Introduction

Over the past two decades, effective antiretroviral therapy has prolonged lifespans of people living with HIV (PLH) and shifted mortality from early AIDS-related causes to cardiovascular death. ^1,2 Evidence has shown that after adjusting for age, sex, and cardiovascular risk factors, PLH have a higher risk of atherosclerotic cardiovascular disease (ASCVD) than the general population. ^3-6 However, PLH are less likely than the general population to receive evidence-based interventions, for ASCVD prevention. ⁷ This module will review current evidence regarding daily aspirin therapy ASCVD prevention among PLH.

Brief Review

Increased platelet activation has been proposed as a potential mechanism increasing ASCVD among PLH. ⁸ While preliminary evidence suggests aspirin may attenuate heightened platelet activity, direct evidence of mortality benefit is lacking. To date, aspirin for ASCVD prevention has not been studied specifically among PLH and literature from the general population must be extrapolated to HIV patients.

Evidence supporting the use of aspirin for secondary ASCVD prevention is well-established. ^9-12 Among patients with a prior cardiovascular or cerebrovascular event, use of anti-platelet agents have consistently shown reductions in mortality. Accordingly, aspirin or an alternative antiplatelet agents are recommended for secondary prevention. ^11,13

Evidence supporting the use of aspirin for primary ASCVD prevention has become increasingly controversial and consideration of individualized risk factors and shared decision making should be employed before initiating therapy. Presently, the United States Preventive Services Task Force (USPSTF) states the decision to initiate low-dose aspirin use for primary prevention among adults aged 60 to 69 with a 10-year risk of ≥10% should be made on a case by case basis. ¹⁴ Patients who are not at increased risk for bleeding and a life expectancy of at least 10 years may be more likely to benefit. As always, patient preference (i.e. those who place a higher value on potential benefits than the potential harm) may choose to initiate low-dose aspirin (C rating).” Current evidence is insufficient to guide decisions for patients <60 years or >69. ^14,15 In general, a 10-year ASCVD risk of 10% is considered a loose benchmark for the benefits of aspirin to outweigh the risks. ^16,17

Recently, the American College of Cardiology in partnership with the American Heart Association downgraded recommendations for aspirin for primary prevention based on “weak evidence.” Guidelines released in March 2019 discourage its use for primary prevention stating: “aspirin should be used infrequently in the routine primary prevention of ASCVD because of lack of net benefit.” ¹⁸ These guidelines further state low-dose aspirin (75-100 mg orally daily) should not be administered for the primary prevention of ASCVD among adults of any age who are at increased risk of bleeding.

When considering aspirin for primary prevention, clinicians must balance the individual ASCVD against the potential for aspirin-induced bleeding, which is most commonly gastrointestinal or intracerebral in nature.

A helpful web tool is available to estimate patient specific risks of bleeding versus experiencing an ASCVD event. This tool, which is also available as an app, can help weigh the risk reduction from aspirin with the patient risk of bleeding.

Balancing the potential benefits and harms is typically based on the number needed to treat (NNT) and the number needed to harm (NNH). These numbers are based on absolute rather than relative risk. For example, if the aspirin reduces 10-year risk of ASCVD by 3% and is associated with a 10% risk for major GI bleeding over 10 years, the corresponding NNT and NNH are based on the inverse of these percentages, i.e. 1/0.03= 33 and 1/0.1=10. This can be understood as 33 people will need to be treated with aspirin for 10 years in order to prevent one ASCVD event whereas only 10 people will need to be treated with aspirin in order for one person to experience a major GI bleed. While these outcomes are not comparable, the numbers help quantify the relative benefit and harm keeping in mind that aspirin has not been shown to reduce all-cause mortality.

In summary, in the absence of a contraindication, aspirin (or other antiplatelet medication) should be prescribed for PLH with known coronary or cerebrovascular disease for secondary prevention. Use of aspirin for primary prevention is of uncertain benefit and should not be used without careful consideration of benefits versus harms.

