Matthew S. Freiberg

Association Between HIV Infection and the Risk of Heart Failure With Reduced Ejection Fraction and Preserved Ejection Fraction in the Antiretroviral Therapy Era: Results From the Veterans Aging Cohort Study

Importance With improved survival, heart failure (HF) has become a major complication for individuals with human immunodeficiency virus (HIV) infection. It is unclear if this risk extends to different types of HF in the antiretroviral therapy (ART) era. Determining whether HIV infection is associated with HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), or both is critical because HF types differ with respect to underlying mechanism, treatment, and prognosis. Objectives To investigate whether HIV infection increases the risk of future HFrEF and HFpEF and to assess if this risk varies by sociodemographic and HIV-specific factors. Design, Setting, and Participants This study evaluated 98u2009015 participants without baseline cardiovascular disease from the Veterans Aging Cohort Study, an observational cohort of HIV-infected veterans and uninfected veterans matched by age, sex, race/ethnicity, and clinical site, enrolled on or after April 1, 2003, and followed up through September 30, 2012. The dates of the analysis were October 2015 to November 2016. Exposure Human immunodeficiency virus infection. Main Outcomes and Measures Outcomes included HFpEF (EF≥50%), borderline HFpEF (EF 40%-49%), HFrEF (EF<40%), and HF of unknown type (EF missing). Results Among 98u2009015 participants, the mean (SD) age at enrollment in the study was 48.3 (9.8) years, 97.0% were male, and 32.2% had HIV infection. During a median follow-up of 7.1 years, there were 2636 total HF events (34.6% were HFpEF, 15.5% were borderline HFpEF, 37.1% were HFrEF, and 12.8% were HF of unknown type). Compared with uninfected veterans, HIV-infected veterans had an increased risk of HFpEF (hazard ratio [HR], 1.21; 95% CI, 1.03-1.41), borderline HFpEF (HR, 1.37; 95% CI, 1.09-1.72), and HFrEF (HR, 1.61; 95% CI, 1.40-1.86). The risk of HFrEF was pronounced in veterans younger than 40 years at baseline (HR, 3.59; 95% CI, 1.95-6.58). Among HIV-infected veterans, time-updated HIV-1 RNA viral load of at least 500 copies/mL compared with less than 500 copies/mL was associated with an increased risk of HFrEF, and time-updated CD4 cell count less than 200 cells/mm3 compared with at least 500 cells/mm3 was associated with an increased risk of HFrEF and HFpEF. Conclusions and Relevance Individuals who are infected with HIV have an increased risk of HFpEF, borderline HFpEF, and HFrEF compared with uninfected individuals. The increased risk of HFrEF can manifest decades earlier than would be expected in a typical uninfected population. Future research should focus on prevention, risk stratification, and identification of the mechanisms for HFrEF and HFpEF in the HIV-infected population.

Increased Echocardiographic Pulmonary Pressure in HIV-infected and -uninfected Individuals in the Veterans Aging Cohort Study

Rationale: The epidemiology and prognostic impact of increased pulmonary pressure among HIV‐infected individuals in the antiretroviral therapy era is not well described. Objectives: To examine the prevalence, clinical features, and outcomes of increased echocardiographic pulmonary pressure in HIV‐infected and ‐uninfected individuals. Methods: This study evaluated 8,296 veterans referred for echocardiography with reported pulmonary artery systolic pressure (PASP) estimates from the Veterans Aging Cohort study, an observational cohort of HIV‐infected and ‐uninfected veterans matched by age, sex, race/ethnicity, and clinical site. The primary outcome was adjusted mortality by HIV status. Measurements and Main Results: PASP was reported in 2,831 HIV‐infected and 5,465 HIV‐uninfected veterans (follow‐up [mean ± SD], 3.8 ± 2.6 yr). As compared with uninfected veterans, HIV‐infected veterans with HIV viral load greater than 500 copies/ml (odds ratio, 1.27; 95% confidence interval [CI], 1.05–1.54) and those with CD4 cell count less than 200 cells/&mgr;l (odds ratio, 1.28; 95% CI, 1.02–1.60) had a higher prevalence of PASP greater than or equal to 40 mm Hg. As compared with uninfected veterans with a PASP less than 40 mm Hg, HIV‐infected veterans with a PASP greater than or equal to 40 mm Hg had an increased risk of death (adjusted hazard ratio, 1.78; 95% CI, 1.57–2.01). This risk persisted even among participants without prevalent comorbidities (adjusted hazard ratio, 3.61; 95% CI, 2.17–6.01). The adjusted risk of mortality in HIV‐infected veterans was higher at all PASP values than in uninfected veterans, including at values currently considered to be normal. Conclusions: HIV‐infected people with high HIV viral loads or low CD4 cell counts have a higher prevalence of increased PASP than uninfected people. Mortality risk in HIV‐infected veterans increases at lower values of PASP than previously recognized and is present even among those without prevalent comorbidities. These findings may inform clinical decision‐making regarding screening and surveillance of pulmonary hypertension in HIV‐infected individuals.

