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Global Burden of Atherosclerotic
Cardiovascular Disease in People Living With HIV - Time to Recognize HIV Infection as a Major Cardiovascular Risk Factor
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"risk of cardiovascular disease was 2-fold higher in people living with HIV.....global burden of HIV-associated cardiovascular disease has tripled over the past 2 decades and is now responsible for 2.6 million DALYs per annum [disability-adjusted life-years]......demands our attention because of its global scope and sobering conclusions: a doubling of cardiovascular risk in people living with HIV, coupled with a tripling of the global burden of CVD in HIV. What are the implications of these findings?"....."the impact of HIV on CVD can only worsen as the HIV population ages...... HIV infection should be recognized as a major cardiovascular risk factor, alongside diabetes mellitus, hypertension, hyperlipidemia, and smoking......In 2004, our group reported rapid carotid artery intima-media progression in HIV and concluded that this finding would presage a high rate of cardiovascular events.15 Fourteen years later, the study by Shah et al8 confirms this high rate of cardiovascular events on a global scale. The rate continues to increase even in the setting of treated and suppressed HIV disease. The key challenges for cardiologists and HIV clinicians continue to be unraveling the mechanisms underlying HIV-associated atherosclerosis, accurately predicting individuals at risk, and providing interventions to reduce this risk."
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EDITORIAL
Time to Recognize HIV Infection as a Major Cardiovascular Risk Factor
Global Burden of Atherosclerotic
Cardiovascular Disease in People Living With HIV
Sept. 11 2018
This analysis evaluates the association between HIV and cardiovascular disease, and estimates the global burden of HIV-associated cardiovascular disease. We report that the risk of cardiovascular disease was 2-fold higher in people living with HIV. Moreover, the global burden of HIV-associated cardiovascular disease has tripled over the past 2 decades and is now responsible for 2.6 million DALYs per annum [disability-adjusted life-years], with the majority in sub-Saharan Africa and the Asia Pacific regions. Our estimates have important policy implications for implementing appropriate cardiovascular risk stratification and treatment strategies across healthcare systems, especially in those countries with the greatest burden where resources remain limited.
"......findings confirm previous studies but on a broader scale (eg, the risk of incident CVD being 2-fold higher in HIV and similar to other high-risk groups such as patients with diabetes mellitus)."
"the study by Shah et al8 demands our attention because of its global scope and sobering conclusions: a doubling of cardiovascular risk in people living with HIV, coupled with a tripling of the global burden of CVD in HIV. What are the implications of these findings?"....."the impact of HIV on CVD can only worsen as the HIV population ages. Has the time come to recognize HIV infection as a major cardiovascular risk factor, alongside diabetes mellitus, hypertension, hyperlipidemia, and smoking?......"Has the time come to recognize HIV infection as a major cardiovascular risk factor, alongside diabetes mellitus, hypertension, hyperlipidemia, and smoking?" YES see Editorial below......"In 2004, our group reported rapid carotid artery intima-media progression in HIV and concluded that this finding would presage a high rate of cardiovascular events.15 Fourteen years later, the study by Shah et al8 confirms this high rate of cardiovascular events on a global scale. The rate continues to increase even in the setting of treated and suppressed HIV disease. The key challenges for cardiologists and HIV clinicians continue to be unraveling the mechanisms underlying HIV-associated atherosclerosis, accurately predicting individuals at risk, and providing interventions to reduce this risk. The time to consider HIV as a cardiovascular risk factor is now."
The global burden of cardiovascular disease attributable to HIV infection has tripled over the past 2 decades, especially in the low- and middle-income nations, and is likely to be a product of both temporal increases in the prevalence of HIV and the morbidity and mortality from cardiovascular disease. The prevalence of HIV varies by region with the greatest proportions seen in sub-Saharan Africa and the Asia Pacific region.