Introduction

The success of antiretroviral therapy (ART) has transformed morbidity and mortality among people living with HIV (PLH) from early AIDS-related causes to later cardiovascular causes. Age and sex-adjusted deaths from cardiovascular disease among PLH are appreciably higher than the general population. The association between antiretroviral therapies and development of dyslipidemia and insulin resistance is well established, and there is also some evidence suggesting a higher incidence of hypertension (HTN) in PLH. ^1,2 The higher prevalence among PLH may be a reflection of ART side effects and/or HIV itself. ^3-5 In addition, PLH are at higher risk for chronic renal diseases such as HIV-associated nephropathy and ART associated renal toxicity. ⁶ Similarly, PLH are at higher risk for systolic and diastolic cardiac dysfunction, including heart failure. ⁷ Appropriate blood pressure control among PLH is important for minimizing progression of renal and cardiovascular disease.

Brief Review

Classification & Blood Pressure Goals

One of the most controversial aspects of the 2017 American College of Cardiology/American Heart Association HTN guideline is classification of hypertension as a blood pressure ≥130/80 mm Hg. ⁸ The impetus behind this recommendation largely is a result of a well cited meta-analysis of 61 prospective studies in which the risk of CVD increased in a log-linear fashion from systolic BP levels <115 mm Hg to >180 mm Hg and from diastolic BP levels <75 mm Hg to >105 mm Hg. ⁹

The updated guideline recommends using the baseline blood pressure and 10-year ASCVD risk to guide decisions about medication therapy (Table 2). Stage I hypertension is defined as a systolic BP 130 – 139 mmHg or a diastolic BP 80 – 89 mmHg and treatment decisions are stratified based on 10-year ASCVD risk. If the 10-year risk is <10%, start with healthy lifestyle recommendations and reassess the BP in 3-6 months. ⁸ Among antihypertensive patients, lifestyle changes have been shown to reduce systolic BP by 4 - 11 mmHg, with the largest improvements stemming from dietary changes and increased exercise. ¹⁰ Approximate reductions in systolic blood pressure following lifestyle changes are displayed in Table 2. ^{8, 10}

Table 2: Updated Classification of High Blood Pressure*

*Individuals with SBP and DBP in 2 categories should be designated to the higher BP category. BP indicates blood pressure (based on an average of ≥2 careful readings obtained on ≥2 occasions, as detailed in DBP, diastolic blood pressure; and SBP systolic blood pressure.)

Table 3: Reductions in Systolic Blood Pressure by Lifestyle Change

Patients with stage I hypertension and a 10-year ASCVD risk ≥10% or CVD, diabetes mellitus, or kidney disease (defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 and/or urine albumin:creatinine ≥300 mg/g), an antihypertensive agent should be initiated along with lifestyle changes. Patients with stage 2 hypertension, which is defined as a BP ≥140/90, should be initiated on 2 antihypertensive agent should be initiated along with lifestyle changes. Patients with stage 2 hypertension, which is defined as a BP ≥140/90, should be initiated on 2 antihypertensive agents of different classes along with lifestyle changes. For all patients, including those with HIV, target BP <130/80 mmHg.

Therapy Selection

Patients who do not have a compelling indication for a specific antihypertensive agent, should initially be treated with one or more agents from the following classes: thiazide/thiazide-like diuretics, dihydropyridine calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers. While, HIV alone is not a compelling indication for a specific class of antihypertensive agents lowering medication, considering the potential for drug interactions is essential when initiating therapy in patients on antiretrovirals. Common interactions between antiretroviral and antihypertensives are presented in Table 4.

Adapted from DHHS Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. ¹¹

Table 4: Common Interactions Between Antiretroviral and Antihypertensives

Key: BIC=Bictegravir; DTG= Dolutegravir; RAL= Raltegravir; EVG/c=Elvitegravir/cobicistat; EFV=Efavirenz; ETR=Etravirine; NVP=Nevirapine; PI=Protease Inhibitor; CCB= Calcium Channel Blocker; ATV/r= Atazanavir/ritonavir; CYP=Cytochrome; AUC=Area Under the Curve

Hypertension & HIV

Literature evaluating management of hypertension specifically among PLH is scarce. However, HIV infection, even in the presence of full HIV viral suppression, is considered a “risk-enhancing” factor associated with ASCVD. HIV status is not included in the pooled cohort calculator and therefore may underestimate risk among PLH. Studies have shown that HIV may increase ASCVD 50 – 100% above what is estimated by the pooled risk calculator.^12,13 Consideration of HIV is particularly relevant for patients with an ASCVD risk estimate that is borderline for pharmacologic therapy. In these instances, true 10-year risk might be >10% suggesting that the patient may benefit from initiation of pharmacologic therapy.

