With the success of antiretroviral therapy (ART), people living with HIV/AIDS (PLWHA) are living longer, and more chronic diseases are being diagnosed in this population. Previous studies showed that PLWHA were associated with a higher incidence of some subtypes of cardiovascular diseases, including coronary artery disease and heart failure.1,2 However, studies determining the association between HIV infection and the risk of sudden cardiac death (SCD) are limited.3 A previous retrospective cohort study from a single center found that the incidence of SCD in PLWHA occurred at a rate more than 4 times expected in the general population.4
The underlying etiologies of SCD may differ between the older and young populations.5 In older populations, SCD was mostly caused by structural heart diseases, including coronary heart disease, heart failure, and cardiomyopathy.5 However, in young adults, 10% of SCDs were induced by nonstructural heart diseases, such as drug-induced long QT syndrome.6,7 Since polypharmacy is common in PLWHA,8 it is imperative to determine the incidence and associated risk factors of SCD in this population.
ART is imperative for improving outcomes in PLWHA. However, ART may cause metabolic abnormalities9 and increase the risk of cardiovascular diseases.10,11 Although ART plays an important role in improving outcomes in PLWHA, little is known regarding the association of ART with the subsequent risk of SCD.
Prevention of SCD should include the identification of specific risk factors. Therefore, this nationwide population-based cohort study aimed to evaluate the risk of SCD in Taiwanese individuals with and without HIV between 2003 and 2014.
This cohort study used data from the Taiwan Centers for Disease Control (CDC) HIV surveillance database from 2003 through 2014. In Taiwan, medical professionals are required to report new HIV cases to the Taiwan CDC within 24 hours of diagnosis. The reported HIV-infected cases in Taiwan were defined as those testing positive on HIV-1 Western blot or polymerase chain reaction analysis. All HIV-infected individuals in Taiwan have been offered ART free of charge since 1997.12 This study was approved by the institutional review board of Taipei City Hospital (TCHIRB-10410122-E).
This cohort study linked the Taiwan CDC HIV surveillance database to the Taiwan National Health Insurance Research Database. Adult PLWHA (aged 15 years and older) between 2003 and 2014 were selected from the Taiwan CDC HIV surveillance database.
The control group was selected from the Taiwan National Health Insurance Research Database. In Taiwan, more than 99% of Taiwanese citizens have been covered by the National Health Insurance Program since 1995.13 The control group in this study was matched by age, sex, and date of enrollment (±7 days). Four controls were randomly selected for each HIV patient.14,15 Control subjects were excluded if they had been reported to the Taiwan CDC as HIV-infected cases. The HIV patients and control groups were both followed up until SCD, mortality for another cause, or till December 31, 2014, whichever occurred first.
After previous studies,16,17 the outcome of SCD was defined as the presence of an appropriate International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code (427.5, 798.1, or 798.2). The occurrence of SCD was confirmed by the death certificate database of Taiwan.18 As per the legal regulations in Taiwan, every death certificate must be registered by the physician in charge according to ICD-9-CM codes within 30 days of a patient's death. Since trained medical registrars review all death certificates at the central office of the National Death Certification Registry, cause of death coding in Taiwan is considered highly accurate.18
The controlling variables included sociodemographics, comorbidities, ART, AIDS status, and opportunistic infections (OIs) after the diagnosis of HIV. The sociodemographics included income levels and urbanization. Low income was defined as monthly incomes lower than 19,200 New Taiwan Dollars.19 Urbanization was categorized based on areas of residence, being either urban or rural. The comorbidities in the study subjects included dyslipidemia (ICD-9 code 272), diabetes (ICD-9 code 250), and hypertension (ICD-9 code 401-405). The OIs after the diagnosis of HIV included Mycobacterium tuberculosis infection (ICD-9 code 011-018), candidiasis (ICD-9 code 112), and herpes zoster (ICD-9 code 053). A person was considered to have a comorbidity or OI only if the condition occurred in an inpatient setting or 3 or more outpatient visits.20
HIV patients were considered to be receiving ART if they received ART before the occurrence of SCD. In an individual with HIV infection, AIDS status was defined as the presence of a CD4 lymphocyte count <200 cells/mm3 or any of the AIDS-defining conditions.21 In Taiwan, when previously reported HIV cases develop an event defining AIDS status, medical professionals are required to notify the national CDC within 24 hours of the diagnosis.
The demographic data of the study subjects were initially analyzed. Categorical data were analyzed by the Pearson χ2 test, where appropriate. Continuous data are presented as mean values and SDs; the two-sample t test was used for comparisons between groups.
