HIV and hypertension epidemiology

Abstract

Purpose of review

The aim of this study was to provide an overview of the burden, pathogenesis, and recent recommendations for treating hypertension among people living with HIV (PLWH). This review is relevant because of the increase in the prevalence of HIV as a chronic disease and the intersection of the increasing prevalence of hypertension.

Recent findings

The contribution of HIV to the pathogenesis of hypertension is complex and still incompletely understood. Evidence suggests that chronic inflammation from HIV, antiretroviral treatment (ART), and comorbidities such as renal disease and insulin resistance contribute to developing hypertension in PLWH. Treatment is not distinct from guidelines for HIV-noninfected people. Nonpharmacological guidelines such as decreasing blood pressure by promoting a healthy lifestyle emphasizing exercise, weight loss, and smoking cessation are still recommended in the literature. The pharmacological management of hypertension in PLWH is similar, but special attention must be given to specific drugs with potential interaction with ART regimens. Further research is needed to investigate the pathways and effects of hypertension on HIV.

Summary

There are different pathways to the pathogenesis of hypertension in PLWH. Clinicians should take it into consideration to provide more precise management of hypertension in PLWH. Further research into the subject is still required.

INTRODUCTION

As of 2021, the estimated number of people living with HIV in the United States was approximately 1.2 million [1]. Deaths in HIV-positive patients have decreased dramatically since the advent of combination antiretroviral treatment (ART) in 1996, and its subsequent advancement [2,3]. ART has grown more readily available, and the drugs themselves have become more effective and easier to use. Recent data suggest that of HIV-positive individuals in the United States receiving medical care, more than 91% were taking combination ART medication, which can ultimately lead to a normal life expectancy for persons living with HIV infection (PLWH) [4]. In a study from the UK, where ART is free through the National Health Service, a 35-year-old HIV-positive person who achieved viral suppression and a CD4⁺ cell count of at least 350 cells/μl within 1 year of starting ART was estimated to live to about 80 years on average [5].

The tremendous success of ART as well as changes in demographics have led to older individuals increasingly affected by HIV, with the number of people over the age of 50 living with HIV projected to double by 2030 [6,7]. It is estimated that the median age of HIV-infected patients on combination ART will increase from 43.9 years in 2010 to 56.6 years in 2030 [8], while the overall proportion of people living with HIV who are aged 50 years or older will increase from 28% in 2010 to 73% in 2030.

The aging of the population living with HIV presents new challenges, as older individuals with HIV are at an increased risk of common age-related conditions. It has been estimated that 2.6 million disability-adjusted life years [9] are lost annually due to HIV-related cardiovascular disease (CVD), which has tripled over the last 20 years. Globally, hypertension is the most important avoidable risk factor for both CVD and all-cause mortality [10,11]. Between 2010 and 2014, hypertension, defined as SBP at least 140mmHg and/or DBP at least 90mmHg, affected approximately 31.1% (1.39 billion) of adults worldwide [12] and 32.2% (74.1 million) [13] in the USA. The purpose of this review is to critically evaluate what is currently known about the prevalence of hypertension in persons living with HIV and to address pertinent questions about its causes and therapeutic treatment.

BURDEN OF HYPERTENSION IN PERSONS LIVING WITH HIV

Among PLWH, hypertension is prevalent, and is likely more frequent than among persons without HIV at similar ages, due to the impacts of chronic inflammation, treatment with combination ART medications, and an excess of traditional risk factors [14]. However, reliable estimates of the prevalence of hypertension in PLWH are difficult to identify and highly dependent on the methodology of data collection, study design, definitions of hypertension, and statistical analysis. Because of these variations between studies, prevalence estimates have been reported to range between 4 and 57%, with estimated incidence rates ranging from 26 to 220 per 1000 person-years of follow-up among PLWH worldwide [15]. Research findings are also conflicting as to whether or not people with treated HIV have a greater prevalence of hypertension than those without the infection [16-19].

According to the findings of a 2017 meta-analysis that included 63 554 individuals from 49 studies that were published between 2011 and 2016, the prevalence of hypertension was estimated to be 35% for PLWH who were receiving ART but only 13% for PLWH who had never had ART [20]. A previous meta-analysis that included 44 903 individuals from 39 studies published between 2003 and 2014 concluded similarly that the prevalence of hypertension was higher among PLWH receiving ART than those who were treatment naive; however, the estimates were substantially different with 14.5% of ART exposed having hypertension compared with 10.5% of those who were treatment naive. The most recent meta-analysis on the subject, which included 11 101 581 people from 59 cross-sectional studies, found that heterogeneity between studies was extremely high, with an I squared statistic of 97% and meta-regression indicating that differences by region and hypertension definition were primarily responsible for the substantial level of variation in estimates [21^■■].

