Cutrell A, Hernandez J, Brothers C et al Is abacavir (ABC)-containing combination antiretroviral therapy (CART) associated with myocardial infarction (MI)? No association identified in pooled summary of 54 clinical trials A Cutrell, J Hernandez, C Brothers, J Yeo, W Burkle, W Spreen. XVII International AIDS Conference, 3-8 August 2008, Mexico City

Cutrell A, Hernandez J, Brothers C et al Background and Objective The D:A:D study group recently reported an unexpected increase in risk of MI with ABC and ddI in a large, prospective observational cohort (Lancet 2008; 371: ). To determine whether there is an increase in cardiovascular events associated with ABC containing CART as compared to non-ABC containing CART using GSK-sponsored clinical trials contained in the GSK HIV Data Repository.

Cutrell A, Hernandez J, Brothers C et al Methods (1) GSK-sponsored clinical trials with > 24 weeks of follow up with data from were analyzed. –Data from 54 clinical trials analyzed: 12/54 adult trials were randomized for ABC vs control 33/54 trials included ABC in background ART 8/54 trials did not include ABC Includes data from subjects (14174 adults and 509 children) Descriptive statistics were summarized for naïve and experienced subjects treated with and without ABC.

Cutrell A, Hernandez J, Brothers C et al Methods (2) To capture events of interest (myocardial ischemia or infarction) all data were queried for events coded as “ Coronary Artery Disorders ” and “ Ischemic Coronary Artery Disorders ”. –Specific preferred terms included: coronary artery atherosclerosis, coronary artery disease, coronary artery occlusion, acute MI, angina pectoris, angina unstable, MI and myocardial ischemia. All fatal cases (any cause) in the HIV Data Repository were reviewed by an external cardiologist. Framingham risk not calculated at baseline – not all factors routinely collected. Rates per 1000 person/years were calculated, and Poisson regression models were used to calculate unadjusted relative rates and 95% confidence intervals using SAS.

Cutrell A, Hernandez J, Brothers C et al Demographic and HIV-disease Characteristics at Baseline ADULT NAIVEADULT EXPERIENCED ABC N=5859 No ABC N=2406 ABC N=3643 No ABC N=2266 Age at Screening, n Median, year (min-max) (17-78) (18-74) (18-78) (18-74) Race, n White Black % 29% % 22% % 21% % 16% Sex, n Male % % % % Viral Load (log 10 ), n Median (Min-Max) ( ) ( ) ( ) ( ) CD4 Count, n Median (Min-Max) (0-1883) (0-1729) (0-2089) (0-1799)

Cutrell A, Hernandez J, Brothers C et al Baseline Lipids and Glucose (mmol/L) n Median (Min-Max) ADULT NAIVEADULT EXPERIENCED ABC N=5859 No ABC N=2406 ABC N=3643 No ABC N=2266 Cholesterol ( ) ( ) ( ) ( ) LDL ( ) ( ) ( ) ( ) HDL ( ) ( ) ( ) ( ) Triglycerides ( ) ( ) ( ) ( ) Glucose ( ) ( ) ( ) ( )

Cutrell A, Hernandez J, Brothers C et al CV Outcomes - Exposure to ABC Compared with No Exposure to ABC Exposure to ABC Events /Patients FrequencyEvents /Person- Years Rate /1000 Person- Years Relative rate (95% CI) Any Myocardial Infarction or Acute Myocardial Infarction: None 7/ %11/ ABC CART11/ %16/ (0.40,1.86) Any ischemic Coronary Artery Disease or Disorder: None 21/ %27/ ABC CART24/ %27/ (0.35,1.01)

Cutrell A, Hernandez J, Brothers C et al CV Outcomes - Exposure to ABC or No ABC (12 Adult Randomized Trials) Exposure to ABC Events /Patients FrequencyEvents /Person- Years Rate /1000 Person- Years Relative rate (95% CI) Any Myocardial Infarction or Acute Myocardial Infarction: None 6/ %7/ ABC CART2/ %4/ (0.15 – 1.79) Any ischemic Coronary Artery Disease or Disorder: None 13/ %13/ ABC CART5/ %8/ ( )

