The risk of developing chronic cardiovascular and pulmonary diseases is increasingly recognized as a major public health problem in patients infected with HIV,1–3 perhaps related to long-term exposure to the virus, the effects of ongoing inflammatory responses, progressive immunologic dysfunction, and/or long-term adverse effects associated with antiretroviral therapy (ART). The inevitable consequences of aging, the development of age-related chronic conditions, and other factors affecting cardiopulmonary health are likely to compound any HIV viral or treatment effect. The overall impact of chronic noncommunicable cardiovascular and pulmonary diseases occurring among HIV-positive people in low- and middle-income countries (LMICs) (defined according to World Bank Country and Lending Group designation) is profound given that most (>70%) of the HIV-positive people reside in these areas and may experience cardiopulmonary risk factors unique to this setting.4 We review available data on chronic noncommunicable cardiovascular and pulmonary diseases among HIV-positive persons in LMICs and suggest directions for future research to stimulate improvements in diagnosis, prevention, and treatment of HIV-associated chronic cardiovascular and pulmonary diseases in LMICs.
METHODS AND EPIDEMIOLOGY
The most frequently reported chronic noncommunicable cardiovascular and pulmonary diseases linked to HIV in LMICs are heart failure, hypertension, coronary artery disease (CAD)/myocardial infarction (MI), stroke, obstructive lung disease (OLD), and pulmonary hypertension (Table 1). This list was derived from a search of the published literature using PubMed to identify articles using subject headings or MeSH terms related to cardiovascular disease, pulmonary disease, HIV, developing countries, and LMICs. The search was not a systematic review. Reference lists were also reviewed for additional articles. Articles were selected based on their relevance to the subject matter and availability of data within the article. Although the epidemiology of these diseases varies by region of the world, we focus on sub-Saharan Africa (SSA) in this review because of the large proportion of the HIV-positive population living there and because the bulk of the published literature emanates from this region. Because many of these conditions have not been extensively studied in LMICs (Table 1), we first discuss these diseases in HIV-positive persons in high-income countries (HICs) and then summarize findings in LMICs. Table 1 is organized according to the most frequently reported conditions; however, because of variation in patient population, method of screening and selection of patients, and definitions of outcomes, there are wide variations in findings.
The link between HIV and heart failure in the ART era has been described in HICs in the last decade.33,34 A population-based retrospective cohort study from the United States found that HIV infection was associated with a 1.8-fold risk of heart failure in HIV-positive persons compared with age- and ethnicity-matched HIV-controls.35 A meta-analysis of 11 studies of heart failure in HIV-positive patients showed a prevalence of 8.3% for systolic dysfunction and 43.4% for diastolic dysfunction.36 In terms of potential pathophysiologic mechanisms, systolic dysfunction was significantly associated with chronic inflammation, tobacco smoking, and history of MI, whereas diastolic dysfunction was associated with hypertension and age in this meta-analysis.36
Most of the LMIC data implicating HIV as a cause of heart failure were generated before the widespread availability of ART in LMICs and document an overall prevalence between 9% and 57%, which, in some instances, was higher than in the general population.5–8,37 During this era, systolic heart failure was commonly reported in association with HIV; however, diastolic dysfunction was documented in a large proportion (86%) of asymptomatic HIV-positive patients.38 HIV-associated cardiomyopathy occurs most often among young persons with low CD4 counts (usually <100), higher viral load, and advanced HIV stage.9,10 Possible causes include opportunistic infections, nutrient deficiency (eg, selenium), HIV viremia, and autoimmunity.10,11,35,39
Studies in the ART era demonstrate that cardiomyopathy is still a relevant form of HIV-associated cardiovascular disease.40 Between 5% and 29% of HIV-positive patients have cardiomyopathy depending on the methods and definitions used and populations studied (Table 1).11–14 Systolic dysfunction remains the most commonly investigated form; however, diastolic dysfunction is concurrent in 21%–46% of HIV-positive patients with cardiomyopathy depending on the clinical presentation.11 The relationship between peripartum cardiomyopathy and HIV remains unclear.15,16 Whether heart failure occurs disproportionately among HIV-positive persons in LMICs in the ART era is not yet known (owing to lack of information on rates of heart failure in the general or HIV-negative population), nor is how common diastolic function is in HIV-positive patients as a function of degree of HIV disease control. Moreover, specific ART drug classes are associated with a higher prevalence of cardiomyopathy.41 Additional work is required to characterize the frequency and causes of heart failure and the role of ART in both HIV-positive and HIV-negative LMIC populations.