The incidence of SCD per 100,000 person-years was calculated in patients with and without HIV infection, respectively. The relative hazards (RHs) of SCD incidence in PLWHA compared with patients without HIV infection were estimated from Cox proportional hazards models.
To determine the association between HIV infection and incident SCD, a Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for age, sex, and comorbidities. To evaluate the association between ART and incident SCD, a time-dependent Cox proportional hazards model was used to identify risk factors for incident SCD among PLWHA. In these models, ART and AIDS status were regarded as time-dependent covariables,22 whereas other confounders such as age, sex, and comorbidities, which were collected at baseline, were considered as fixed covariates. AHRs with 95% CIs are reported to indicate the strength and direction of associations.
To examine the robustness of the main findings, subgroup and sensitivity analyses were conducted after stratifying study subjects by age, sex, and comorbidities. All data management and analyses were performed using the SAS 9.4 software package (SAS Institute, Cary, NC).
A total of 25,061 HIV-infected individuals were reported to the Taiwan CDC between January 1, 2003, and December 31, 2014. After excluding those younger than 15 years (n = 33) and those with incomplete data (n = 722), the remaining 24,306 PLWHA were included in the analysis (see Fig. S1, Supplemental Digital Content, http://links.lww.com/QAI/B372). Another 97,224 subjects without HIV infection, matched for age and sex, were randomly selected for the control group. The overall mean (SD) age was 32.7 (10.0) years; 93.81% of the PLWHA subjects were men. Mean (SD) follow-up durations were 5.84 (3.37) and 5.86 (3.37) years in the PLWHA and control groups, respectively. During the study follow-up period, 5342 subjects died, of whom 150 (2.81%) died of SCD.
Incidence Rate of SCD
During the study follow-up period, 150 individuals had SCD, including 97 (0.40%) PLWHA and 53 (0.05%) controls (Table 1). The incidence rate of SCD per 100,000 person-years was 68.31 and 9.31 in the PLWHA and control groups, respectively (P < 0.001). The RHs of incident SCD between the PLWHA and control groups was 9.73 (95% CI: 6.73 to 14.1). Time to the occurrence of SCD was significantly shorter in PLWHA than in those without HIV infection (P < 0.001, log-rank test; Fig. 1).
Association of HIV Infection With Incident SCD
A Cox proportional hazards model was used to identify independent risk factors for SCD (Table 1). After adjusting for age, sex, and comorbidities, HIV infection significantly increased the risk of SCD (AHR 8.15; 95% CI: 5.58 to 11.90) (Table 2). Other risk factors associated with SCD included low income and urban areas of residence.
Subgroup and Sensitivity Analysis for the Association Between HIV Infection and SCD
Figure 2 shows the results of subgroup analysis of the association between HIV and SCD, after adjustment for patient demographics and comorbidities. HIV infection was significantly associated with a higher risk of SCD in all patient subgroups.
Association of ART With Incident SCD Within PLWHA
The incidence rates of SCD in PLWHA taking and not taking ART were 29.28 and 169.36 per 100,000 person-years, respectively (Table 3). After adjusting for age, sex, comorbidities, and OIs after HIV diagnosis, a time-dependent Cox proportional hazards model showed that the RHs of SCD between PLWHA receiving ART and those not receiving ART were 0.53 (95% CI: 0.32 to 0.87).
After adjusting for demographic data and comorbidities, this nationwide cohort study found that compared with controls, PLWHA were at a significantly higher risk of SCD. Moreover, ART was associated with a lower risk of SCD in PLWHA.
Our study revealed robust associations between HIV infection and incident SCD after stratifying patients according to age, sex, and comorbidities. HIV infection significantly increased the risk of SCD in all patient subgroups.
This study found that PLWHA had a higher risk of SCD than HIV-uninfected individuals. Although previous studies have shown that HIV infection could increase the risk of cardiovascular diseases (eg, coronary artery disease and heart failure),1,2,23 the association between HIV infection and SCD has not been extensively studied. A single-center retrospective study of 2860 consecutive HIV-infected patients showed that the rate of SCD was 2.6 per 1000 person-years, which was 4.5-fold higher than that of the general population.4 This study followed up 24,306 HIV-infected patients and found that the risk of SCD in PLWHA was 8.15-fold higher than that of HIV-uninfected patients. The findings of our study suggest that HIV infection is an independent risk factor for SCD.
