Higher rate of antiretroviral therapy reinitiation among HIV-HBV coinfected patients in the episodic arm of the SMART study Dore G.1, Soriano V.2, Neuhaus J.3, Peters L.4, Puoti M.5, Rockstroh J.6, Klein M.7, Tedaldi E.8, Mocroft A.9, Clotet B.10, Lundgren J.4, The SMART study group and INSIGHT 1. National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia, 2. Service of Infectious Diseases, Hospital Carlos III, Madrid, Spain, 3. School of Public Health, University of Minnesota, Minnesota, United States, 4. Copenhagen HIV Programme, Hvidovre University Hospital, Copenhagen, Denmark, 5. Institute of Infectious and Tropical Diseases, Brescia, Italy, 6. Medizinische Universitaetsklinik, Bonn, Germany, 7. Montreal Chest Institute, Royal Victoria Hospital, Montreal, Canada, 8. Temple University School of Medicine, Philadelphia, United States, 9. Royal Free and University College Medical School, London, United Kingdom, 10. Hospital Universitari Germans Trias I Pujol, Badalona, Spain

SMART: ART reinitiation by hepatitis status Background HBV (5 – 10%) and HCV (10 – 30%) are common coinfections among HIV infected populations HIV associated with higher HBV DNA and HCV RNA levels Increased liver disease mortality in HIV-HCV and HIV-HBV compared to monoinfected populations, even in era of HAART Increasing use of dual HIV/HBV active agents in setting of HIV-HBV coinfection SMART study presents an ideal opportunity to examine HIV-hepatitis immunopathogenesis This international study was designed to address the question of whether HIV management with ART could be done differently to allow sparing use of ART minimising cost and toxicity. Clinical endpoint study which will allow us to say whether these strategies improve quality of life minimising toxicity but maintains HIV control and does not lead to an increase in clinical events

CD4 cell count > 350 cells/mm³ Virologic Suppression SMART study design CD4 cell count > 350 cells/mm³ N=5472 Virologic Suppression (VS) Strategy continuous ART N=2752 Drug Conservation (DC) Strategy defer ART until CD4 <250; then episodic ART until CD4 >350 N= 2720 SMART, which is an acronym for Strategic Management of Antiretroviral Therapy, is a large randomized clinical trial, which studied CD4 cell count guided interruption of antiretroviral therapy. 5472 patients, with a CD4 cell count of more than 350/ml, were included and assigned to either continuous use of antiretroviral therapy (the viral suppression,VS, arm) or the drug conservation (DC) arm where the patients received episodic ART based on the CD4 cell count. In this group ART was deferred until the CD4 cell count decreased below 250 cells/ml and then the patients were on therapy until the CD4 cell count had increased to more than 350/ml The patients were followed for an average of 16 months El-Sadr WM et al, N Engl J Med 2006; 355:2283-2296.

SMART: ART reinitiation by hepatitis status SMART study Median follow-up 16 months Primary endpoint: opportunistic disease or death higher in DC (3.3/100 py) than VS (1.3/100 py) group (HR=2.6, 1.9 – 3.7). El-Sadr WM et al, N Engl J Med 2006; 355(22):2283-2296 SMART eligibility allowed HBsAg+ and anti-HCV+, had no ALT-based exclusion, but recommended that subjects requiring continued ART for management of hepatitis should not be enrolled. HBsAg 2.0%; anti-HCV 14.6%; HBV/HCV 0.3% This international study was designed to address the question of whether HIV management with ART could be done differently to allow sparing use of ART minimising cost and toxicity. Clinical endpoint study which will allow us to say whether these strategies improve quality of life minimising toxicity but maintains HIV control and does not lead to an increase in clinical events

SMART: ART reinitiation by hepatitis status Objective To examine rates of ART reinitiation within the DC (episodic) group of the SMART study according to baseline hepatitis status Sub-groups: 1) HBV; 2) HCV; 3) non-HBV/HCV ART reinitiation examined by Kaplan-Meier analysis Cox proportional hazard models adjusting for age, gender, prior AIDS, baseline and nadir CD4 count, and HIV viral load This international study was designed to address the question of whether HIV management with ART could be done differently to allow sparing use of ART minimising cost and toxicity. Clinical endpoint study which will allow us to say whether these strategies improve quality of life minimising toxicity but maintains HIV control and does not lead to an increase in clinical events