A number of studies have suggested that the initiation of treatment with combination ART is associated with an increase in BP, which seems to be mediated at least in part by weight gain [22^■■,23,24]. Untreated HIV is typically associated with lower blood pressure [25], which may be the result of weight loss, uncontrolled inflammation, and states of vascular permeability. For example, using data from 527 HIV-infected and 517 uninfected participants in the AGEhIV Cohort Study, a prospective comparative cohort study investigating age-related comorbidities and their risk factors in the Netherlands [24], the association between HIV and hypertension was statistically significant [odds ratio (OR), 1.65; 95% confidence interval (95% CI) 1.25–2.19] even after adjusted for age, sex, ethnicity, family history of hypertension, smoking, alcohol use, physical activity, and BMI, but was attenuated after additional adjustment for waist-to-hip ratio (OR, 1.29;95% CI, 0.95–1.76). In a Ugandan matched case–control study known as the ACHIEvA (Aging and Cardiovascular Diseases in HIV Patients of East Africa), HIV infection was inversely associated with both SBP and DBP, with BMI mediating 25% of the association [23]. Both of these studies suggest that body weight and phenotype are involved in the association between HIV and BP but further reinforce the differences in study results by region noted in the aforementioned meta-analysis [21^■■].

Hypertension in adults was re-defined in 2017 by the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines as having a SBP of at least 130mmHg and/or a DBP at least 80mmHg [26], increasing the prevalence among U.S. adults aged 18 years and over to 45.4% [13,27]. Among PLWH, however, the majority of data use the prior definition and are likely to underestimate the disease burden. In a study of 957 PLWH in Texas [28], the redefinition of hypertension increased prevalence in the sample by 44.3%, from 47.6 to 68.7%. Although prevalence was nearly equal between men and women using the older criteria of at least 140/90 mm Hg (47.4 and 48.5%, respectively), men were 2.36 times more likely to have hypertension than women (95% CI: 1.55–3.60) using the 2017 criteria of at least 130/80 mmHg.

PATHOPHYSIOLOGY

The pathogenesis of hypertension in HIV-treated patients is incompletely understood and likely complex. PLWH are susceptible to the same factors associated with the onset of hypertension in HIV-negative persons, including sociodemographic, hereditary, and behavioral factors and comorbidities. In addition, the length of HIV-related immunological deficiency, immune activation, and chronic inflammation varies even before initiating combination ART. At the same time, some treatment regimens directly affect blood pressure. Thus, a complicated interplay between HIV-related factors, traditional hypertension risk factors, and antiretroviral medication exposure likely contributes to hypertension in PLWH. Those with HIV who have access to combination ART are living longer and may be at higher risk for age-related illnesses such as cardiovascular disease. With the median age of HIV patients receiving ART rising to 56.5 years in 2030, 78% of HIV-positive individuals will have been diagnosed with cardiovascular illness [8]. The increasing prevalence of these conditions affects the treatment and care of HIV-infected patients with loss of therapeutic efficacy and virological breakthrough from increased polypharmacy, drug interactions, and adverse effects [29,30]. A schematic description of the intricate pathways of hypertension pathophysiology among PLWH is shown in Fig. 1.

FIGURE 1.

HIV-related mechanisms for hypertension. It depicts the different mechanisms and pathways for hypertension pathogenesis that are related to HIV infection. ART, antiretroviral therapy; CD163, Cluster of Differentiation 163 Protein; CD4, Cluster of Differentiation 4 Helper T-Cell; CMV, cytomegalovirus; GALT, gut-associated lymphoid tissue; IL-6, interleukin-6; LPS, lipopolysaccharide; RAAS, renin angiotensin aldosterone system; sCD14, Soluble Cluster of Differentiation 14 Protein. Adapted from [32].

HIV infection alone increases the risk of cardiovascular disease via various mechanisms, including elevated cytokine levels, chronic inflammation, immune reconstitution, and lipodystrophy, which uniquely influences common downstream pathways, such as the sympathetic and renin-angiotensin-aldosterone systems (RAAS) [31,32]. Inflammatory indicators, such as subsets of lymphocytes and their cytokines, cause vascular and endothelial remodeling, resulting in elevated blood pressure [33]. Elevated interleukin-6 (IL-6) levels precede and predict hypertension in PLWH (OR 1.8; 95% CI: 1.4–2.5; P = 0.001) [34]. In addition, soluble CD14 (sCD14), a marker of monocyte activation, was found to be related to cardiovascular risk factors, including hypertension, in a genome-wide association analysis of nearly 3000 older persons who were HIV-negative [35]. The translocation of microorganisms from the gut is also linked to the pathogenesis of hypertension in PLWH [36,37]. HIV primarily infects CD4⁺ T-cells in gut-associated lymphoid tissue (GALT), which disrupts the body’s natural mucosal defenses and allows pathogens to enter the systemic circulation [36-39]. In PLWH, lipopolysaccharides (LPS) and sCD14, both indicators of microbial gut translocation, have been related to hypertension. Plasma concentrations of LPS are elevated in PLWH before and after the beginning of ART [36,37]. LPS has also been linked to stimulation of the RAAS, which promotes angiotensin II action by acting on endothelial adhesion leukocytes [40]. Nevertheless, prolonged ART usage may partially mediate the precise mechanism by which LPS produces endothelial damage.