Cardiovascular disease now accounts for >10% of all morbidity and mortality in sub-Saharan Africa with rates that are comparable to high-income regions. Consequently, the sub-Saharan region accounted for half of all DALYs from cardiovascular disease attributable to HIV. The population-attributable fraction of HIV-associated cardiovascular disease in the UNAIDS high-priority countries was up to 25% and similar to traditional lifestyle, metabolic, and environmental risk factors.23,24
The combined burden of HIV and cardiovascular disease in the UNAIDS high-priority countries is of growing concern and has important implications with respect to regional health policies, guidelines, and resource allocation. Risk stratification and identification of patients at intermediate or high risk of future cardiovascular disease are already challenging in resource-limited nations.
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EDITORIAL
Time to Recognize HIV Infection as a Major Cardiovascular Risk Factor
Priscilla Y. Hsue, MD
David D. Waters, MD
According to statistics from the World Health Organization, ≈36.7 million people are currently living with HIV, and 1.8 million become infected every year. Antiretroviral therapy has largely transformed HIV infection into a chronic disease. As a consequence, it is estimated that by the year 2030, 73% of HIV-infected individuals will be ≥50 years of age, and 78% of individuals living with HIV will have cardiovascular disease (CVD).1 Individuals infected with HIV have a significantly increased risk for a variety of cardiovascular complications, including acute myocardial infarction,2 heart failure with both reduced and preserved ejection fraction,3 sudden cardiac death,4 peripheral arterial disease,5 and stroke.6 In the United States, CVD has become a key contributor to mortality among individuals living with HIV.7
The systematic review of longitudinal studies of CVD in HIV by Shah and colleagues8 in this issue of Circulationincludes 80 studies with 793 635 individuals living with HIV and a follow-up of 3.5 million person-years. A random-effects meta-analysis was performed to derive a pooled rate and risk of CVD among people living with HIV and to estimate the burden of CVD and HIV at the national, regional, and global levels. The authors report that the relative risk of CVD in persons living with HIV is 2.16 (95% CI, 1.68-2.77) as compared with uninfected individuals. Over the past 26 years, the global population attributable fraction from CVD in the setting of HIV increased from 0.36% (95% CI, 0.21-0.56) to 0.92% (95% CI, 0.55-1.41), and disability-adjusted life-years increased from 0.74 (95% CI, 0.44-1.16) to 2.57 (95% CI, 1.53-3.92) million. Most of these increases took place in sub-Saharan Africa and the Asia Pacific regions.
The authors deserve high praise for the vast scope of their study and the large volume of work involved. Some of their findings confirm previous studies but on a broader scale (eg, the risk of incident CVD being 2-fold higher in HIV and similar to other high-risk groups such as patients with diabetes mellitus).2 Most of the limitations of the study are inherent in this type of research and are unavoidable. First, myocardial infarction and stroke are defined differently across the aggregated studies, and the majority of cases were not clinically adjudicated but were categorized using coding. This lack of standardization of myocardial infarction definition may be particularly problematic in HIV, where approximately half are type 29 (ie, demand related, such as in the setting of sepsis or illicit drug use).
Second, in a meta-analysis such as this without patient-level data, the contributions of traditional risk factors (eg, high levels of smoking and the metabolic syndrome) and HIV-specific risk factors (eg, HIV medication, degree of HIV control, level of inflammation) cannot be adjusted for or even ascertained. In addition, the cardiovascular risk of patients infected with HIV is likely distinctly different before and after the introduction of antiretroviral therapy. Although the authors report that the impact of HIV and CVD was highest among individuals in sub-Saharan Africa, this finding is based on only a small number of studies from this region; most of the data come from the United States and Europe. All of these issues likely contributed to the substantial heterogeneity for pooled risk ratios, as noted by the authors.
However, despite these limitations, the study by Shah et al8 demands our attention because of its global scope and sobering conclusions: a doubling of cardiovascular risk in people living with HIV, coupled with a tripling of the global burden of CVD in HIV. What are the implications of these findings?
Among the general population, the relative impact of traditional risk factors has been shifting over the past 2 to 3 decades. Hypercholesterolemia can now be well controlled with drug therapy in most patients, and control of hypertension has improved, at least in wealthier countries. The incidence and prevalence of type 2 diabetes mellitus has increased dramatically across most of the globe because of a higher prevalence of overweight and obesity, but outcomes in well-treated patients with established diabetes mellitus has improved.10 The impact of smoking on cardiovascular risk has diminished because smoking rates have decreased in many countries and many at-risk groups, whereas in other places, little progress has been made.