HIV-associated vascular inflammation, ventricular arrhythmias, and myocardial fibrosis may account for the higher risk of SCD in PLWHA. The HIV virion or its particles (eg, GP120 or TAT) can stimulate the endothelium directly and increase endothelial permeability, which assists the invasion of leukocytes into vessel walls, resulting in vascular inflammation.24,25 HIV-associated vascular inflammation has been associated with the development of atherosclerosis26 and a higher risk of ischemic heart disease,27,28 which could increase the risk of SCD in PLWHA.
HIV-associated ventricular arrhythmias may contribute to the increased risk of SCD in PLWHA. Previous studies have shown that presentation of prolonged QTc interval was more likely in PLWHA than in the general population because of non-ART polypharmacy and electrolyte imbalances.29,30 Moreover, PLWHA had a high prevalence of autonomic dysregulation, including parasympathetic and sympathetic dysfunction.31,32 High prevalence of prolonged QTc interval and autonomic dysregulation in PLWHA could cause the ventricular arrhythmias and increase the risk of SCD.33
HIV-associated myocardial fibrosis may also account for the higher risk of SCD in PLWHA. Myocardial fibrosis is a consequence of previous myocarditis and is characterized by an accumulation of collagen, which could cause cardiac dysfunction.34 A previous magnetic resonance imaging study showed that 76% of asymptomatic HIV-infected patients had myocardial fibrosis, which was higher than the 13% prevalence among HIV-uninfected patients.35 Myocardial fibrosis has been identified as a risk factor for the development of diastolic dysfunction and arrhythmias,36,37 which could increase the risk of SCD.
This study found that PLWHA receiving ART had a lower incidence of SCD than those not receiving the treatment. ART could significantly suppress viral replication and prevent the development of endothelial dysfunction and atherosclerosis,38,39 potentially lowering the risk of SCD in PLWHA. ART could also prevent the development of cardiomyopathy,40 which could reduce the risk of SCD in PLWHA.
Older age, a traditional risk factor for SCD,5 was not associated with the development of SCD in our study. The limited number of older PLWHA with SCD in our study may prevent the analysis of the association between older age and SCD in this population.
This nationwide cohort study has several strengths. First, our research design, which included unbiased subject selection and strict HIV diagnosis, supported the validity of these findings. Also, this nationwide population-based study traced all PLWHA and control patients with minimal referral bias since all medical care was covered by the Taiwan National Health Insurance. Moreover, the data on timing of ART were collected for all the study patients, and ART was regarded as a time-dependent variable in the analysis. In comparison, longitudinal studies that failed to account for changes in exposure during the study period could not yield precise estimates of the exposure effect on outcomes.41
Some limitations should be considered when interpreting the findings of this nationwide population-based cohort study. First, when a new HIV-infected individual was reported to the Taiwan CDC, the HIV surveillance system did not mandate entering data regarding viral loads and CD4 counts, the indices of advanced-stage HIV infections. However, the Taiwan CDC enforces medical professionals to report HIV-infected individuals' AIDS status, an indicator of immune status, within 24 hours of AIDS diagnosis. The multivariable analysis in our study controlled for AIDS status among all PLWHA and treated AIDS status as a time-dependent variable to mimic the real scenario regarding the immune status of HIV-infected individuals. Second, the diagnosis of SCD relied on administrative claims data recorded by physicians or hospitals and was not confirmed by paramedic records, family/witness interviews, or autopsy. Although the cause of death coding in the mortality certificate database of Taiwan is highly accurate,18 the outcome of SCD may have been misclassified. However, there is no reason to suspect that the validity of claims data would differ with a patient's HIV status. This nondifferential misclassification of outcome would bias the results toward a null association. Third, data of some potential risk factors (eg, smoking and family history of SCD) were not available for our analysis. Fourth, the presence of comorbidities in our study subjects was determined using the National Health Insurance Research Database and may have been underreported. However, this would be less likely because more than 99% of Taiwanese citizens were enrolled in the National Health Insurance Program.13 Finally, the external validity of our findings may be a concern because almost all study subjects were Taiwanese. The generalizability of our results to other non-Asian ethnic groups requires further verification. However, our findings suggest new avenues for future research.
In conclusion, this nationwide, long-term cohort study found a link between HIV infection and SCD. After adjusting for demographic data and comorbidities, HIV infection was found to be an independent risk factor for SCD. Moreover, among PLWHA, ART was associated with a relatively lower incidence of SCD. As PLWHA are living longer, clinicians need to be aware of the higher risk of SCD in this population.
The authors are grateful for statistical consultation at the Biostatistical Consultation Centre, National Yang-Ming University, Taipei, Taiwan.
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