Association Between Depressive Disorders and Incident Acute Myocardial Infarction in Human Immunodeficiency Virus–Infected Adults: Veterans Aging Cohort Study

ImportancenWith the advent of highly effective antiretroviral therapy and improved survival, human immunodeficiency virus (HIV)-infected people are living longer and are now at an increased risk for cardiovascular disease (CVD). There is an urgent need to identify novel risk factors and primary prevention approaches for CVD in HIV. Although depression is prevalent in HIV-infected adults and is associated with future CVD in the general population, its association with CVD events has not been examined in the HIV-infected population.nnnObjectivenTo examine whether depressive disorders are prospectively associated with incident acute myocardial infarction (AMI) in a large cohort of adults with HIV.nnnDesign, Setting, and ParticipantsnIncluded in this cohort study were 26u202f144 HIV-infected veterans without CVD at baseline (1998-2003) participating in the US Department of Veterans Affairs Veterans Aging Cohort Study from April 1, 2003, through December 31, 2009. At baseline, 4853 veterans (19%) with major depressive disorder (MDD; International Classification of Diseases, Ninth Revision [ICD-9] codes 296.2 and 296.3) and 2296 (9%) with dysthymic disorder (ICD-9 code 300.4) were identified. The current analysis was conducted from January 2015 to November 2015.nnnMain Outcomes and MeasuresnIncident AMI (defined by discharge summary documentation, enzyme/electrocardiography evidence of AMI, inpatient ICD-9 code for AMI (410), or AMI as underlying cause of death [International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code 121]) between the enrollment date and December 31, 2009.nnnResultsnThe mean (SD) age of those with MDD was 47.3 (7.9) years and for those without MDD was 48.2 (9.7) years. During 5.8 years of follow-up, 490 AMI events (1.9%) occurred. Baseline MDD was associated with incident AMI after adjusting for demographics (hazard ratio [HR], 1.31; 95% CI, 1.05-1.62), CVD risk factors (HR, 1.29; 95% CI, 1.04-1.60), and HIV-specific factors (HR, 1.30; 95% CI, 1.05-1.62). Further adjustment for hepatitis C, renal disease, substance abuse, and hemoglobin level (HR, 1.25; 95% CI, 1.00-1.56) and antidepressant use (HR, 1.12; 95% CI, 0.87-1.42) attenuated associations. Baseline dysthymic disorder was not associated with incident AMI.nnnConclusions and RelevancenWe report novel evidence that HIV-infected adults with MDD have a 30% increased risk for AMI than HIV-infected adults without MDD after adjustment for many potential confounders. Our findings raise the possibility that MDD may be independently associated with incident atherosclerotic CVD in the HIV-infected population.

FIB-4 Stage of Liver Fibrosis Predicts Incident Heart Failure Among HIV Infected and Uninfected Patients.