Although HIV accounts for a relatively small proportion of CVD compared with these major risk factors, the relative risk of a cardiovascular event in a person living with HIV is in the range of traditional risk factors. The Figure compares the relative risk and population attributable risk of HIV from the study of Shah et al8 and odds ratios and traditional risk factors from the INTERHEART study.11 Because odds ratios can give inflated estimates of risk when the outcome is common,12 it is likely that the relative risks of traditional risk factors in INTERHEART are smaller and thus closer to that of HIV. Although the relative risk is unlikely to change much, the impact of HIV on CVD can only worsen as the HIV population ages. Has the time come to recognize HIV infection as a major cardiovascular risk factor, alongside diabetes mellitus, hypertension, hyperlipidemia, and smoking?
Figure. Cardiovascular risk of HIV compared to traditional risk factors.
Because ORs can give inflated estimates of risk when the outcome is common,12 it is likely that the RRs of traditional risk factors in the INTERHEART study are smaller and thus closer to that of HIV. aRisk of acute MI, adjusted for age, sex, and smoking. Adjustment for confounders was limited to those available in the primary studies. bRisk of ASCVD (CVD, stroke, or MI). cHigh ApoB/ApoA1 ratio. dOR (99% CI) for current smoking; PAR for any smoking. ePAR for 2015 using prevalence
data for HIV for the 15- to 49-year-old group. Apo indicates apolipoprotein; ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; HIV, human immunodeficiency virus; MI, myocardial infarction; OR, odds ratio; PAR, population attributable risk; and RR, risk ratio.
Such recognition might have salutary consequences. First, elevating HIV infection to the status of a major cardiovascular risk factor might stimulate research in this area.
Treatment of CVD among individuals living with HIV relies on clinical trial data from non-HIV populations, although HIV-associated atherosclerosis has distinct features (such as more noncalcified plaques) and mechanisms, including chronic inflammation/immune activation and the impact of antiretroviral therapy. Clinical trial data specific to HIV would be helpful; however, it is not feasible in an era of limited resources to do outcome-driven clinical trials for all types of interventions and patient populations. As such, smaller proof-of-concept mechanistic studies that target HIV-specific factors will be critical to move the field forward. Precision medicine approaches, including omics methodologies, studies of healthcare disparities, digital monitoring, and implementation science aimed at cardiovascular risk in HIV, will also be invaluable.
It is important to note that elevating HIV to the level of the other major risk factors could improve awareness, and thus the prevention, detection, and treatment of CVD among individuals living with HIV, along with better control of their traditional risk factors.
All of these things could theoretically reduce CVD and CVD mortality in HIV. Often neither the HIV specialist nor the cardiologist has the requisite knowledge to treat these individuals optimally, and awareness among all caregivers of the excess cardiovascular risk remains crucial. Traditional risk calculators underestimate cardiovascular risk in HIV,13 but recognition of HIV as a major risk factor would reduce the need for risk calculation. The European Society of Cardiology guidelines recommend lipid-lowering therapy to reduce low-density lipoprotein cholesterol to <70 mg/dL in individuals infected with HIV.14
In 2004, our group reported rapid carotid artery intima-media progression in HIV and concluded that this finding would presage a high rate of cardiovascular events.15 Fourteen years later, the study by Shah et al8 confirms this high rate of cardiovascular events on a global scale. The rate continues to increase even in the setting of treated and suppressed HIV disease. The key challenges for cardiologists and HIV clinicians continue to be unraveling the mechanisms underlying HIV-associated atherosclerosis, accurately predicting individuals at risk, and providing interventions to reduce this risk. The time to consider HIV as a cardiovascular risk factor is now.
