moderate-intensity statin therapy for those with a 10-year ASCVD risk score <5% (CI), and the decision to initiate a statin should take into account the presence or absence of HIV- and non-HIV-related factors that can increase ASCVD risk.

Initiation of statin therapy should be deferred until after pregnancy for those with HIV and low‑to‑intermediate ASCVD risk, and statin therapy should be discontinued if pregnancy occurs in the context of HIV. As in the general population, breastfeeding is not recommended while taking statin therapy.

REPRIEVE did not enroll people with HIV under 40 years of age. In the general population, lifestyle modifications targeting traditional risk factors (e.g., diet, exercise, smoking cessation, and blood pressure control) are recommended for people under 40 years of age.⁵ Still, some of these individuals also may benefit from statin therapy, and recommendations for the general population suggest risk factors such as familial hypercholesterolemia or a family history of premature ASCVD may favor statin therapy. There are insufficient data to inform whether risk enhancers, such as HIV-related factors, would favor statin therapy among people with HIV under 40 years of age. However, some younger people with HIV may be at increased ASCVD risk—particularly those with a very long duration of HIV infection (e.g., due to perinatal exposure); in these cases, decisions on statin therapy should be individualized.

Key Recommendations for the General Population (Including People With HIV) Based on AHA/ACC/Multisociety Guidelines

The 2018 ACC/AHA/Multisociety Guidelines recommend the use of statins as primary prevention for all people at high risk, defined as those aged 40 to 75 years with a 10-year ASCVD risk estimate of ≥20%, as well as those aged 20 to 75 years with an LDL-C ≥190 mg/dL.⁵ In this context, an LDL-C reduction of ≥50% should be achieved, which typically requires high-intensity statin therapy (see the Intensity of Statin Therapy table below). For people with diabetes mellitus, the 2018 ACC/AHA/Multisociety Guidelines recommend at least a moderate-intensity statin, with additional risk assessment to inform consideration of initiating a high-intensity statin. These general population guidelines are based on high-quality randomized trial data and should inform the management of people with HIV who meet these criteria.⁵

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

In REPRIEVE, pitavastatin was chosen in part due to lower drug–drug interaction potential with certain ARV medications compared with other statins.¹¹ Although there are no clinical outcome comparative effectiveness trials analyzing different statins among people with HIV, some studies support the treatment effect of other moderate-intensity statins for lipid lowering or reductions in inflammation and immune activation, as well as a treatment effect on surrogate measures of ASCVD. 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 demonstrated reductions in inflammatory, monocyte, and T-cell immune activation biomarkers among people with HIV.^12-14 Finally, in two separate Phase 2 placebo-controlled randomized trials of statin therapy in people with HIV, atorvastatin (initiated at 20 mg daily) was associated with reductions in coronary noncalcified plaque by computed tomography angiography, and rosuvastatin (10 mg daily) was associated with slower progression of common carotid artery intima-media thickness.^15,16 Cumulatively, these data among people with HIV who are aged 40 to 75 years old and with ASCVD risk between 5% and <20% motivated the Panel’s recommendation for use of at least moderate-intensity statins to include pitavastatin 4 mg daily (AI), atorvastatin 20 mg daily (AII), or rosuvastatin 10 mg daily (AII).

The recommendation for which statin agent to select and the intensity of therapy is based on the person’s overall risk profile. As outlined in the 2018 AHA/ACC/Multisociety Guideline on the Management of Blood Cholesterol, statin intensity consists of three categories—high, moderate, and low—based on the LDL-C lowering effect.⁵ Table 11b below outlines the statin agent and dose that qualify for each intensity, as well as the anticipated LDL-C lowering effect. More specifically, for every 39 mg/dL reduction in LDL-C, there is approximately a 20% reduction in ASCVD events and a 10% reduction in all-cause mortality.¹⁷ However, it should also be noted that the magnitude of LDL-C lowering is variable in clinical practice.

Drug–Drug Interactions Between Statin Therapies and Antiretroviral Medications 

Drug–drug interaction potential varies among the statins based on susceptibility to cytochrome P450 (CYP) and transporter-mediated interactions. Pitavastatin, pravastatin, and rosuvastatin are not significantly metabolized by CYP enzymes. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4, whereas fluvastatin is a major substrate of CYP2C9. All statins are susceptible to interactions related to drug transporters (e.g., OATP1B1).¹⁸

Ritonavir (RTV)- and cobicistat (COBI)-boosted ARVs are particularly prone to drug–drug interactions with statins. When RTV- or COBI-boosted ARVs are coadministered with atorvastatin or rosuvastatin, statin dose reduction, a switch to an alternative statin, or increased monitoring for statin-related adverse effects may be required. Lovastatin and simvastatin are contraindicated when coadministered with COBI or RTV.

In general, some degree of drug–drug interactions may be expected between certain statins and HIV PIs, COBI-boosted elvitegravir, older non-nucleoside reverse transcriptase inhibitors, fostemsavir, and lenacapavir. The magnitude of the interaction and management strategy vary based on the individual statin and ARV combination. For more information on drug–drug interactions between pitavastatin, atorvastatin, and rosuvastatin with ARV drugs, see Table 11c below. Interactions between other statins and ARV drugs can be found in the Drug Interaction tables (Tables 23, 24a, 24b, 24c, 24d, 24e, 24f, 24g, 25a, 25b).

Common Adverse Effects of Statin Therapy

Statin therapy is well tolerated and safe; however, some side 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.⁵ The reason for this nomenclature is due to the fact that most people are able to tolerate statin rechallenge with an alternative statin agent or regimen. The most frequent adverse events are statin-associated muscle symptoms, with reported occurrence in 5% to 25% of people who receive statins.¹⁹

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 ≥2 risk factors, such as elevated baseline fasting glucose level, elevated fasting triglycerides, elevated body mass index, or history of hypertension.^20,21 Pitavastatin has previously been shown to have a neutral effect on glucose levels among people with metabolic syndrome, and this effect was consistent in REPRIEVE where there was no difference in glucose levels between pitavastatin and placebo groups over follow-up (median levels at Month 84 were 92 mg/dL and 90 mg/dL, respectively).^7,22 However, in REPRIEVE, there was a small increase in new-onset diabetes (6.0% in the pitavastatin group; 4.7% in the placebo group). Data are lacking on the risk of new-onset diabetes with other statins among people with HIV. However, a randomized controlled trial in people with HIV demonstrated increases in insulin resistance and impaired fasting glucose levels with rosuvastatin use.²³

Mild increases in liver enzymes are seen in some individuals, though these are usually transient without clinical complications. However, the overall clinical benefits of statin use outweigh the overall risks of adverse effects, especially for people with greater estimated 10-year ASCVD risk.²⁴ Data related to any concerns of cognitive decline have been weak or contradictory and, as such, do not warrant statin avoidance or cessation.⁵ Any time statins are initiated, clinicians should perform a comprehensive evaluation of musculoskeletal symptoms, an assessment of risk factors for diabetes, and a clinician–patient shared decision-making discussion focused on indications, benefits, risks, and patient concerns and preferences. When mild adverse events occur, close clinical follow-up is important.

References

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