US Pharm. 2024;49(10):28-31.

ABSTRACT: Because antiretroviral therapy (ART) has prolonged survival in many patients with HIV, the HIV treatment focus has been shifting to address noncommunicable diseases. Patients with HIV are more prone to developing certain chronic diseases, such as cardiovascular disease. Pitavastatin has emerged as a novel therapeutic option for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in patients whose HIV is well managed on ART. In a landmark clinical trial, pitavastatin substantially reduced major adverse cardiovascular events in patients with HIV, and the drug is currently recommended for primary prevention of ASCVD in HIV patients deemed to be at risk. Pharmacists should be knowledgeable about pertinent information on pitavastatin when counseling patients with HIV who are considering or already taking pitavastatin for prevention of cardiovascular disease.

HIV has been one of the largest public-health challenges worldwide. As of 2022, approximately 39 million people across the globe have been diagnosed with HIV.1 It has been an ongoing mission of public-health agencies and various organizations to prevent HIV transmission and provide increased access to appropriate care for individuals with HIV infection. Although HIV can affect anyone, regardless of race or ethnicity, it has been found to disproportionately impact those of black/African American or Hispanic/Latino descent. In 2021, the CDC reported that black/African American persons accounted for 40% of estimated HIV infections even though they comprise only 12% of the U.S. population.2 Many socioeconomic factors, such as HIV stigma, discrimination, poverty, and limited access to care, contribute to the disparities seen in those seeking treatment for HIV.

Most commonly, HIV is spread through sexual transmission or by contact with the blood of someone who has a detectable HIV viral load. HIV also spreads through the blood via the sharing of needles, syringes, or other drug-injection equipment. To prevent the spread of HIV, the CDC encourages proper use of condoms during sexual intercourse, clean needles and syringes, and abstinence from sexual activity or injection drug use. In addition, the CDC recommends preexposure prophylaxis and postexposure prophylaxis to prevent the transmission of HIV.3,4

In HIV infection, the virus attacks cluster of differentiation 4 (CD4) T lymphocytes, which have a key role in coordinating immune responses against infections. The loss of CD4 cells leads to an increased risk of the patient acquiring various infections, other illnesses, and certain cancers.5 HIV can be divided into three stages: acute infection, chronic infection, and AIDS. Acute HIV infection typically develops within 2 to 4 weeks after an individual is infected; the virus is actively destroying CD4 T lymphocytes and the level of HIV in the blood is extremely high, increasing the risk of HIV transmission. During chronic HIV infection, the virus continues to multiply in the body at very low levels.6 Patients with chronic infection may not have any HIV-related symptoms, and with the use of antiretroviral therapy (ART), they can remain in this stage for several decades. AIDS is the most severe stage of HIV infection, as the virus has damaged the immune system to the point that it is unable to fight off opportunistic infections (i.e., infections that typically would not occur in someone with a healthy immune system).6 Those with AIDS have a high viral load and can easily transmit HIV to others.

HIV and Cardiovascular Disease

Given the advances in ART, most of the deaths in HIV patients are related to noncommunicable diseases, such as cardiovascular disease.7 Because HIV patients are living longer, optimization of treatment for these noncommunicable diseases has been a recent focus of research. The risk of cardiovascular events, including myocardial infarction and stroke, is twice as likely in persons with HIV infection than in the general population.8 Two main factors associated with an increased risk of cardiovascular events are chronic systemic inflammation and immune dysregulation.9 HIV patients have heightened levels of inflammatory markers including interleukin-6, which predisposes them to a procoagulant state and increases the likelihood of atherosclerosis.

