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2 Recent study publications from Kaiser on Dementia & Heart Failure in PLWH
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Comparison of dementia incidence and prevalence between individuals with and without HIV infection in primary care from 2000 to 2016 - (01/03/22)
apparently in demographics table 17% at baseline were on ARTs, the study did not differentiate between which ARTs PLWH were taking over the years.
December 13, 2021 Mayo Clinic Proceedings
Abstract
Objectives
To evaluate the risk of heart failure (HF) linked to human immunodeficiency virus (HIV) infection, how risk varies by demographic characteristics, and whether it is explained by atherosclerotic disease or risk factor treatment.
Patients and Methods
We performed a retrospective cohort study of persons with HIV (PWHs) from January 1, 2000, through December 31, 2016, frequency-matched 1:10 to persons without HIV on year of entry, age, sex, race/ethnicity, and treating facility. We evaluated the risk of incident HF associated with HIV infection, overall and by left ventricular systolic function, and whether HF risk varied by demographic characteristics.
Results
Among 38,868 PWHs and 386,586 matched persons without HIV, mean ± SD age was 41.4±10.8 years, with 12.3% female, 21.1% Black, 20.5% Hispanic, and 3.9% Asian/Pacific Islander. During median follow-up of 3.8 years (interquartile range, 1.4-9.0 years), the rate (per 100 person-years) of incident HF was 0.23 in PWHs vs 0.15 in those without HIV (P<.001). The PWHs had a higher adjusted HF rate (adjusted hazard ratio [aHR], 1.73; 95% confidence interval [CI], 1.57 to 1.91), which was only modestly attenuated after accounting for interim acute coronary syndrome events. Results were similar by systolic function category. The adjusted risk of HF in PWHs was more prominent for those 40 years and younger (aHR, 2.45; 95% CI, 1.92 to 3.03), women (aHR, 2.48; 95% CI, 1.90 to 3.26), and Asian/Pacific Islanders (aHR, 2.46; 95% CI, 1.27 to 4.74).
Conclusion
HIV infection increases the risk of HF, which varied by demographic characteristics and was not primarily mediated through atherosclerotic disease pathways or differential use of cardiopreventive medications.
In the present, substantially larger and more diverse cohort of both women and men, we found a 65% higher adjusted risk of HF in PWHs not explained by known confounders, receipt of cardiopreventive therapies, or interim ACS events, which materially expands beyond results of other cohorts within and outside the United States.
In a large, ethnically and geographically diverse, multi-institutional cohort of adults with and without HIV, HIV infection was associated with an increased risk of HF even after adjustment for potential explanatory effects of sociodemographic and clinical risk factors, cardiovascular-related medication use, and interim ACS events. This relationship was present for all HF subtypes and was strongest for HFpEF and HFmrEF. Furthermore, the adjusted excess risk of HF in PWHs seemed stronger in younger (age 21-40 years) patients, women, and Asian/Pacific Islander adults.
Because persons living with human immunodeficiency virus (HIV) (PWHs) are living longer, they face an evolving, expanding set of challenges beyond treatment of HIV and acquired immunodeficiency syndrome–related illnesses.
These challenges include multiple comorbidities, such as atherosclerotic cardiovascular diseases (ASCVDs), cancer, and liver and kidney diseases.1 The risk of ASCVD emerged as a concern early in the antiretroviral therapy (ART) era, although recent data suggest a lower excess ASCVD risk in PWHs.
Less is known about other cardiovascular complications, such as heart failure (HF), in PWHs. In the United States, HF affects more than 6 million adults and is a leading cause of hospitalization and death in older persons. The epidemiology of HF is also shifting, with greater than 50% of patients having HF with preserved ejection fraction (HFpEF), a syndrome associated with differential but poor outcomes compared with HF with reduced ejection fraction (HFrEF). Although common contributors to HF exist in those with and without HIV, several potential risk factors unique to PWHs include exposure to chronic immune activation and immunodeficiency and certain ARTs.
The Veterans Aging Cohort Study-Virtual Cohort (VACS-VC) suggested a higher risk of HF in PWHs after accounting for cardiovascular risk factors but studied nearly all men, had limited ethnic diversity, and did not account for differential receipt of cardiopreventive therapies.