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Global Burden of Atherosclerotic
Cardiovascular Disease in People Living
With HIV
Systematic Review and Meta-Analysis
Anoop S.V. Shah, MD,
MPH, PhD
Dominik Stelzle, MD
Kuan Ken Lee, MD
Eduard J. Beck, MD, PhD,
FFPH
Shirjel Alam, MD
Sarah Clifford, MD
Chris T. Longenecker, MD
Fiona Strachan, PhD
Shashwatee Bagchi, MD
William Whiteley, MD
Sanjay Rajagopalan, MD
Shyamasundaran Kottilil, MD
Harish Nair, PhD
David E. Newby, MD, PhD
David A. McAllister, MD
Nicholas L. Mills, MD, PhD
10 Sep 2018 Circulation. 2018
Abstract
Background:
With advances in antiretroviral therapy, most deaths in people with HIV are now attributable to noncommunicable illnesses, especially cardiovascular disease. We determine the association between HIV and cardiovascular disease, and estimate the national, regional, and global burden of cardiovascular disease attributable to HIV.
Methods:
We conducted a systematic review across 5 databases from inception to August 2016 for longitudinal studies of cardiovascular disease in HIV infection. A random-effects meta-analysis across 80 studies was used to derive the pooled rate and risk of cardiovascular disease in people living with HIV. We then estimated the temporal changes in the population-attributable fraction and disability-adjusted life-years (DALYs) from HIV-associated cardiovascular disease from 1990 to 2015 at a regional and global level. National cardiovascular DALYs associated with HIV for 2015 were derived for 154 of the 193 United Nations member states. The main outcome measure was the pooled estimate of the rate and risk of cardiovascular disease in people living with HIV and the national, regional, and global estimates of DALYs from cardiovascular disease associated with HIV.
Results:
In 793 635 people living with HIV and a total follow-up of 3.5 million person-years, the crude rate of cardiovascular disease was 61.8 (95% CI, 45.8-83.4) per 10 000 person-years. In comparison with individuals without HIV, the risk ratio for cardiovascular disease was 2.16 (95% CI, 1.68-2.77). Over the past 26 years, the global population-attributable fraction from cardiovascular disease attributable to HIV increased from 0.36% (95% CI, 0.21%-0.56%) to 0.92% (95% CI, 0.55%-1.41%), and DALYs increased from 0.74 (95% CI, 0.44-1.16) to 2.57 (95% CI, 1.53-3.92) million. There was marked regional variation with most DALYs lost in sub-Saharan Africa (0.87 million, 95% CI, 0.43-1.70) and the Asia Pacific (0.39 million, 95% CI, 0.23-0.62) regions. The highest population-attributable fraction and burden were observed in Swaziland, Botswana, and Lesotho.
Conclusions:
People living with HIV are twice as likely to develop cardiovascular disease. The global burden of HIV-associated cardiovascular disease has tripled over the past 2 decades and is now responsible for 2.6 million DALYs per annum with the greatest impact in sub-Saharan Africa and the Asia Pacific regions.
Clinical Perspective
What Is New?
• Recent studies have identified plausible biological mechanisms, including endothelial dysfunction and arterial inflammation, to explain the association between HIV infection and atherosclerotic disease.
• This article represents a systematic analysis to evaluate the association between HIV and cardiovascular disease and estimate the burden of HIV-associated cardiovascular disease at a national, regional, and global level.
• We report that the risk of cardiovascular disease is increased 2-fold in people living with HIV, and the global burden of HIV-associated cardiovascular disease has tripled over the past 2 decades with the majority of the burden experienced in sub-Saharan Africa and the Asia Pacific region.
What Are the Clinical Implications?
• The combined burden of HIV and cardiovascular disease, especially in high-prevalence regions, has important implications with respect to regional health policies, guidelines, and resource allocation.
• Risk stratification and identification of patients at risk of future cardiovascular disease are already challenging in these regions.
• Whether patients living with HIV should be considered high-risk and appropriate primary prevention pharmacotherapy such as statin therapy should be implemented remains unclear.
• Our estimates have important policy implications for implementing appropriate cardiovascular risk stratification and treatment strategies across healthcare systems, especially in low- and middle-income nations where both HIV and cardiovascular disease remain highly prevalent.