Liver fibrosis is common, particularly in individuals who are infected with human immunodeficiency virus (HIV). HIV‐infected individuals have excess congestive heart failure (CHF) risk compared with uninfected people. It remains unknown whether liver fibrosis stage influences the CHF risk or if HIV or hepatitis C virus (HCV) infection modifies this association. Our objectives were to assess whether 1) stage of liver fibrosis is independently associated with incident CHF and 2) the association between stage of liver fibrosis and incident CHF is modified by HIV/HCV status. Participants alive on or after April 1, 2003, in the Veterans Aging Cohort Study were included. Those without prevalent cardiovascular disease were followed until their first CHF event, death, last follow‐up date, or December 31, 2011. Liver fibrosis was measured using the fibrosis 4 index (FIB‐4), which is calculated using age, aminotransferases, and platelets. Cox proportional hazards regression models were adjusted for cardiovascular disease risk factors. Among 96,373 participants over 6.9 years, 3844 incident CHF events occurred. FIB‐4 between 1.45 and 3.25 (moderate fibrosis) and FIB‐4u2009>u20093.25 (advanced fibrosis/cirrhosis) were associated with CHF (hazard ratio [95% confidence interval], 1.17 [1.07‐1.27] and 1.65 [1.43‐1.92], respectively). The association of advanced fibrosis/cirrhosis and incident CHF persisted regardless of HIV/HCV status. Conclusion: Moderate and advanced liver fibrosis/cirrhosis are associated with an increased risk of CHF. The association for advanced fibrosis/cirrhosis persists even among participants without hepatitis C and/or HIV infection. Assessing liver health may be important for reducing the risk of future CHF events, particularly among HIV and hepatitis C infected people among whom cardiovascular disease risk is elevated and liver disease is common. (Hepatology 2017;66:1286‐1295)

Association of Human Immunodeficiency Virus Infection and Risk of Peripheral Artery Disease

Background: The effect of human immunodeficiency virus (HIV) on the development of peripheral artery disease (PAD) remains unclear. We investigated whether HIV infection is associated with an increased risk of PAD after adjustment for traditional atherosclerotic risk factors in a large cohort of HIV-infected (HIV+) and demographically similar HIV-uninfected veterans. Methods: We studied participants in the Veterans Aging Cohort Study from April 1, 2003 through December 31, 2014. We excluded participants with known prior PAD or prevalent cardiovascular disease (myocardial infarction, stroke, coronary heart disease, and congestive heart failure) and analyzed the effect of HIV status on the risk of incident PAD events after adjusting for demographics, PAD risk factors, substance use, CD4 cell count, HIV-1 ribonucleic acid, and antiretroviral therapy. The primary outcome is incident peripheral artery disease events. Secondary outcomes include mortality and amputation in subjects with incident PAD events by HIV infection status, viral load, and CD4 count. Results: Among 91 953 participants, over a median follow up of 9.0 years, there were 7708 incident PAD events. Rates of incident PAD events per 1000 person-years were higher among HIV+ (11.9; 95% confidence interval [CI], 11.5–12.4) than uninfected veterans (9.9; 95% CI, 9.6–10.1). After adjustment for demographics, PAD risk factors, and other covariates, HIV+ veterans had an increased risk of incident PAD events compared with uninfected veterans (hazard ratio [HR], 1.19; 95% CI, 1.13–1.25). This risk was highest among those with time-updated HIV viral load >500 copies/mL (HR, 1.51; 95% CI, 1.38–1.65) and CD4 cell counts <200 cells/mm3 (HR, 1.91; 95% CI, 1.71–2.13). In contrast, HIV+ veterans with time updated CD4 cell count ≥500 cells/mm3 had no increased risk of PAD (HR, 1.03; 95% CI, 0.96–1.11). Mortality rates after incident PAD events are high regardless of HIV status. HIV infection did not affect rates of amputation after incident PAD events. Conclusions: Infection with HIV is associated with a 19% increased risk of PAD beyond that explained by traditional atherosclerotic risk factors. However, for those with sustained CD4 cell counts <200 cells/mm3, the risk of incident PAD events is nearly 2-fold higher whereas for those with sustained CD4 cell counts ≥500 cells/mm3 there is no excess risk of incident PAD events compared with uninfected people.

Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV‐Positive and HIV‐Negative Individuals in VACS (Veterans Aging Cohort Study)

Background Bilirubin may protect against cardiovascular disease (CVD) by reducing oxidative stress. Whether elevated bilirubin reduces the risk of CVD events among HIV + individuals and if this differs from uninfected individuals remain unclear. We assessed whether bilirubin independently predicted the risk of CVD events among HIV + and uninfected participants in VACS (Veterans Aging Cohort Study). Methods and Results We conducted a prospective cohort study using VACS participants free of baseline CVD. Total bilirubin was categorized by quartiles. CVD as well as acute myocardial infarction, heart failure, and ischemic stroke events were assessed. Cox regression was used to evaluate hazard ratios of outcomes associated with quartiles of total bilirubin in HIV + and uninfected people after adjusting for multiple risk factors. There were 96 381 participants (30 427 HIV +); mean age was 48 years, 48% were black, and 97% were men. There were 6603 total incident CVD events over a mean of 5.7 years. In adjusted models, increasing quartiles of baseline total bilirubin were associated with decreased hazards of all outcomes (hazard ratio, 0.86; 95% confidence interval, 0.80–0.91). Among HIV + participants, results persisted for heart failure, ischemic stroke, and total CVD, but nonsignificant associations were observed for acute myocardial infarction. Conclusions VACS participants (regardless of HIV status) with elevated bilirubin levels had a lower risk of incident total CVD, acute myocardial infarction, heart failure, and ischemic stroke events after adjusting for known risk factors. Future studies should investigate how this apparently protective effect of elevated bilirubin could be harnessed to reduce CVD risk or improve risk estimation among HIV + individuals.

Brief Report: Racial Comparison of D-dimer Levels in Us Male Military Personnel Before and After Hiv Infection and Viral Suppression

Background: D-dimer blood levels in persons with HIV infection are associated with risk of serious non-AIDS conditions and death. Black race has been correlated with higher D-dimer levels in several studies. We examined the effects of race and HIV on D-dimer over time and the impact of viral load suppression by longitudinally comparing changes in levels among healthy young adult male African Americans and whites before HIV seroconversion and before and after initiation of antiretroviral therapy (ART). Methods: We analyzed D-dimer levels and clinical and laboratory data of 192 participants enrolled in the US Military HIV Natural History Study, a 30-year cohort of military personnel infected with HIV. D-dimer levels were measured on stored sera from each participant at 3 time points: (1) before HIV seroconversion (Pre-SC), (2) ≥6 months after HIV seroconversion but before ART initiation (Post-SC), and (3) ≥6 months after ART with documented viral suppression (Post-ART). Levels were compared at each time point using nonparametric and logistic regression analysis. Results: Compared with whites (n = 106), African Americans (n = 86) had higher D-dimer levels post-SC (P = 0.007), but in the same individuals, pre-SC baseline and post-ART levels were similar (P = 0.40 and P = 0.99, respectively). There were no racial differences in CD4 cell counts, HIV RNA viral load, time from estimated seroconversion to ART initiation, and duration on ART. Conclusions: Observed longitudinally, racial differences in D-dimer levels were seen only during HIV viremia. Higher levels of D-dimer commonly observed in African Americans are likely due to factors in addition to race.

HIV and Cardiovascular Disease: Update on Clinical Events, Special Populations, and Novel Biomarkers

Purpose of ReviewThe objective of this review is to provide an update on the link between HIV infection and cardiovascular disease (CVD). We will focus our review mainly on literature describing clinical CVD events and understudied topics of importance.Recent FindingsHeart failure, peripheral artery disease, and stroke are CVD modalities deserving more attention in the context of HIV infection in the highly active antiretroviral therapy era. Incidence data on clinical CVD from HIV populations in low- and middle-income countries are limited. Multisubstance use is common in HIV, but understudied as a moderator or mediator of the association between HIV and CVD. CVD risk assessment in HIV remains challenging, but new research into novel biomarkers may provide further insights. There is also a need for inclusion of non-biologic factors in our attempts to understand, quantify, and predict CVD risk among PLWHA.SummarySignificant attention has been paid to generating and testing hypotheses to understand the mechanisms of myocardial infarction in HIV. Similar attention is deserving for heart failure, PAD, stroke, and cardiovascular disease risk in resource-limited settings and among substance users with HIV.