ART induces inflammatory pathways, fat distribution alterations, and metabolic abnormalities, such as insulin resistance, dyslipidemia, and hypertension [32,41]. As mentioned before, obesity plays a role in the prevalence of hypertension. Both HIV infection and particular antiretrovirals have been related to changes in body composition and lipodystrophy, which may raise the risk of hypertension [18,24,42]. Studies have shown a correlation between abdominal fat distribution and hypertension in PLWH [42,43^■], most likely as a result of RAAS activation [44]. Hypertension in PLWH using ART may also result from immune suppression and reconstitution. CD4⁺ T-cell counts drop dramatically and rise rapidly after ART initiation, and studies have linked lower nadir CD4⁺ T-cell counts to a greater prevalence of hypertension after ART [32,45]. In people with CD4⁺ cell counts larger than 500 cells/μl at baseline, researchers discovered that ART did not affect blood pressure or arterial stiffness [45]. The increased occurrence of hypertension in adults who have received ART is likely a result of the immunological reconstitution generated by these medications rather than a direct effect of the drugs on blood pressure [37]. Nonetheless, the effects of ART may explain a portion of the increased risk of hypertension in HIV-infected adults, but not all of it.

Comorbidities such as renal disease and insulin resistance are also contributors [41]. Several studies have demonstrated that microalbuminuria, a sign of renal damage, is independently related to hypertension in HIV-infected individuals [46,47]. PLWH have higher rates of albuminuria than uninfected adults, with a prevalence of up to four times that of the general population [56]. These elevated albuminuria rates in PLWH are related to direct HIV viral impact and chronic inflammation [32].

In addition, the stress of HIV-related stigma and discrimination in healthcare settings are likely to play a key role. Transgender people are disproportionately impacted by HIV and represent the fastest-growing minority in the United States. There is a growing corpus of research investigating health inequities in this community; nonetheless, the cardiovascular risk profiles of transgender men and women are little understood [48]. More than 75% of transgender men and women take hormone therapy [49], and endogenous hormones directly impact vascular endothelial function through androgen receptors and estrogen receptors present on endothelial cells [50].

TREATMENT OF HYPERTENSION AND HIV

Although it is common knowledge that HIV infection raises the risk of cardiovascular risks and diseases, only 31% of PLWH had ever discussed hypertension, hypercholesterolemia, family history of cardiovascular disease, or smoking with their healthcare providers [51]. Furthermore, studies in the United States have demonstrated that controlling coronary heart disease risk factors, such as hypertension, is more affected by lack of access to care in PLWH than those without HIV [52]. This underscores the necessity of increasing PLWH primary care providers’ awareness of cardiovascular disease risk reduction measures.

The treatment of hypertension in HIV-positive individuals is comparable to that in the general population, with the primary goal of decreasing blood pressure and reducing related risks for cardiovascular disease [53]. Most available data support using existing guidelines for the general population. For instance, the American Heart Association Statement on HIV and Cardiovascular Disorders has no specific therapy recommendations to treat hypertension among individuals with HIV [54]. In contrast, the European AIDS Clinical Society Guidelines Version 11.1 (2022) recommends the use of a comprehensive risk algorithm and includes a drug sequencing algorithm [57]. The British HIV Association guidelines (2019 interim update) recommend annual screenings for those with CVD and an elevated risk (10-year risk > 10%) [58]. The Malawi HIV Testing Services Guidelines (2016) also recommends assessing blood pressure when initiating ART therapy and every year afterward. When blood pressure reaches thresholds defining hypertension, management should include the initiation of lifestyle changes and pharmacological treatment as needed [59]. Lifestyle counseling should address modifiable risk factors such as nutrition, physical activity, excess adiposity, and smoking. However, no tailored strategies have been developed for HIV patients’ cardiovascular risk reduction [52,55].