Introduction
Editorial, see p 1113
Currently, >35 million people are infected with HIV, with two-thirds being resident in sub-Saharan Africa. 1Although the global incidence for HIV has stabilized, the provision and widespread distribution of combined antiretroviral therapy2 has dramatically improved survival with the prevalence of HIV steadily increasing over the past 2 decades.3 This improvement in survival has been primarily attributed to a reduction in opportunistic infections, especially in the low- and middle-income nations.1,4 Indeed, most deaths now arise from noncommunicable illnesses, especially cardiovascular disease.5-7
Cardiovascular disease is the leading cause of morbidity and mortality worldwide.8,9 The past 2 decades have seen a substantial increase in the morbidity attributable to cardiovascular disease, with a significant proportion of the burden borne by low- and middle-income nations.10,11 The highest prevalence rates of HIV have been observed in sub-Saharan Africa. This region has also seen a steady increase in the burden of cardiovascular disease over the past 2 decades.2,12 Recent studies have shown a link between the development of cardiovascular disease and HIV infection with multiple potential mechanisms, including direct vascular inflammation,13,14 dyslipidemia,15 and insulin resistance.16,17
The aim of this systematic analysis was to review and to meta-analyze the rate of cardiovascular disease in people living with HIV, to determine the association between HIV infection and the risk of cardiovascular disease, and to estimate the national, regional, and global burden of HIV-associated cardiovascular disease.
Discussion
In this systematic review, meta-analysis, and burden assessment, we evaluated the association between HIV infection and cardiovascular disease, and estimated the national, regional, and global burden of cardiovascular disease attributable to HIV infection. We make a number of important and novel observations. First, the crude rate for incident cardiovascular disease was 60 per 10 000 person years and is comparable to other high-risk cardiovascular groups, such as diabetes mellitus.42 Second, the risk of incident cardiovascular disease was 2-fold higher in people living with HIV. Third, the number of DALYs attributable to HIV-associated cardiovascular disease has increased 3-fold over the past 2 decades, but has now plateaued. Finally, there were major regional variations in both the attributable fraction and the rates of cardiovascular disease attributable to HIV, with much of the burden seen in sub-Saharan Africa, followed by Asia and the Pacific.
Many factors may have affected the estimates that we have derived and are based on several assumptions that merit discussion. First, the pooled risk ratios used to calculate the population-attributable fraction and the subsequent cardiovascular burden were primarily obtained from developed nations but were applied to all regions. This approach is ubiquitous in these types of analyses43,44 and highlights the paucity of data from these regions. In a recent analysis evaluating the global burden of cardiovascular disease attributable to hypertension and obesity, <10% of cohorts originated from low- and middle-income nations.44,45 Second, the incidence rate does not consider competing risk from noncardiovascular mortality. This would further underestimate the rate of cardiovascular disease in people living with HIV, especially in earlier studies when antiretroviral therapy was not widely available. Third, although many of the individual studies evaluating the risk ratio of cardiovascular disease adjusted for important traditional risk factors, there remains the risk of residual confounding. Previous studies have already shown higher frequencies of both modifiable and nonmodifiable cardiovascular risk factors in people living with HIV.17 As such, a higher prevalence of factors that do not lie on the causal pathway may have influenced the overall association between HIV and cardiovascular events. Fourth, the pooled relative risk estimates used to calculate the population-attributable fraction for DALY for ischemic heart and cerebrovascular disease was obtained solely from studies including acute myocardial infarction or stroke and so did not specifically include estimates for angina pectoris or other chronic manifestations of atherosclerotic disease. However, relative to the overall cardiovascular DALY attributable to ischemic heart disease, the burden from angina is minimal.10 Therefore, the impact of this limitation on the overall burden estimate is likely to be small. Fifth, the majority of studies evaluating the risk of cardiovascular disease in people living with HIV have recruited participants before 2010, with a large number conducted in the previous century. The epidemiology of HIV diagnosis and care has changed significantly over the past 2 decades, with better provision of antiretroviral therapy and improved survival, resulting in an increased prevalence of HIV.46 Sixth, when calculating the burden at a global and regional level, we have made the assumption that the prevalence of HIV infection in the younger age group (15-49 years old) is consistent across the entire age range. There is a paucity of data in the prevalence of HIV in the older population, especially in high-prevalence regions such as sub-Saharan Africa.47 However, analysis of the populations in these regions shows that the prevalence in the older population remains similar to that of the 15- to 49-year group.47 Finally, we noticed substantial heterogeneity for our overall pooled risk ratios. The source for this degree of heterogeneity is likely to be multifactorial and reflect differences in population demographics, sample size and small-study effect, patient characteristics, selection or publication bias, and case ascertainment bias because the majority of data were based on national statistics.
