DOCKs Study A Prospective study of Doxorubicin Cardiotoxicity in Aids-associated Kaposi sarcoma patients ICASA 2015 Dr Godfrey Mungwadzi Prof M.Z. Borok

INTRODUCTION HIV and Heart Disease HIV-CMP(pre-ART) –prevalence % (Africa) 1998 small DRC post-mortem study Toxoplasma gondii 19 % Cryptococcus neoformans 19% Mycobacterium avium intracellulare 12% Direct HIV invasion 50% 1996 Zimbabwe Echo study - abnormalities in 50% Median survival to AIDS-related death -101 (LVD) vs 472 days Mpiko Ntsekhe and James Hakim, Circulation 2005 Hakim J.G. et.al Heart 1996 Barbaro Giuseppe; Circulation; 2002

AIDS-associated Kaposi sarcoma Most prevalent malignancy in AIDS patients Zimbabwe (pre-ART) -5 year survival 4% Deaths in ART programmes (southern Africa) 1- MTB 21% 2- Cryptococcus neoformans 20% 3- AIDS-KS 14% Chemotherapy + HAART › improved & faster RR Doxorubicin is the cornerstone of treatment of KS Borok M.Z. INCTR Annual Meeting, Anatalya, March 2009 Borok M et.al. Cancer Control, 2014, 91 Mosam A. et.al, The KAART Trial (Suppl 1):A80

Anthracycline Cardiotoxicity Cardiotoxicity risk CDD of 450mg/m 2 = 5% ↑ comorbid myocardial & pericardial disease Grade 1: 10% to 20% ↓↓ EF Grade II: > 20% ↓ EF Grade III: CHF Jorge Lax et.al. Argent Cardiol 2013 M. D. Anderson Cancer Centre Cancer and The Heart

Objective To determine the incidence of cardiotoxicity induced after treatment with doxorubicin for AIDS-KS by assessments of clinical exam, ECG (QTc), Troponins [cTn] Brain Natriuretic Peptide (NT- proBNP) changes in left ventricular ejection fraction [EF] Study Design Analytical Prospective cohort

Methodology

6 Excluded 2 EF < 40% With Isolated LVSD 2 With Isolated LVSD 1 LV & LA Dilated 1 Dilated LV Methodology

6 Excluded 2 EF < 40% With Isolated LVSD 2 With Isolated LVSD 1 LV & LA Dilated 1 Dilated LV Methodology

6 Excluded 2 EF < 40% With Isolated LVSD 2 With Isolated LVSD 1 LV & LA Dilated 1 Dilated LV 15 Patients lost to follow up 8 Patients died Methodology

6 Excluded 2 EF < 40% With Isolated LVSD 2 With Isolated LVSD 1 LV & LA Dilated 1 Dilated LV 15 Pts lost to follow up 8 Patients died Methodology

Results Cardiac feature Baseline measure mean (SD) After 5 pulses mean (SD) p-value Ejection Fraction % 61.9(0.78)56.7(1.01)p<0.001 Fractional Shortening % 33.2(0.64)29.6(0.69)p<0.001 NT- proBNP(pg/ml) 132.8(17.67)105.1(11.82)p=0.024 QTc(ms)433(2.01)436(2.72)p=0.152

Cardiotoxicity Incidence Percent reduction change in ejection n% < 520(37.1) 5-<1024(44.4) > (13.0) >203(5.5) Total incidence of cardiotoxicity was 18.5 %

Associated Risk factors OR 95% CI p-value – NT-proBNP

Conclusions AIDS-KS Doxorubicin Rx ► ↑↑ incidence of cardiotoxicity 18.5% vs even ↓↓ doses – 218 vs 450 mg/m 2 Best predictor of cardiotoxicity - Echo EF cTn & BNP ► poor predictors of cardiotoxicity The inverse relationship between BNP & treatment of AIDS-KS needs further Ix An ↑ in [BNP]is a significant risk factor for the development cardiotoxicity

Recommendations Perform baseline Echo (EF) & monitor closely [every 4 pulses] during and after Rx The role of ACEI & - Blockers as cardioprotective agents needs further investigation Use of less cardiotoxic AC [Epirubicin, mitoxantrone & PLD] though expensive need serious consideration

Acknowledgements Professor M.Z. Borok Dr Golden T. Fana Professor J.A Matenga Professor J.G. Hakim The Department of Medicine, KS Patients Professor T.B Campbell Professor Stephen Leong MEPI funding through NIH Grant Number TW and TW ICOHRTA Grant number 2U2RTW from the Fogarty International Centre, National Institutes of Health (NIH, USA)