Cutrell A, Hernandez J, Brothers C et al Strengths and Limitations Prospective clinical trial data with large number of patients exposed to ABC, consistent data collection Standard and real-time monitoring and follow up of all reported AEs External expert review supportive Post-hoc analysis Duration of exposure on average weeks Studies not designed to detect CV risk specifically Low event rate therefore less power

Cutrell A, Hernandez J, Brothers C et al Conclusion Overall, among pts in the GSK HIV Data Repository: –the incidence rate of MI and Coronary Artery Disorders was low –there was no difference in incidence of ischemic coronary artery events or myocardial infarction in subjects who received abacavir-containing vs. non- ABC containing CART Further study is needed to fully evaluate the association of ABC and cardiovascular disease.

Cutrell A, Hernandez J, Brothers C et al What’s Next to Further Address the Question? Analysis of Internal Clinical Trial Data Continued vigilance of spontaneous event data and published literature  In all future studies, incorporate cardiovascular risk factor and biomarker collection  Mechanism research  Analyze inflammatory markers in current and future studies  Support additional cohort collaborations

Cutrell A, Hernandez J, Brothers C et al HEAT Biomarker Analysis: Geometric Mean (95% CI) by Study Week (ITT-E) n (obs) ABC/3TC = TDF/FTC = Interleukin 6 (IL-6) High Sensitivity C-Reactive Protein (hsCRP) Adapted from Smith K, et al. IAC Abstract LBPE1138.

Cutrell A, Hernandez J, Brothers C et al Acknowledgments The authors wish to thank… Harry Staines, Suki Pabla, Dupe Bassey, Lee Tombs and Pinal Patel at SRG Interesource Satellite Operations for statistical support Drs. Peter Kowey & Gary Koch for expert input Investigators who supported the clinical trials All of the patient volunteers.

Cutrell A, Hernandez J, Brothers C et al Back up slides

Cutrell A, Hernandez J, Brothers C et al Percent n/N= ABC 12/9639 Non-ABC 7/5043 Total 19/ % 0.139% 0.129% Cutrell A, Hernandez J, Brothers C et al. 2008

Percent n/N= ABC 11/5859 Non-ABC 3/2406 Total 14/ % 0.125% 0.188% Cutrell A, Hernandez J, Brothers C et al. 2008

Percent n/N= ABC 1/3643 Non-ABC 4/2266 Total 5/ % 0.177% 0.027% Cutrell A, Hernandez J, Brothers C et al. 2008

Abacavir and Risk of MI: Evaluation of potential biologic mechanisms Review of preclinical, clinical pharmacology and clinical information does not indicate a clear contribution of abacavir therapy to enhanced risk of MI via plausible biologic mechanisms. Rather, the preponderance of data support a conclusion of a generally favorable cardiovascular safety profile. Cutrell A, Hernandez J, Brothers C et al. 2008

Safety pharmacology Isolated cardiac muscle (rat, guinea-pig & cat): –No inotropic, chronotropic or dysrythmic effects. Concious normotensive rat: –No effect on Arterial BP or heart rate (100mg/Kg). Anesthetized dog: –Little effect on ABP or HR, no arrhythmia (50 mg/Kg IV) No effect on 19 receptor binding sites, including: –cholinergic, adrenergic, histaminergic and serotonergic. No effect in tissue responsiveness to arachidonic acid, bradykinin and angiotensin II Cutrell A, Hernandez J, Brothers C et al. 2008

Incidence of Serious CV Events D:A:D Study, VA Study & GSK Data Repository D:A:D VA GSK DR Patient numbers33,00041,21314,680 Total patient f/u, PY156,667168,21312,498 Average patient f/u, yrs Incidence of serious CV events/MI 1.6%4.2%0.31% 0.129% Incidence 1000/PY /1.92 Sabin C, et al. 15th CROI 2008: Abstract. Bozzette S, et al. J Acquir Immune Defic Syndr 2007;0:1-4.