Many studies have evaluated the association between HIV infection and the risk of atherosclerotic disease including the potential role of antiretroviral therapy.17,48-50 This is the first study to review and meta-analyze systematically the association between HIV infection and cardiovascular disease, and to estimate the burden of cardiovascular disease attributable to HIV. The mechanisms underlying this association remain poorly understood.17 Possible mechanisms include endothelial dysfunction51 and increased systemic13 and coronary arterial inflammation14 associated with elevated inflammatory markers.13 Furthermore, patients with HIV have more traditional metabolic risk factors for cardiovascular disease17 including dyslipidemia,15 insulin resistance and abnormal glucose homeostasis,16 and abnormalities in body fat composition.52-54 The increased risk of cardiovascular disease in people living with HIV is thus a consequence of both accelerated atherosclerosis attributable to chronic infection and the increased prevalence of traditional risk factors.
The global burden of cardiovascular disease attributable to HIV infection has tripled over the past 2 decades, especially in the low- and middle-income nations, and is likely to be a product of both temporal increases in the prevalence of HIV and the morbidity and mortality from cardiovascular disease. The prevalence of HIV varies by region with the greatest proportions seen in sub-Saharan Africa and the Asia Pacific region.
Cardiovascular disease now accounts for >10% of all morbidity and mortality in sub-Saharan Africa with rates that are comparable to high-income regions. Consequently, the sub-Saharan region accounted for half of all DALYs from cardiovascular disease attributable to HIV. The population-attributable fraction of HIV-associated cardiovascular disease in the UNAIDS high-priority countries was up to 25% and similar to traditional lifestyle, metabolic, and environmental risk factors.23,24
The combined burden of HIV and cardiovascular disease in the UNAIDS high-priority countries is of growing concern and has important implications with respect to regional health policies, guidelines, and resource allocation. Risk stratification and identification of patients at intermediate or high risk of future cardiovascular disease are already challenging in resource-limited nations.55 Furthermore, traditional risk scores perform poorly because they consistently underestimate risk in HIV-infected populations.35,56,57 Whether patients living with HIV should be considered high risk and started on primary prevention, such as statin therapy, remains unclear. A recent randomized controlled trial of rosuvastatin in patients with HIV demonstrated a reduction in carotid artery intima-media thickness despite these individuals having low low-density lipoprotein cholesterol concentrations at baseline.58 Although the latest international guidelines have expanded the use of lipid-lowering therapy in the general population, over two-thirds of people living with HIV with evidence of high-risk morphology coronary atherosclerotic plaque would not have been recommended for statin therapy.59 The REPRIEVE study (Randomised Trial to Prevent Vascular Events in HIV) is now underway to evaluate the efficacy of statin therapy in people living with HIV who are deemed low-risk based on traditional risk scores.60,61
Conclusions
This analysis evaluates the association between HIV and cardiovascular disease, and estimates the global burden of HIV-associated cardiovascular disease. We report that the risk of cardiovascular disease was 2-fold higher in people living with HIV. Moreover, the global burden of HIV-associated cardiovascular disease has tripled over the past 2 decades and is now responsible for 2.6 million DALYs per annum, with the majority in sub-Saharan Africa and the Asia Pacific regions. Our estimates have important policy implications for implementing appropriate cardiovascular risk stratification and treatment strategies across healthcare systems, especially in those countries with the greatest burden where resources remain limited.