REPRIEVE Trial

Previously, data were lacking to guide the prevention of cardiovascular disease in HIV patients. To bridge this knowledge gap, a global clinical trial called Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) was conducted to assess the efficacy of a statin (pitavastatin) in reducing the risk of major adverse cardiovascular events (MACE) in patients whose HIV is well controlled on ART. Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) have the ability to reduce LDL cholesterol, a key player in atherosclerotic disease, and to decrease inflammation.10

This landmark trial was conducted from March 26, 2015, to July 31, 2019, with a total of 7,769 participants enrolled; 3,888 received pitavastatin and 3,881 received placebo. Participants’ median age was 50 years, 5,065 (65.2%) were nonwhite, and 2,419 (31.1%) were women. All participants were categorized as having low-to-moderate cardiovascular risk as defined by their score on the American Heart Association/American College of Cardiology 2013 Pooled Cohort Equation risk calculator.11 The primary outcome was the incidence of MACE, with events comprising cardiovascular death, myocardial infarction, transient ischemic attack, peripheral arterial ischemia, revascularization of a coronary, carotid, or peripheral artery, or death from an undetermined cause.

After 5 years of follow-up, the trial was concluded ahead of schedule because of favorable efficacy outcomes. The pitavastatin group had a 35% lower risk of MACE compared with the placebo group. Furthermore, the pitavastatin group had a 21% decrease in risk of MACE and death from any cause compared with the placebo group. One major concern with the use of statin therapy is the development of muscle-related side effects. The majority of muscle-related symptoms in the treatment and placebo groups were myalgias and low-grade muscle-related weakness with a low incidence of myopathy.10

Guideline Recommendations

As a result of the positive findings from the REPRIEVE trial, the U.S. Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents has developed recommendations for the use of statins in HIV patients for primary prevention of cardiovascular disease.10 These recommendations are stratified by atherosclerotic cardiovascular disease (ASCVD) risk and age.

Recommendations for HIV patients with low-to-intermediate (<20%) 10-year ASCVD risk estimates are as follows10:
• For those aged 40 to 75 years with a 10-year ASCVD risk estimate of 5% to 20%, moderate-intensity statin therapy is recommended (AI; explained below); i.e., pitavastatin 4 mg once daily (AI), atorvastatin 20 mg once daily (AII; explained below), or rosuvastatin 10 mg once daily (AII).
• For those aged 40 to 75 years with a 10-year ASCVD risk estimate <5%, initiate at least moderate-intensity statin therapy (CI; explained below). Because the absolute benefit from statin therapy is modest in this population, the determination to initiate statin therapy should consider the presence or absence of HIV-related factors that can raise the risk of ASCVD.
• For those aged <40 years, data are insufficient for making a recommendation for or against statin therapy for primary prevention of ASCVD; in the general population, lifestyle modifications are recommended for those aged <40 years, with statin therapy considered only in selected patient populations.

(Explanatory note: In the above points, A = strong recommendation and C = weak recommendation. Also, I = 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.)

Key recommendations for the general population, including HIV patients, are as follows10:
• For patients aged 40 to 75 years with high (≥20%) 10-year ASCVD risk estimates, initiate high-intensity statin therapy.
• For those aged 20 to 75 years with LDL cholesterol ≥190 mg/dL, initiate high-intensity statin therapy at the maximum tolerated dose.
• For those aged 40 to 75 years with diabetes mellitus, initiate at least moderate-intensity statin therapy and conduct additional risk assessment to consider high-intensity statin use.

ASCVD risk is a percentage that estimates the 10-year risk of a patient having a cardiovascular event, such as a heart attack or stroke. Based on the factors of ASCVD risk and age, a specific intensity of statin therapy is recommended, as described in TABLE 1.10


In the REPRIEVE trial, pitavastatin was selected from the statins class because of its compatibility with ART, with a reduced risk of drug interactions (TABLE 2).10 Atorvastatin and rosuvastatin have a high likelihood of drug interactions with the combination of ART used for HIV treatment, including nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs, and protease inhibitors. In addition, most statins are metabolized by the CYP450 enzyme system—specifically CYP3A4—and excreted from the body. Many antiretrovirals (ARVs) are also metabolized by the same enzyme system, which increases the risk of drug interactions. The metabolization and excretion of pitavastatin involve glucuronidation via UGT.12 Pitavastatin is minimally metabolized by the CYP enzyme system, making it a superior candidate for cardiovascular risk prevention in HIV patients.