A relationship between higher systolic blood pressure and duration of HIV has been reported in HICs. In the Multicenter AIDS Cohort, Seaberg et al42 noted that the odds of developing systolic hypertension among men followed between 1984 and 2003 was the greatest after 5 years or more of ART (odds ratio, 1.7; 95% CI: 1.34 to 2.16). The effect is the greatest for protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI)–based regimens, but it may also be mediated through metabolic derangements.43–45 Hypertension and prehypertension are associated with increased risk of acute MI in the US Veterans Aging Cohort, which highlights the importance of treating this risk factor at the appropriate level in HIV-positive patients.46 Failure of blood pressure to normally decrease by >10% overnight is also more common in HIV-positive patients in HICs and is a risk factor of cardiovascular events.47
The prevalence and severity of hypertension among HIV-positive patients in LMICs is only recently gaining attention. Studies from Kenya and Uganda describe hypertension prevalence rates between 11% and 28% among HIV-positive patients, and men are disproportionately affected.17,18 CD4 count is positively correlated with hypertension, especially among younger individuals.17 Some studies suggest HIV-positive patients have a higher prevalence of hypertension than those who are HIV-negative,19 whereas others report lower blood pressure in HIV-positive patients or no difference in blood pressure between HIV-positive and HIV-negative patients (Table 1).14,20–22 Importantly, many of these studies were not designed to compare blood pressure among patients, were focused on specific subgroups, included patients with and without AIDS and often specifically excluded patients with hypertension or other cardiac diseases. Kalyesubula et al48 also describe the evidence-linking HIV status, hypertension, and chronic kidney disease in SSA. Clearly, there is a great need for prospective data to establish the relationship between hypertension, HIV infection, and ART in LMICs.
CAD and Myocardial Infarction
In HICs, the linkage between HIV infection and CAD has been established by observational data, prospective and retrospective registries, and pathology studies.1,2,49,50 In addition, surrogate end points related to atherosclerosis (eg, endothelial dysfunction, carotid intima–media thickness, and flow-mediated dilatation) are also more common among HIV-positive patients compared with HIV-negative patients.51,52 The overall increase in risk for CAD/MI in HIV-positive persons is approximately 1- to 2-fold and is attenuated slightly by adjusting for tobacco use.2,49,52 Data suggest the use of protease inhibitors and recent/current abacavir use may increase MI risk by approximately 2-fold53; however, the risk with abacavir has not been noted in other cohorts.54 The role of HIV infection as a factor in CAD was identified in observations of accelerated atherosclerosis in HIV-positive patients before the use of ART.55
In general, CAD seems to be relatively uncommon among HIV-positive patients in LMICs, but this low frequency is possibly related to diagnostic limitations. A 2012 meta-analysis of 11 studies of acute coronary syndromes in HIV-positive patients included one study from an LMIC representing only 60 of the 2442 patients reported.56 HIV-positive patients in this group were all ART-naive, were younger than HIV-negative controls (43 vs. 54 years), had higher rates of smoking (73% vs. 33%), and lacked other traditional cardiovascular risk factors.23 HIV-positive patients more commonly presented with large thrombus burden rather than having substantial atherosclerotic plaques, suggesting a unique pathophysiology that is incompletely understood but may be related to thrombophilia.23,24 Some antiretroviral drugs (PIs and NNRTIs) are known to adversely affect atherogenic lipid profiles and may thereby enhance the likelihood of developing CAD.57 Future studies of HIV-positive patients at risk for CAD/MI should include investigation of a potentially unique CAD pathophysiology and the role of surrogate markers for CAD,25 in addition to describing the roles of age, ART use, and other potentially relevant HIV characteristics.