Results
A total of 80 studies were identified to estimate the rate and risk ratio of cardiovascular disease in people living with HIV. One hundred twenty-two estimates from 73 studies were used to calculate the pooled crude incident rates of fatal and nonfatal cardiovascular disease in people living with HIV ( Table IV in the online-only Data Supplement; Figure 1). This comprised 793 635 people with HIV and a total follow-up of 3.5 million person-years. The crude incidence rate for cardiovascular disease per 10 000 person-years was 61.8 (95% CI, 45.8-83.4). When stratified by incident myocardial infarction and stroke, the rate was 25.9 (95% CI, 20.3-33.0) and 17.9 (95% CI, 13.2-24.3), respectively ( Figure IIA through IIC in the online-only Data Supplement). The cardiovascular mortality rate was 14.1 per 10 000 person-years (95% CI, 10.3-19.4) ( Figure IID through IIF in the online-only Data Supplement). Of the 122 estimates, only 12 (9.8%) estimates (across 11 studies) provided information on crude rates in the non-HIV population ( Table V in the online-only Data Supplement).
A further 17 estimates from 16 studies were identified to estimate the pooled risk ratio of incident cardiovascular disease in individuals with HIV infection (Table, Figure 2B). Studies originated mainly from Europe, North America, and the Asia Pacific region with few studies from low- and middle-income nations (Table) and primarily involving black and white participants ( Table VI in the online-only Data Supplement). The majority of studies used physician diagnosis or the International Classification of Diseases coding system to define cardiovascular disease. The pooled risk ratio was 2.16 (95% CI, 1.68-2.77) (Figure 2B). The risk ratio when stratified by type of event was 2.36 (95% CI, 1.50-3.70) for any cardiovascular disease (including myocardial infarction and stroke), 1.79 (95% CI, 1.54-2.08) for myocardial infarction, and 2.56 (95% CI, 1.43-4.61) for stroke. Risk ratios for older studies, those with moderate/high risk of bias, and those with longer follow-up were larger ( Table VII in the online-only Data Supplement). Selection bias attributable to potential unpublished studies or to small-study effects was noticed for the overall risk ratio. Imputing for asymmetry using the trim-and-fill method did not alter the effect direction, but, as expected, did attenuate the effect size ( Table VII in the online-only Data Supplement and Figure III in the online-only Data Supplement). We observed substantial heterogeneity for the overall estimate (Figure 2).
Trends in the Global and Regional Burden of Disease
Globally, the population-attributable fraction for cardiovascular disease associated with HIV infection increased from 0.36% (95% CI, 0.21%-0.56%) in 1990 to 0.92% (95% CI, 0.55%-1.41%) in 2015. This was associated with a >3-fold increase in DALYs from HIV-associated cardiovascular disease from 0.74 million (95% CI, 0.44-1.16) in 1990 to 2.57 million (95% CI, 1.53-3.92) in 2015 (Figure 3A). Similar temporal increases were seen when stratified by sex (Figure 3B, Table VIII in the online-only Data Supplement).
There was marked regional variation in the temporal change in the DALYs because of cardiovascular disease attributable to HIV (Figure 3C). In 2015, East and Southern Africa, Asia and the Pacific, and West and Central Africa accounted for over two-thirds of all DALYs (Figure 3C). The largest annual increase across the 26-year period was observed in East and Southern Africa (15 870 DALYs per year [95% CI, 7600-32 660]) with the lowest increases observed in the Middle East and North Africa (530 DALYs per year [95% CI, 280-950]) and Western and Central Europe and North America (700 DALYs per year [95% CI, 410-1070]) ( Table IX in the online-only Data Supplement).
National Estimates
National estimates of prevalence and cardiovascular burden were available for 154 countries. The highest population-attributable fraction was observed in countries within sub-Saharan Africa, with HIV accounting for >15% of the cardiovascular burden in Swaziland, Botswana, Lesotho, and South Africa (Figure 4A, Table X in the online-only Data Supplement). Similarly, the largest burden was observed in sub-Saharan Africa (Figure 4B). In the UNAIDS Global Plan priority countries, the population-attributable fraction was comparable to other traditional cardiovascular risk factors ( Table XI in the online-only Data Supplement).
Data for the burden of cardiovascular DALYs attributable to HIV were available for 20 of the 21 priority countries from sub-Saharan Africa in the UNAIDS Global Plan.22 HIV-associated cardiovascular DALYs across these countries increased from 0.21 million (95% CI, 0.11-0.38) in 1990 to 0.74 million (95% CI, 0.39-1.37) in 2015 ( Figure IV in the online-only Data Supplement).
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