Lifestyle modifications

Every preventive cardiovascular program and healthy lifestyle promotion strategy for individuals with HIV should include advice to increase physical activity, and among those who are overweight or obese, weight loss [60]. The increase in life expectancy due to ART and HIV has predisposed PLWH to develop comorbidities [61] and decreased age-predicted fitness performance, oxygen consumption (VO₂max), grip strength, and walked distance, compared with their noninfected counterparts. This can impact their ability to conduct independent activities of daily living [62]. Anemia, neuromuscular problems, and pulmonary disease may impair exercise capacity among PLWH [63]. Myalgia affects twice as many PLWH than uninfected controls, independent of ART usage [64]. Aerobic and resistance training improves maximal oxygen consumption and blood pressure, and have the potential to decrease age-related cardiovascular and metabolic risk [65,66]. Management of hypertension in PLWH should also focus on nutrition. Individuals with HIV tend to consume more total fat, saturated fat, and cholesterol than their uninfected counterparts. This suggests the potential benefit of dietary guidance among PLWH [67]. A study examined whether a lifestyle modification program that includes weekly one-on-one dietary counseling on healthy eating and exercise would improve metabolic syndrome criteria and cardiovascular risk in HIV patients. Waist circumference and SBP were the two most improved parameters after 6 months of intensive lifestyle adjustment. This study reduced SBP significantly, similar to the DASH lifestyle modification trial [68]. Given that limited strategies have proved successful in treating hypertension in PLWH, lifestyle modification might be an advantageous strategy without the risk of drug-related adverse effects or medication interactions.

The benefits of smoking cessation are well established in the general population, but despite the increased frequency of smoking among PLWH, these benefits are less clear [69]. There is research examining smoking cessation strategies among HIV-positive individuals; interventions that integrate therapy for anxiety and depression with smoking cessation have been associated with superior outcomes [70]. Pharmacologic therapies may be beneficial. Bupropion, often used as a smoking cessation medication, is metabolized by the cytochrome P450 enzyme and was known to interact with less-used antiretroviral medications (e.g., ritonavir) [71]. However, a study demonstrated that Cytochrome P2B6 is primarily responsible for the metabolism of bupropion, and an open-label trial revealed that the usage of bupropion was effective and well tolerated among HIV-infected patients [72].

The pharmacological management of hypertension in HIV patients is comparable to that of the general population. However, there are important considerations to remember when treating HTN in PLWH using ART. Calcium channel blockers (CCBs) have the highest potential for interaction with antiretroviral drugs [73]. CYP3A4 is inhibited by the dihydropyridine CCBs, verapamil, and diltiazem [74]. Thus, these drugs interact with antiretrovirals such as Nonnucleoside reverse transcriptase inhibitors, CYP3A4 inducers (such as nevirapine and efavirenz), and drugs that inhibit this enzyme (e.g., protease inhibitors and cobicistat) [75]. CYP2D6 metabolizes beta-blockers such as propranolol, carvedilol, metoprolol, pindolol, and timolol [76]. These medications may interact with CYP2D6 inhibitors, including efavirenz and ritonavir; therefore, clinical monitoring is indicated [73]. Except for losartan, ACE inhibitors and angiotensin II receptor blockers (ARBs) have limited interactions with antiretrovirals. Losartan is bioactivated by CYP2C9 and metabolized by CP3A4, rendering it sensitive to interactions with CYP2C9 inhibitors, such as efavirenz or elvitegravir, and CYP3A4 inhibitors, such as protease inhibitors [73]. In some instances, coadministration of antiretroviral medications and antihypertensive drugs may raise the concentration of the antiretroviral drug, as is the case with etravirine, rilpivirine, maraviroc, and tenofovir when taken with specific CCBs or diuretics [15].

CONCLUSION: FUTURE DIRECTIONS FOR RESEARCH

We have summarized evidence regarding hypertension’s prevalence, mechanisms, and management in HIV-infected adults. It is worth highlighting that, to date, most of the literature describes the pathophysiology and management of cardiovascular disease in the context of HIV. Further research is needed to investigate more specific pathways and treatment strategies related to hypertension. Larger, multinational prospective studies are needed to determine the systematic factors that precede and predict hypertension in PLWH. Most data regarding hypertension in HIV-infected adults come from cross-sectional studies, and there are no tailored screening guidelines for hypertension among those living with HIV. Optimal algorithms for initiating antihypertensive therapy and ongoing management should be explored. Furthermore, larger interventional studies of novel approaches to prevent and treat HIV-infected adults with hypertension that target the pathophysiological pathways described here are needed. These strategies should also take into consideration special populations among PLWH. Transgender individuals are a vulnerable population that faces constantly shifting social policies and clinical challenges due to the complex interplay of CVD risk factors, HIV, and hormone therapy. A multidisciplinary team is needed to tackle the healthcare needs of PLWH and hypertension.

KEY POINTS.

• Due to successful treatment and aging of the population with HIV, in Western countries, hypertension is more prevalent in PLWH than in their noninfected counterparts.

• The pathophysiology of hypertension in individuals with HIV is incompletely understood, complex, and likely involves inflammation, immune activation, lipodystrophy, excessive RAAS activation, microbial translocation in the gut, and other mechanisms.

• There are no guidelines specific to the treatment of hypertension in those with HIV; however, drug interactions are a concern and should be carefully considered before an antihypertensive regimen is started.