Stroke is a leading cause of death and disability worldwide and is now common in LMICs.58,59 Compelling evidence-linking HIV infection with stroke in the ART era comes from a large European-based retrospective study showing that HIV-positive patients had an increased risk of stroke relative to the comparison cohorts (adjusted incidence rate ratio, 1.60; 95% CI: 1.32 to 1.94).60 Ischemic stroke is the predominant type in HICs, and the age at presentation varies from 35 to 48 years, a substantially younger group than the HIV-negative stroke population.60,61
Proposed mechanisms for HIV-related stroke include HIV-associated vasculopathy, thrombophilia, cardioembolism, and opportunistic infection.62 Suppression of HIV by ART may be incomplete, and ART does not eradicate the virus. As a result, ART may delay rather than extinguish HIV-associated factors, such as ongoing inflammation and the proinflammatory state.63,64 As with CAD/MI, some types of ART may increase rates of dyslipidemia and accelerate atherosclerosis.57
There are no data from LMICs prospectively assessing the role of HIV infection on stroke risk in the ART era. A single retrospective case-control study in South Africa showed a trend towards an increased risk of stroke in HIV-positive patients; however, another in the same location showed no association (Table 1).26,27 Other studies have attempted to identify a link based on observations such as increased hospital admissions for young immunosuppressed HIV-positive patients with ischemic stroke and without other obvious causes.28,29 Better data are essential in understanding the problem and its scope.
The phenotype of HIV-positive patients with stroke in LMICs seems to differ from those in HICs; in LMICs, this population is younger and there is no difference in prevalence by gender, and the comorbidity occurs most often among heterosexuals not receiving ART.62 The difference is likely a consequence of the differing epidemiology of HIV infection in LMICs compared with HICs. The additional burden and interplay with HIV, hypertension, other vascular risk factors, and stroke risk in LMICs are yet to be fully explored.
Obstructive Lung Disease
Noninfectious pulmonary complications such as OLD have been reported in HIV-positive populations starting in the pre-ART era.65 The types of OLD that may occur with HIV include fixed airway obstruction, emphysema, diffusing capacity for carbon monoxide (DLco) impairment, chronic bronchitis, bronchial hyperresponsiveness, and asthma.66–69 OLD is of particular interest in the current era because it is likely to increase as the HIV-positive population ages.
Available data from HICs indicate that OLD occurs more frequently in HIV-positive persons and that obstruction is worse and progresses more rapidly among persons with higher HIV viral levels. HIV infection is an independent predictor of DLco impairment.69–73 Although smoking is strongly associated with OLD, it is not the only cause of OLD in HIV-positive patients, and lung function abnormalities may be present even in individuals who have never smoked.68 The impact of ART on OLD is uncertain and may depend on underlying patient characteristics.68,69,74 Asthma has also been reported to be highly prevalent in HIV-positive patients and may have different risk factors than in the HIV-negative population.67,75
HIV-positive patients in LMICs may have additional risk factors for OLD. Where mining is common, the associated exposures to dust (eg, silica) may contribute to significant pulmonary morbidity.76 Household air pollution (HAP) from burning solid fuels is another important risk factor of OLD, disproportionately affecting women and children.77,78 For example, the Burden of Obstructive Lung Disease study demonstrated that the highest prevalence of OLD worldwide was in South Africa (men, 22% and women, 17%)—a country that has a high HIV prevalence and uses a significant amount of biomass fuels.79 Other factors such as infectious lung diseases (eg, tuberculosis) may also contribute to greater risk of OLD.30 Improved understanding of OLD in HIV-positive LMIC populations requires better data on relationships between HIV infection, tuberculosis, tobacco smoking, environmental exposures, and overall pulmonary heath.31,80,81
Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH) is one of the most severe complications of HIV infection, carrying high mortality.82 Its prevalence in developed countries is low (<1%).75,83,84 HIV-associated PAH has a slight female predominance and an average age at presentation of 33 years.85 Knowledge derived from studies in HICs suggests that PAH is more common in HIV-positive persons compared with HIV-negative; the prevalence of HIV-associated PAH has not changed substantially after the introduction of ART; the severity of PAH does not correlate consistently with the degree of immunosuppression, and the impact of ART on the severity of PAH is uncertain.3,14,70,82,84,86,87 Illicit drug use may potentiate the impact of HIV on pulmonary endothelial dysfunction and is associated with increased prevalence of PAH.87,88
Although data are limited, the prevalence of HIV-associated PAH may be higher in LMICs than in HICs. Two studies in the pre-ART era showed a prevalence of 5%–6% in SSA among hospitalized patients.5,6 In the ART era, estimates range from 8% to 13% in HIV-positive populations.11,14 The second most common form of PAH in South African women and men is PAH related to concurrent HIV infection (Table 1).32 Studies of the prevalence and severity of HIV-associated PAH from LMICs suffer from limitations of diagnostic tools, leading to inaccurate estimates of the frequency and magnitude of the problem.89,90 The considerable disparity in prevalence of illicit drug use in LMICs vs. many HICs would seem to favor lower HIV-associated PAH rates in LMICs, the opposite of what seems to be the case. Thus, there is clearly a need to describe more completely the risk factors for HIV-associated PAH from HIV cohorts around the world.