Introduction

The success of antiretroviral therapy has transformed morbidity and mortality among people living with HIV (PLH) from early AIDS-related causes to later cardiovascular causes.^1,2 Age and sex-adjusted deaths from cardiovascular disease (CVD) among PLH are appreciably higher than the general population. ^3-5 Moreover, one in three patients with HIV smoke, and smoking accounts for 60% of all deaths among PLH. ⁶ While the benefits of smoking cessation among patients with and without HIV are clear, the literature suggests evidence-based treatment for smoking is underused, particularly among PLH. ^6-9 This brief discusses the role of smoking cessation treatment in reducing CVD risk among PLH.

Brief Review

The 5 A’s is an evidence-based method of assessing a patient’s willingness to quit smoking. This approach, which can be delivered in as little as 3 minutes, incorporates motivation interviewing to guide patients towards smoking cessation. ¹⁰ The 5A’s approach is displayed in Figure 1.

Figure 1: The 5 A’s for Smoking Cessation Assessment

The 5 A’s begin by asking patients about current and past tobacco use. Never smokers should be encouraged to continue healthy patterns and prior users should be commended and educated on avoidance of triggers, including the importance of avoiding “just one cigarette”. Current smokers should be asked about frequency and type of tobacco products used. Annual assessments are reasonable for non-smokers while more frequent assessments may be appropriate for prior or current smokers.

After the initial assessment, the clinician should encourage all current users to quit and provide personalized education and recommendations which could assist in their efforts. Even this brief interaction may have a positive impact on cessation rates. ¹¹ At this point, the clinician should assess the patient’s willingness to quit. The stages of change model is commonly used to describe a patient’s attitude towards quitting: ¹²

• Pre-contemplative: Not considering quitting in the near future.
• Contemplative: Considering a quit attempt within 6 months.
• Preparation: Considering a quit attempt within 30 days.

Clinicians should aim to understanding motives and barriers to cessation for patients in pre-contemplative and contemplative states and motivational interviewing strategies should be employed to move patients towards an actionable state. The 5 R’s is another useful technique to help move patients towards the preparation state: ¹³

Figure 2: 5 R’s for Patients Who Are Not Ready to Quit

Patient in the preparation phase should be encouraged to set a quit date within 2 – 4 weeks. Encourage patients to share this date with family, friends, and coworkers, and request support. Establishing a clear date with patients prepared to quit is an important but often omitted aspect of cessation counseling. ^9,14 Pharmacotherapy should be offered to all patients attempting to quit as assistive medications increase their likelihood of success. First line agents include nicotine replacement therapies (NRT), varenicline (Chantix®) and bupropion (Wellbutrin XR®, Zyban®).¹⁵ Choice of medication should be based on patient preference and comorbid disease states. In general, initial regimens should consist of one of the following: short and/or long NRT, varenicline, or bupropion. Varenicline is a nicotine receptor blocker and therefore use in combination with an NRT is theoretically without benefit. Evidence supporting use of bupropion in combination with NRT is mixed, with some studies showing positive results and others indicating no additional benefits. ^16,17 Use of two NRTs has been shown to be more effective than a single NRT alone. ^8,18,19 A common NRT combination regimen consists of the long acting nicotine patch with a short acting NRT (i.e. gum or lozenges). The role of electronic cigarettes (“e-cigarettes”) in smoking cessation remains unclear and is limited by lack of long-term safety data. ²⁰

In general, pharmacotherapies for smoking cessation are well tolerated. Both varenicline and bupropion should be initiated at least 7-10 days before the quit date. To improve tolerance, both agents should be started at a low dose and titrated to therapeutic doses; varenicline is available as a “starter pack” whereas bupropion may be started at 150 mg daily and increased to 300 mg daily after 3 – 7 days.

Common side effects, HIV-specific drug interactions, and other contraindications are displayed in Table 1.