SMART: ART reinitiation by hepatitis status Baseline characteristics in DC group HBV (n=65)* HCV (n=402) Non-HBV/HCV (n=2202) Median age (years) 43 41 46 Median baseline CD4 (/mm3) 560 608 595 Baseline HIV-RNA <400 (%) 71 68 72 Median nadir CD4 (/mm3) 207 265 250 Median highest HIV-RNA (log10) 4.7 4.9 Prior AIDS (%) 28 27 24 ART at entry (%) 80 82 85 3TC/FTC, not tenofovir (%) 45 55 57 Tenofovir, not 3TC/FTC (%) 6 5 3TC/FTC and tenofovir (%) 17 12 * Includes 6 subjects with HBV/HCV

SMART: ART reinitiation by hepatitis status ART reinitation in DC group HBV (n=65) HCV (n=402) Non-HBV/HCV (n=2202) Reinitiated ART (%) 63.1 45.5 39.2 Median CD4 at reinitiation (/mm3) 233 240 232 <150 (%) 4.9 8.3 10.1 150 – 249 (%) 61.0 47.0 49.8 250 – 349 (%) 26.8 19.9 19.7 350 – 449 (%) 7.3 10.5 8.1 450+ (%) 0.0 14.4 12.3

SMART: ART reinitiation by hepatitis status Reasons for ART reinitiation in DC group HBV (n=65) HCV (n=402) Non-HBV/HCV (n=2202) CD4 count <250 65.9% 54.6% 59.6% Low CD4% 31.7% 31.1% 27.2% Rapid CD4 decline 24.4% 16.4% 21.6% HIV-related symptoms 7.3% 10.9% 10.6% Progression of HIV disease 0.0% 5.5% 2.8% High HIV-RNA 17.1% 24.0% 20.6% Patient wish 22.0% 28.4% 22.8% Other 19.5% 18.5% 16.0%

SMART: ART reinitiation by hepatitis status

SMART: ART reinitiation by hepatitis status Multivariate model of predictors of ART reinitiation Hazard ratio P value HBV 1.67 (1.22 – 2.29) 0.0014 HCV 1.03 (0.88 – 1.21) 0.70 Prior AIDS 1.41 (1.23 – 1.61) <0.0001 Nadir CD4 count (/100 cells) 0.67 (0.63 – 0.71) Baseline CD4 (/100 cells) 0.87 (0.85 – 0.90) Baseline HIV-RNA <400 c/ml 1.19 (1.04 – 1.37) 0.012 Highest HIV-RNA 1.19 (1.11 – 1.28) Female 0.98 (0.85 – 1.12) 0.75 Age (per 10 years) 1.14 (1.07 – 1.21) 0.0001

SMART: ART reinitiation by hepatitis status Conclusions / discussion HIV-HBV coinfected patients have a higher rate of ART reinitiation (not seen in HIV-HCV coinfected) Higher ART reinitiation due largely to faster decline to CD4 <250 Hepatic flare or reinitiation at higher CD4 counts does not explain higher rate Impact of HBV-DNA rebound on ART reinitiation will be explored Potential insights into HIV-HBV immunopathogenesis This international study was designed to address the question of whether HIV management with ART could be done differently to allow sparing use of ART minimising cost and toxicity. Clinical endpoint study which will allow us to say whether these strategies improve quality of life minimising toxicity but maintains HIV control and does not lead to an increase in clinical events

Acknowledgements INSIGHT HIV/Hepatitis sub-group: Dore G, Soriano V, Neuhaus J, Peters L, Puoti M, Rockstroh J, Klein M, Tedaldi E, Mocroft A, Clotet B, Lundgren J SMART investigators who collected these data, the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) Executive Committee for their oversight of the SMART study and valuable editorial assistance. SMART was supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID); U01AI68641, U01AI042170 and U01AI46362. The NCHECR is funded by the Australian Commonwealth Department of Health and Ageing and is affiliated through the Faculty of Medicine with The University of New South Wales.