Factors Affecting Expression of Noncommunicable Diseases in LMICs
Environmental exposures in LMICs, such as tobacco smoking and HAP, are associated with increased risk for cardiopulmonary diseases,91 and it is possible that HAP might trigger pulmonary inflammation and/or other mechanisms increasing susceptibility of HIV-positive patients to pulmonary diseases.92 For some diseases, such as CAD, the increasing trend seen in HICs is yet to be realized in LMICs. The difference in expression may result from low baseline incidence of CAD or dyslipidemia, differences in ART regimens, degree of HIV disease control, poor access to diagnostic tools or low awareness among clinicians, differences in rates of illicit drug use, comorbidities, genetic variation, tobacco use, and other cardiopulmonary risk factors, including lower average age.93
KEY POPULATIONS AT HIGHER RISK
Children may be particularly susceptible to chronic noncommunicable diseases (NCDs), and vulnerability to NCDs may start in utero according to the “Developmental Origins of Health and Disease” hypothesis.94,95 Birth cohorts, although potentially logistically challenging in low-resource settings, offer an opportunity to characterize the relationships between in utero exposures (such as maternal ART use), maternal health, and HIV.96 Concerted efforts to bring together birth cohorts in LMICs are ongoing.97
Sickle cell disease is not uncommon in LMICs and occurs in HIV endemic regions.98 Stroke and PAH are especially prevalent in children and young adults with this disease.99,100 Although HIV may pose an additional burden to this vulnerable population, its interplay with sickle cell disease and NCDs is unknown.
Use of substances that increase risk for NCDs is greater among HIV-positive patients. Alcohol use accentuates the risk for hypertension, stroke, heart failure, and OLD,101–105 whereas tobacco smoking predisposes to a number of cardiopulmonary conditions (eg, OLD and CAD).106 Methamphetamine use is associated with PAH.107 Although its use is generally low in LMICS, in countries where methamphetamine use is more prevalent, it is associated with HIV risk behaviors,108 and these patients may be at higher risk of developing PAH. Attention is needed to understand the burden of substance use among HIV-positive patients in LMICs and its effects on cardiopulmonary morbidity.
RESEARCH PRIORITIES AND CHALLENGES
Strategies to improve understanding of the relationship between HIV and noncommunicable cardiovascular and pulmonary disorders are essential to maximize the impact of interventions and optimize resource allocation. Epidemiological, clinical, and mechanistic studies using standard methods of disease definition, patient selection, and outcomes are needed (Table 2). Specific research priorities and examples of potential existing resources, research designs, and major challenges to implementation are discussed below and in Table 2.
- Careful analysis of existing and novel epidemiologic data: The expected outcomes of these analyses are to identify those areas in which the presence of HIV infection clearly plays a role in the pathogenesis, expression, or severity of disease and to identify diseases in which HIV-positive persons are a significant proportion of the overall affected population. These efforts will also allow focus on diseases of relatively high prevalence so that successful interventions will impact a substantial population. One example of a research approach is leveraging the National Heart Lung and Blood Institute/United Health Group Global Centers of Excellence (COE) network in LMICs to pool existing data and compare the prevalence of hypertension in comparable HIV-positive and HIV-negative cohorts.
- Incorporate HIV and NCD data capture into existing population surveillance: The goal of these studies is to collect population-based estimates of the diseases' comorbidity burden. Health and Demographic Surveillance Systems offer an opportunity, for example, to identify the longitudinal association between the very long-term complications of ART and stroke risk.109 Health and Demographic Surveillance Systems or birth cohorts also offer an opportunity to understand the comorbidity impact over the lifespan and plan meaningful interventions.