Table 1. Pharmacotherapies for Smoking Cessation ⁸

A critical but often overlooked step is arranging follow up. Ideally, follow up should be scheduled within 1 – 2 weeks of the quit date and can be accomplished in person or via phone. The is an important opportunity to evaluate response to pharmacotherapies, identify early barriers, and provide reinforcement. Subsequent visits should focus on congratulating success, evaluating continued need for pharmacotherapies, and proactively identifying potential triggers for relapse. Remain mindful that relapse is common, particularly in the initial months to years and that the literature shows nearly two-thirds of those who relapse wish to make another quit attempt within 30 days. ^22,23

Introduction

Poor medication adherence is understood to be a leading cause of treatment failure. In trials, patients take approximately 40 – 80% of doses as prescribed and it is likely that real-world rates of poor adherence exceed what has been reported in these closely-monitored settings. ¹ Moreover, non-adherence often goes unrecognized. One survey found that while 64% of patients believed they had good medication adherence (defined as followed prescriber instructions “extremely closely”), 31% reported not filling a prescription they were given and 24% admitted to taking less than the prescribed dose. ² Likewise, physicians tend to over-estimate the degree to which patients are taking medications as prescribed. ³ The combined unawareness among patients and providers has caused non-adherence to become a common but often unrealized reason that patients fail to achieve treatment goals.

Brief Review

Poor adherence can be an intentional or unintentional process. Unintentional non-adherence may most commonly be thought of as simple forgetfulness (i.e. a patient inadvertently misses doses) but there are several other underlying causes. It often suggests that the patient has failed to establish an adherence habit in which taking medication has been integrated into a person’s daily routine to the point where adherence becomes automatic.⁴ In addition, patients with poor health literacy or cognitive impairment may lack the ability to follow the prescribed instructions for medication use needed to develop an adherence habit. Even in patients with adequate health literacy, complex regimens, such as those with multiple daily doses and/or a high number of medications, can also prove problematic for adherence. Transportation to and from the pharmacy may also present barriers, particularly among low-income patients and older adults. Increasingly, cost is another barrier to taking medications as prescribed.

Intentional non-adherence refers to patients who are making a conscious decision as to how they are going to take their medications. Typically, intentional non-adherence reflects the patient’s beliefs about the relative benefits vs harms and side effects. ⁵ Adverse effects, including actual and fear of potential ones, is a common contributor. Similarly, lack of perceived benefit may also contribute to intentional non-adherence, particularly if patient develops (or are is concerned about developing) adverse effects to a medication used to treat an asymptomatic condition. Increasingly, cost is becoming a significant barrier to medication adherence; ⁶ it is not uncommon for patients, particularly those with deductibles or in the Medicare Part D coverage gap, to “ration” medications due to affordability concerns.

Identifying & Addressing

Reviewing prescription fill histories is a simple way to gauge medication use in patients with suspected non-adherence. While electronic medical records have this technology embedded, this can also be accomplished by contactinged the patient’s pharmacy and requesting the refill dates for a given medication. Though gaps in fill histories suggest a pattern of non-adherence, one must be careful not to assume that filling a medication means a patient is taking a medication. Pill counts may also be used, however this method tends to be time consuming and may be skewed if patients combine the contents of old prescription vials with new ones. Another clue to non-adherence is failing to see an expected effect, e.g. reduction in blood pressure or cholesterol.

There are multiple patient-reported tools that can be used to assess adherence. The Morisky Medication Adherence Scale (MMSAS) is a 4 or 8-item survey that is a validated measure of medication adherence across a number of chronic disease states. ^7-9

Figure 1: Morisky Medication Adherence Scale (MMAS)

Ultimately, it is important for providers to create a non-judgmental environment where patients feel comfortable discussing their true manner of medication use. A trusting relationship between the patient and the clinician is associated with improved ART adherence.¹⁰ Similarly, a trusting relationship increases the chances that the patients will be more forthright about their non-adherence when asked about their adherence in a non-judgmental way. Approaches for addressing intentional and unintentional non-adherence are included in Table 1. Examples of talking points include:

• "Many people find it hard to take to their medication every day. Tell me about your experience."
• “What have you read about your medications? Did you come across anything in your research that makes you concerned?”
• “Do you have any concerns about paying for your medications?”
• “Before we add a second medication for your blood pressure, let’s talk about how you are taking the first. Your refill history shows you filled this medication about 2 weeks later than we would expect if you were taking it every day. Thinking about the last week, were there any days you missed a dose?”
• “What do you use to help you to remember to take your medications?”

