Presenter Disclosure Information Jason J. Sico, MD FINANCIAL DISCLOSURE: No relevant financial relationship exists 1

Matthew S. Freiberg, MD, Msc 3,4 HIV, Hepatitis C, and the risk of Stroke after adjustment for death as a Competing Risk Jason J. Sico, MD1,2 Matthew S. Freiberg, MD, Msc 3,4 Amy C. Justice, MD, PhD 1,2 Yale University School of Medicine1; VA Connecticut Healthcare System2; University of Pittsburgh School of Medicine3; University of Pittsburgh Graduate School of Public Health4 Greetings. My name is Jason Sico. 2

HIV, HCV and Vascular Disease HIV is associated with CVD and CHF Coinfection confers an even greater risk for cardiovascular disease Few studies have examined stroke after the introduction of HAART Those with HIV infection and AIDS experience a stepwise increased risk of intracranial hemorrhage HIV has been associated with cardiomyopathy, congestive heart failure and premature cardiovascular disease. CVD has been in part because of side effects of HAART. This audience is well versed in some of the metabolic complications of antiretrovirals, especially insulin resistance and dyslipidemia. Further, persons with HIV are aging, and becoming old enough to develop additional comorbidities of CVD (HTN, diabetes, obesity). Transition: many of these same risk factors are associated with development of stroke. 1. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination. N Engl J Med 2004 Dec 16;351(25):2611-8. 2. The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination Antiretroviral Therapy and the Risk of Myocardial Infarction. N Engl J Med 2003 Nov 20;349(21):1993-2003. 3. Freiberg M, Cheng DM, Kraemer KL, Saitz R, Kuller LH, Samet JH. The association between hepatitis C infection and prevalent cardiovascular disease among HIV-infected individuals. AIDS 21[2], 193-197. 1-11-2007. 4. Restrepo L, McArthur J, Modi G, Mochan A, Modi M. Stroke and HIV Infection Response. Stroke 2003;34:e176-e177. 5. Justice A, Zingmond D, Gordon K, Fultz S, Goulet J, King J, et al. Drug Toxicity, HIV Progression, or Comorbidity of Aging: Does Tipranavir Use Increase the Risk of Intracranial Hemorrhage? Clinical Infectious Diseases 2008 Nov 1;47(9):1226-30. 3

Objective To examine whether HIV/HCV co-infection is associated with an increased risk of ischemic stroke 4

Methods Design: Prospective cohort study Population: 8,579 male participants (28% HIV+, 9% HIV+ HCV+) from VACS-VC who participated in 1999 Large Health Study of Veteran Enrollees Exclusion Criteria: Stroke, CHD and CHF (n=3,116) Cancer (except non-melanomatous; n=856) Failed to answer questions re: cancer (n=860) Women (n=279) 5

Variables Independent Variables: HIV and HCV infection status into four groups: Dependent Variables: Incident stroke form 1/2000 to 7/2007 Death Stroke: by ICD-9 codes Death was confirmed by using: using the VA vitals status file; the Social Security administration death master file, the Beneficiary Identification and Records Locator Subsystem, and the VHA medical SAS inpatient datasets. 6

Analysis Plan Descriptive statistics Cox proportional hazard models used to estimate hazard ratio and 95% confidence intervals for stroke associated with HIV, HCV after adjusting for confounders Death treated first as a censoring event and then as a competing risk 7