Furthermore, few data exist about whether risk of HF in PWHs varies by demographic characteristics and potentially contributing modifiable factors.
We addressed these knowledge gaps by evaluating the association between HIV infection and the risk of developing HF overall and by type of HF, contributing risk factors, and whether variation in risk of HF exists across age, sex, and race/ethnicity within a large, multicenter, contemporary, diverse matched population of adults with and without HIV.
Discussion
In a large, ethnically and geographically diverse, multi-institutional cohort of adults with and without HIV, HIV infection was associated with an increased risk of HF even after adjustment for potential explanatory effects of sociodemographic and clinical risk factors, cardiovascular-related medication use, and interim ACS events. This relationship was present for all HF subtypes and was strongest for HFpEF and HFmrEF. Furthermore, the adjusted excess risk of HF in PWHs seemed stronger in younger (age 21-40 years) patients, women, and Asian/Pacific Islander adults.
The present study represents one of the largest, most comprehensive investigations evaluating the risk of HF associated with HIV infection, overall, by HF type (HFpEF, HFmrEF, and HFrEF), and across demographic subgroups. A VACS-VC analysis primarily in the pre-ART era reported an 81% higher adjusted risk of HF in 2391 veterans with HIV compared with 6095 matched veterans without HIV, with a subsequent larger analysis in predominantly White or Black male veterans observing a 41% higher adjusted risk of HF in PWHs.
In the present, substantially larger and more diverse cohort of both women and men, we found a 65% higher adjusted risk of HF in PWHs not explained by known confounders, receipt of cardiopreventive therapies, or interim ACS events, which materially expands beyond results of other cohorts within and outside the United States. The present study also provides important insights into higher rates of HFpEF and HFmrEF in PWHs. Although PWHs experienced higher adjusted rates of HFrEF in this cohort consistent with that observed in the VACS-VC, there were stronger associations for HFpEF and HFmrEF.
The present finding that the excess adjusted rate of incident HF in PWHs was more prominent in younger persons (age 21-40 years) supports and extends results from previous studies. In an analysis of billing claims data among 19,798 PWHs and 59,302 age- and sex-matched persons without HIV, Alonso et al reported a higher adjusted risk of diagnosed HF in those younger than 50 years (aHR, 5.9; 95% CI, 3.4 to 10.1) than in those 50 years and older (aHR, 2.5; 95% CI, 1.8 to 3.5), but only limited adjustment for potential confounders was performed and type of HF was not addressed. In the primarily White male veteran VACS-VC sample, there was a greater than 3.5-fold higher rate of incident HF in PWHs compared with persons without HIV (aHR, 3.59; 95% CI, 1.95 to 6.58) for those younger than 40 years,
and HF occurred at a younger age in veterans with HIV compared with those without HIV. Specific reasons for why HIV infection can be more harmful in younger persons remain unclear.
Concern exists that women living with HIV might be at higher risk for HF with associated potential sex-specific risk factors and mechanisms that can differ than for complications such as myocardial infarction. Importantly, existing studies have primarily included modest sample sizes and yielded conflicting results. For example, in 26,272 PWHs in Taiwan, Lai et al reported a higher age- and calendar period–standardized incidence of HF in women (2.51; 95% CI, 1.71 to 3.56) than in men (1.41; 95% CI, 1.22 to 1.62), whereas no interaction by sex was observed in the excess risk of incident HF in PWHs in the HIV Electronic Comprehensive Cohort of CVD Complications (HIVE-4CVD) involving 4640 PWHs and 4250 persons without HIV frequency-matched on age, sex, race/ethnicity, zip code, and clinic location.
In contrast, after adjustment for a wide range of confounders, receipt of cardiovascular-related medications, and interim ACSs, we found that the excess risk of incident HF in PWHs was more prominent in women (aHR, 2.48; 95% CI, 1.90 to 3.26) than in men (aHR, 1.57; 95% CI, 1.41 to 1.75). The HIV infection is associated with increased myocardial fibrosis, intramyocardial triglyceride deposition, and impaired diastolic function, as well as immune activation and dysregulation of selected metabolic pathways in women, but it remains unclear whether HIV has direct negative effects or works through promoting existing aging-related mechanisms differentially in women than in men.