Impact of illicit opioid use on T cell subsets among HIV-infected adults

Objectives Opioids have immunosuppressive properties, yet opioid effects on T cell abnormalities consistent with the immune risk phenotype among HIV-infected individuals are understudied. Methods To assess associations between illicit opioid use and T cell characteristics (CD4/CD8 ratio, memory profiles based on CD45RO and CD28 expression, and senescence based on CD57 expression), we conducted an exploratory cross-sectional analysis of Russia ARCH, a cohort of antiretroviral therapy (ART)-naïve HIV-infected individuals recruited 11/2012 to 10/2014 in St. Petersburg, Russia. The main independent variable was past 30 day illicit opioid use (yes vs. no). Secondary analyses evaluated none (0 days), intermittent (1 to 7 days), and persistent (8 to 30 days) opioid use. Outcomes were determined with flow cytometry. Analyses were conducted using linear regression models. Results Among 186 participants, 38% reported any illicit opioid use (18% intermittent and 20% persistent). Any illicit opioid use was not significantly associated with T cell characteristics. Intermittent opioid use appeared to be associated with decreased memory CD8+ T cells proportion (CD45RO+CD45RA- CD8+ T cells: adjusted mean difference [AMD] [95% CI] = -6.15 [-11.50, -0.79], p = 0.02) and borderline significant increased senescent T cells (%CD57+ of total CD28-CD8+ T cells (AMD [95% CI] = 7.70 [-0.06, 15.46], p = 0.05). Conclusions Among ART-naïve HIV-infected Russians, any illicit opioid use was not significantly associated with T cell abnormalities although intermittent illicit opioid use may be associated with CD8 T cell abnormalities. Longitudinal studies are warranted to confirm these findings given increased risk of infections and comorbidities seen among HIV-infected individuals with illicit opioid use.

HIV and Obesity Comorbidity Increase Interleukin 6 but Not Soluble CD14 or D-Dimer

Objectives: Obesity prevalence among people living with HIV (HIV+) is rising. HIV and obesity are proinflammatory states, but their combined effect on inflammation (measured by interleukin 6, IL-6), altered coagulation (D-dimer), and monocyte activation (soluble CD14, sCD14) is unknown. We hypothesized inflammation increases when obesity and HIV infection co-occur. Methods: The Veterans Aging Cohort Study survey cohort is a prospective, observational study of predominantly male HIV+ veterans and veterans uninfected with HIV; a subset provided blood samples. Inclusion criteria for this analysis were body mass index ≥ 18.5 kg/m2 and biomarker measurement. Dependent variables were IL-6, sCD14, and D-dimer quartiles. Obesity/HIV status was the primary predictor. Unadjusted and adjusted logistic regression models were constructed. Results: Data were analyzed for 1477 HIV+ and 823 uninfected participants. Unadjusted median IL-6 levels were significantly higher and sCD14 levels significantly lower in obese/HIV+ compared with nonobese/uninfected (P <0.01 for both). In adjusted analyses, the odds ratio for increased IL-6 in obese/HIV+ patients was 1.76 (95% confidence interval: 1.18 to 2.47) compared with nonobese/uninfected, and obesity/HIV+ remained associated with lower odds of elevated sCD14. We did not detect a synergistic association of co-occurring HIV and obesity on IL-6 or sCD14 elevation. D-dimer levels did not differ significantly between body mass index/HIV status groups. Conclusions: HIV–obesity comorbidity is associated with elevated IL-6, decreases in sCD14, and no significant difference in D-dimer. These findings are clinically significant, as previous studies associated these biomarkers with mortality. Future studies should assess whether other biomarkers show similar trends and potential mechanisms for unanticipated sCD14 and D-dimer findings.