Baseline Characteristics: Demographics Uninfected HCV-Infected Only HIV-Infected Coinfected P-value †† N=5,453 N=701 N=1,687 N=738 Age (median, mean ± S.D.) 48  48.2 ± 9.9 47  47.4 ± 5.6  47.8 ± 10.7  48.4 ± 6.7 0.02 Race/ethnicity (%) White 39.0 29.8 47.5 30.4 < 0.001 African American 39.2 52.9 32.7 53.1 Hispanic 9.8 9.6 8.5 11.8 Other 12.1 7.7 11.2 4.7 Hypertension (%) 29.3 27.4 17.3 23.6 <0.001 Diabetes (%) 24.8 25.8 15.9 18.7 0.001 Hypercholesterolemia (%) 33.7 33.9 20.1 Current Smoking (%) 42.5 66.2 49.9 65.6 Baseline CD4 count (median, mean ± S.D.)† -- 371, 418.2 ± 283.0 357, 402.1 ± 267.2 0.37 Smoking Status (%) Never Current Past Uninfected: 26.5 Uninfected: 42.5 Uninfected: 31.0 HCV Only: 9.6 HCV Only: 66.2 HCV Only: 24.2 HIV Only: 23.3 HIV Only: 49.9 HIV Only: 26.7 Coinfected: 10.9 Coinfected: 65.6 Coinfected: 23.5 Cocaine History (<0.001) Uninfected: 12.3 HCV Only: 41.9 HIV Only: 12.9 Coinfected: 42.4 Alcohol History <0.001 Uninfected: 28.3 HCV Only: 67.1 HIV Only: 24.1 Coinfected: 56.8 Body Mass Index (median, mean ± S.E.) 27.4, 28.2 ± 5.3 26.4, 27.1 ± 5.0 24.4, 25.1 ± 4.2 24.4, 25.1 ± 4.3 < 0.001 † n=1124 for HIV+ hepatitis C- participants and n=535 for HIV+ hepatitis C+ participant 8

Incidence Stroke Risk with and without adjustment for Competing Risk Kaplan-Meier Analysis of Incident Stroke by viral status before and after adjusting for death as a competing risk.

Association between HIV and HCV Status and Stroke Viral Status No. of death events (%) Adjusted mortality rate* (95% CI) No. of stroke events Adjusted stroke incidence rate* Model 1: HR for stroke (95% CI†) Model 2: HR for stroke (95% CI‡) HIV+HCV+ N=738 252 (21.3) 60.6 (58.5-62.6) 29 (18.1) 6.99 (6.68-7.30) 2.08 (1.31-3.31) 2.21 (1.62-3.02) HIV+HCV- N=1687 380 (32.2) 39.0 (37.6-40.5) 28 (17.5) 2.93 (2.79-3.07) 1.34 (0.87-2.07) 2.13 (1.65-2.75) HIV-HCV+ N=701 94 (8.0) 20.5 (19.8-21.1) 19 (11.9) 4.13 (3.96-4.29) 1.36 (0.79-2.35) 1.44 (0.99-2.11) HIV-HCV- N=5453 455 (38.5) 12.9 (12.6-13.1) 84 (52.5) 2.38 (2.33-2.44) 1.0 Rates are per age and race adjusted per 1000 person years. † Model 1 adjusted for age, race, education, body mass index, hypertension, diabetes, smoking, hypercholesterolemia, alcohol abuse and dependence, cocaine abuse and dependence, congestive heart failure in the follow-up period prior to stroke, and death as a censoring event. ‡ Model 2 treated death as a competing risk, adjusting for all covariates in Model 1.

Strengths and Limitations This is the first prospective study examining stroke in the post-HAART era Stroke outcome variable was determined using ICD-9 codes While treatment of HIV was examined, we did not take into account treatment of HCV infection While our models controlled for anti-thrombotic agents, data on aspirin use is not routinely available in VA dataset Cannot comment on the type of ischemic stroke (cardioembolic, thromboembolic or small- vessel disease) Second: some misclassification may have occurred. However, ICD-9 codes have been demonstrated to be accurate for stroke Third: Our prior studies in clinical settings have shown that treatment rates are low for HCV mono-infected people, and even lower for HIV HCV co-infected persons 11

Conclusions and Implications Chronic HIV infection with and without hepatitis C coinfection is associated with an increased risk of stroke HCV infection confers additional cerebrovascular risk among HIV infected veterans when death is considered as a competing risk 12

Future Directions Stroke events can be adjudicated Analysis of imaging (MRI brain, carotid ultrasound) and laboratory (cryoglobulins, RDW, CRP) data at time of stroke Analyzing if specific drugs or drug regimens are more strongly associated with ischemic stroke 13