Even less is known about how race and ethnicity influence risk of incident HF in PWHs. In HIVE-4CVD, no significant racial difference was reported in the excess risk of developing HF in PWHs, but relatively few cases of HF were observed and they were unable to examine racial/ethnic groups beyond White and Black. Within the VACS-VC, similar associations were observed for White (aHR, 1.31; 95% CI, 1.12 to 1.52) and Black (aHR, 1.41; 95% CI, 1.26 to 1.59) adults, but they also were not able to evaluate other racial/ethnic groups.
Importantly, although crude rates of HF were highest in Black adults overall, we observed that the multivariable point estimate for HIV-associated incident HF was highest in Asian/Pacific Islander adults (aHR, 2.46; 95% CI, 1.27-4.74), was similar in White adults (aHR, 1.67; 95% CI, 1.45 to 1.93) and Black adults (aHR, 1.52; 95% CI, 1.26 to 1.83), but was not statistically significant in Hispanic adults. Little is known about the risk and mechanisms of HF associated with HIV infection in Asian/Pacific Islander adults, especially given the many different subgroups, with one small study in Chinese patients reporting that PWHs were more likely to have diastolic dysfunction, mildly reduced left ventricular systolic dysfunction, and greater left ventricular mass.
Beyond larger sample size, we had significantly greater representation of Hispanic adults (20.4%), Asian/Pacific Islander adults (3.9%), and women (12.2%) compared with previous studies, with results that are likely more generalizable to contemporary US PWHs (26% Hispanic, 2% Asian/Pacific Islander, and 19% women). We also accounted for potential influences of lifestyle factors, socioeconomic status, HIV infection route, and use of cardiovascular-related medications, in addition to controlling for baseline ART use on the risk of incident HF. Participating institutions employ comprehensive HIV registries and validated algorithms to systematically capture HF events, potential confounders, and mediating factors based on EMR data. The present findings also reflect the most contemporary data of incident HF and HF type among adults with and without HIV.
The present findings carry important implications. Despite recommendations about preventing coronary disease in PWHs, current guidelines do not address screening for or prevention of HF. Implementing validated HF screening methods, including a history and physical examination supported by selected biomarker testing (N-terminal pro–B-type natriuretic peptide or B-type natriuretic peptide) and echocardiography, in PWHs can expedite time to diagnosis and treatment of ventricular dysfunction and possibly prevention of clinical HF.
The present findings also reinforce the importance of preventing or aggressively treating vascular risk factors and disease and other associated HF-related risk factors (eg, anemia, sleep-disordered breathing). Additional efforts to prevent HIV infection and to detect HIV infection early should also be prioritized to reduce excess population burden of HF, among other HIV-associated complications.
This study also had limitations. Data were not systematically available for certain risk factors and laboratory tests (eg, kidney function, lipoproteins, natriuretic peptides, troponin, HIV genotype, and non-HIV viral serologies) that can be associated with HF risk. Although we subtyped most HF cases, information on left ventricular systolic function or cardiac structure was not universally available due to limitations in available echocardiographic data primarily from earlier study years, which would be a nondifferential type of bias, and this was supported by the excess risk of each HF type in PWHs. We were unable to delineate specific mechanisms by which HIV infection could increase risk of HF separate from ASCVD-related pathways. The involved pathways are likely multifactorial, with contributions from chronic immune activation on myocardial function and fibrosis, direct myocyte invasion, and induction of mitochondrial dysfunction and adverse cellular signaling pathways by HIV, co-infection with other viruses (eg, Coxsackie virus B3, cytomegalovirus), impaired nutritional status, and possible adverse effects of different ART regimens on cardiac function. We studied insured adults receiving care in integrated health care delivery systems, so the results might not be completely generalizable to all geographic areas or settings.
Conclusion
Compared with persons without HIV, PWHs had a higher risk of HF, overall and for each HF type, that was not primarily explained through atherosclerotic pathways or differential use of cardiopreventive medications. Excess HF risk varied significantly by demographic characteristics, which supports improved risk stratification and systematic surveillance for HF and delineation of HIV-specific mechanisms that could serve as therapeutic targets to prevent HIV-associated HF.
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