- Collaborations to elucidate pathways by which HIV and ART impact NCDs: Identification of disorders with high morbidity or mortality, or for which a plausible mechanism is postulated, should be a priority. Mechanistic studies will provide guidance for selection of disease targets for which HIV-linked interventions (eg, initiation of ART) can be expected to have favorable impact (Fig. 1). When possible, use of animal models or pilot studies in small numbers of patients should be pursued initially. HIV-associated PAH, owing to its great morbidity and lack of therapies, is one disorder for which identification of molecular targets for therapy could reap substantial benefits. The advances in the molecular causes of other cardiovascular diseases that have emanated from institutions in South Africa, for example, could theoretically be extended into the realm of HIV-associated PAH.110
- Health outcomes research: Outcomes research offers an opportunity to optimize management of HIV/NCD comorbidities and inform appropriate allocation of resources. There are examples of ongoing monitoring and evaluation efforts in HIV treatment programs (eg, www.iedea.org) that could be expanded to other disease states or linked with data from health information systems in LMICs. A variety of research designs are potentially feasible where the informatics capabilities exist. For example, establishing an accurate and timely diagnosis of heart failure is challenging owing to limitations in access to echocardiography. The extent to which different screening strategies (eg, questionnaire- vs. laboratory- vs. imaging-based) in the general population are effective at reducing morbidity or mortality from HIV-associated heart failure is an unanswered question. Applying these strategies to the specifics of the region for which the intervention is intended will optimize the allocation of resources.
- Close examination of the effect of ART on the condition: The effect of ART on different NCDs may be independent of the type of antiretroviral agent used or class-specific. Within the AIDS Clinical Trial Group, for example, measures of forced expiratory volume in 1 second or other spirometric data could be collected to understand and predict how OLD responds to ART exposure in LMICs. Clinical trial networks that are primarily investigating ART regimens could include electrocardiograms, carotid intima–media thickness, wall motion abnormalities on echocardiogram, or other surrogate measures of atherosclerosis as end points. It is also essential to consider drug–drug interactions because patients become increasingly exposed to HIV and NCD therapies simultaneously. It should be ensured that the intervention proposed has a favorable effect without a concomitant potential negative effect when determining the way forward.
Even if the data gaps identified were to be addressed, the problems of a limited number of health care providers and inadequate access to health care facilities would remain. Solutions to these problems might require a restructuring of health systems and an investment in capacity building, both being great challenges to LMICs.111 Several models that address the needs of LMICs have already been developed and are being tested for effectiveness [eg, “The PIH Guide to Chronic Care Integrations for Endemic Non-Communicable Diseases” (http://www.pih.org) and “Primary Care 101” (http://www.knowledgetranslation.co.za)]. These efforts require training and supporting a cadre of health care providers with the tools and knowledge to work in those environments.
The new generation of NCD researchers is multidisciplinary, eager to work in global health, and uses social media platforms to discuss and seek opportunities for collaboration (eg, http://ncdaction.org/). It is necessary to create opportunities for cross learning among disciplines, from fundamental discovery to clinical research and care, that bring together the expertise in HIV/AIDS and different NCDs. Platforms on HIV/AIDS, like the HIV/AIDS Clinical Trials Networks from the National Institute of Allergy and Infectious Diseases (http://www.niaid.nih.gov/about/organization/daids/networks/pages/daidsnetworks.aspx), and on chronic diseases, like the National Heart, Lung and Blood Institute/United Health Group Global Centers of Excellence,112 and the global research networks developed by the Global Alliance for Chronic Diseases (http://www.gacd.org/projects), are excellent infrastructures to train researchers and integrate research programs.
The landscape of cardiovascular and pulmonary diseases in HIV-positive patients in LMICs is dynamic. Factors that may impact the changing landscape include increasing access to ART, increasing life expectancy, more exposure to HIV viremia and ongoing inflammation, lifestyle pattern changes, and increasing awareness among practitioners and patients. A shift in the epidemiology of cardiovascular and pulmonary diseases has been seen in HICs, and data are slowly emerging from LMICs as well.
Although the types of research and training needed are myriad and may differ in specifics, similarities exist (Fig. 1). Carefully collected epidemiologic data comparing HIV-positive to HIV-negative patients in LMICs are critical to improved understanding. The answers to many important clinical questions will lead to improved outcomes for HIV-positive patients. Where infrastructure and capabilities exist, researchers in LMICs may discover important mechanistic pathways and therapeutic targets. Only with thoughtful and meticulous collaborations will there be appreciation of the true burden of cardiovascular and pulmonary comorbidities in HIV-positive persons living in LMICs and the development of sound strategies to optimally manage and prevent these chronic conditions as a way to improve the world's health.
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