Introduction

The dramatic success of antiretroviral therapy (ART) is transforming morbidity and mortality among people living with HIV (PLH) from early AIDS-related causes to later cardiovascular causes. ^1,2 Age and sex-adjusted deaths from cardiovascular disease (CVD) among PLH are appreciably higher than the general population. ^3-5 PLH have higher risk for atherosclerotic cardiovascular disease (ASCVD) than the general population after controlling for ASCVD risk factors. ⁶ Yet, PLH are less likely than the general population to receive proven interventions commonly referred to as the ABCS for aspirin, blood pressure control, cholesterol control, and smoking cessation for prevention of ASCVD. ^7-9 Underuse of these interventions in PLH is worse for African Americans. ¹⁰

Reasons for underuse of these interventions likely reflects an underestimation of ASCVD risk and lack of knowledge regarding safety of medications (e.g., statins in combination with ART) in this population. In the absence of formal risk calculation, clinician’s estimates are inaccurate and tend to underestimate ASCVD risk. ¹¹ In practice, clinicians tend to emphasize one or two risk factors and fail to appreciate the impact of compounded risk, particularly the impact of age, sex, and other risk factors. ¹²

Use of risk calculation improves risk assessment beyond clinician estimates ¹³ and results in greater reduction in risk factors without clinical harm. ¹⁴ While risk calculators tend to underestimate risk for PLH,⁶ their use provides a foundation for shared patient decision-making regarding risk reduction. ¹⁵

National Clinical Practice Guidelines for management of hypertension (2017) and also for cholesterol (2018) recommend use of the American College of Cardiology/American Heart Association (ACC/AHA) ASCVD Risk Estimator Plus Calculator to estimate a patient’s 10-year ASCVD risk. ^16,17 This calculator has the advantage of including white and black participants in the original cohorts. In addition, the current version allows estimation of treatment with aspirin, antihypertensive agents, statins, and smoking cessation. ¹⁸ The ASCVD Risk Estimator Plus can be accessed through the Web. It is also available as an App for free download for IOS and Android phones.

This brief discusses how to assess ASCVD risk among PLH.

Brief Review

The ASCVD Risk Estimator Plus should be used at an initial visit with a patient to establish a reference point and forecast the impact of various interventions on patient risk. ^13,19 Risk should be reassessed at follow-up visits (after use of an ABCS) to monitor change in a patient’s 10-year risk. ASCVD risk can be estimated for patients 40-79 years of age. Patients with a history of known ASCVD, i.e. a diagnosis of coronary artery disease, cerebrovascular disease, aortic disease or peripheral vascular disease, are considered high risk, typically 10-year risk >20% for future coronary or cerebrovascular events. Individuals with high risk should be considered for secondary prevention that may include: aspirin prophylaxis, blood pressure control, use of high intensity statins to reduce LDL-C by at least 50%, and smoking cessation counseling/pharmacotherapy.

For primary ASCVD prevention, calculation of ASCVD risk is based on the following risk factors: age, biological sex, race (White, African American, or Other), systolic and diastolic blood pressure, total, HDL, and LDL cholesterol, presence of diabetes, smoking status (current, former, never), current treatment for hypertension and currently on a statin or aspirin therapy.

Most ASCVD related guidelines recommend shared decision making. ^17,20 This includes discussion of potential benefits from risk reduction and potential harms. A patient’s risk estimate can be used during the clinician-patient discussion to determine approach to therapy for risk reduction when indicated. In addition to reviewing the risk estimate, consideration should be given to the burden, severity, and control of CVD risk factors along with the presence of any risk-enhancing conditions (Figure 2). HIV infection (even in the presence of controlled viremia) is considered a “risk-enhancing” factor associated with increased risk of an ASCVD event, affecting the 10-year risk estimate. HIV often increases risk 50-100% beyond calculated risk. ⁶ Consideration of HIV is particularly relevant for patients with a “borderline” ASCVD risk estimate, i.e. 5-7.4%. In these instances, the actual 10-year risk might be closer to 7.5-10%, suggesting the need for firmer recommendation for drug therapy (i.e., statin).

Our online CME modules address each of the ABCS. These include discussion of the U.S. Preventive Services Task Force (USPSTF) for use of aspirin and a calculator to assist in personalizing the benefits and harms of use of aspirin to prevent CVD, discussion of current hypertension guidelines, including a stepped care approach to achieve control, use of statins for PLH, and USPSTF guidelines to address smoking.