The Pharmacist’s Role

Thanks to ongoing developments and innovations in the therapeutic management of HIV, patients with this disease have an enhanced life expectancy. Accordingly, optimal management of noninfectious chronic diseases, such as cardiovascular disease, is essential to prevent morbidity and mortality. This change in treatment focus allows pharmacists to play an even more pivotal role as healthcare providers at the forefront of patient care. Pharmacists can proactively identify HIV patients who have an ASCVD risk in the age ranges specified by the DHHS guidelines, and they can spread awareness about pitavastatin as a novel option for primary prevention of cardiovascular disease.

Pharmacists are also uniquely positioned to identify and recommend management of drug interactions. ARVs are well known to have a multitude of interactions, so it is essential to ask at every visit about all medications and supplements that an HIV patient is taking. Since pitavastatin is used specifically as preventive therapy for cardiovascular disease, interactions with ARVs are not an issue. However, statin therapy is commonly associated with muscle pain. Pharmacists should counsel patients about the potential side effects of muscle weakness or pain. Patients should also be encouraged to seek medical treatment immediately if the muscle pain is severe.

Pitavastatin may be taken with or without food, and it is recommended to take it at the same time each day. Pitavastatin is contraindicated with cyclosporine because of an increased risk of severe muscle-related side effects. Pitavastatin is contraindicated in acute liver failure or decompensated cirrhosis, and its use is not recommended during pregnancy and lactation. Some common side effects are back pain, pain in the extremities, and diarrhea or constipation. Clinical studies have also reported adverse effects including arthralgia, headache, influenza, and nasopharyngitis. Medical attention is warranted for more severe side effects, such as the inability to pass urine, right upper abdominal discomfort, and jaundice.12 These side effects are rare, and pitavastatin is generally well tolerated by many patients. Pharmacists should be knowledgeable about the above points when counseling patients with HIV who are considering or already taking pitavastatin for prevention of cardiovascular disease.

REFERENCES

1. HIV.gov. Global statistics: the global HIV and AIDS epidemic. www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics. Accessed June 14, 2024.
2. CDC. Fast facts: HIV in the US by race and ethnicity. www.cdc.gov/hiv/data-research/facts-stats/race-ethnicity.html. Accessed June 14, 2024.
3. CDC. Preexposure prophylaxis for the prevention of HIV infection in the United States—2021 update—a clinical practice guideline. www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf. Accessed June 20, 2024.
4. Dominguez KL, Smith DK, Vasavi T, et al. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV. CDC; 2016. https://stacks.cdc.gov/view/cdc/38856. Accessed June 20, 2024.
5. National Institutes of Health. HIV and AIDS: the basics. https://hivinfo.nih.gov/understanding-hiv/fact-sheets/hiv-and-aids-basics. Accessed June 14, 2024.
6. National Institutes of Health. The stages of HIV infection. https://hivinfo.nih.gov/understanding-hiv/fact-sheets/stages-hiv-infection. Accessed June 14, 2024.
7. Shah ASV, Stelzle D, Lee KK, et al. Global burden of atherosclerotic cardiovascular disease in people living with HIV: systematic review and meta-analysis. Circulation. 2018;138(11):1100-1112.
8. Grinspoon SK, Fitch KV, Zanni MV, et al. Pitavastatin to prevent cardiovascular disease in HIV infection. N Engl J Med. 2023;389(8):687-699.
9. Feinstein MJ. HIV and cardiovascular disease: from insights to interventions. Top Antivir Med. 2021;29(4):407-411.
10. Clinicalinfo.HIV.gov. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV: statin therapy in people with HIV. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-arv/statin-therapy-people-hiv. Accessed June 14, 2024.
11. American College of Cardiology. ASCVD risk estimator plus. https://tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate. Accessed June 20, 2024.
12. Livalo (pitavastatin) product information. Montgomery, AL: Kowa Pharmaceuticals America, Inc; March 2024.

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