1. Lessons from a decade of collaboration in Thailand Sharon R Lewin Professor and Head, Department of Infectious Diseases Alfred Hospital and Monash University Co-head, Centre for Biomedical Research, Burnet Institute, Melbourne, Australia Track A Workshop Linking Clinical Cohorts and Basic/ Clinical Science, IAS2013, Kuala Lumpur, Malaysia

2. HIV-HBV co-infection 350 million Hep B HBsAg+ 33 million 3 million HIV

3. HIV NAT: Netherlands Australia Thailand David Cooper Joep Lange Praphan Phanuphak Kiat Ruxrungtham Anchalee Avihingsanon

4. the beginning – tenofovir in co-infection (TICO)

5. The beginning: TICO 2005 LAM / TDF / EFV AZT / TDF / EFV n=36 HIV/HBV Naïve to ART AZT / LAM / EFV 0 24 48 TICO: Tenofovir in co-infection Greg Dore PBMC Liver biopsy + + + + + +

6. TICO: evidence for combination anti- HBV therapy (WHO, DHHS, IAS) Gail Matthews HEPATOLOGY, Vol. 48, No. 4, 2008 2005 TICO (n=36) 2007 Anchalee Avihingsanon

7. A second RCT: HIVNAT023 2005 TCF / FTC / EFV AZT / FTC / EFV n=19 HIV/HBV Naïve to ART 0 24 48 HIV NAT 023 PBMC Liver biopsy + + + + + + Anchalee Avihingsanon Kiat Ruxrungtham

8. Sub-studies of TICO and HIVNAT023 2005 TICO (n=36) HIV NAT (n=19) 2007 Bx HBV-specific T-cells Hepatic flare Immune restoration disease Intrahepatic events Judy Chang Sunee Sirivichayakul Fiona Wightman

9. HBV specific T-cells Judy Chang Megan Crane 2005 TICO (n=36) HIV NAT (n=19) 2007

10. Hepatic flare and HBV-IRD 2005 TICO (n=36) HIV NAT (n=19) 2007 JID 2009:199 (1 April)

11. Intrahepatic Events David Iser 2005 TICO (n=36) HIV NAT (n=19) 2007

12. the benefits of a long term cohort study

13. TICO and HIVNAT extension study 2005 TICO (n=36) HIV NAT (n=19) 20072013 Bx HIV NAT EXTENSION – TDF (n=48) Bx PBMC + + + + +

14. Understanding HBV seroconv Gail Matthews 1 April 2013 | Volume 8 | Issue 4 | e61297 2005 TICO (n=36) HIV NAT (n=19) HIV NAT EXTENSION – TDF(n=48) 20072013

15. Immune activation and liver disease Megan Crane LPS, immune activation and liver abnormalities in HIV-HBV coinfected individuals on HBV-active combination antiretroviral therapy Megan Crane 1,2, Anchalee Avihingsanon 3, Reena Rajasuriar 1,2,4, Pushparaj Velayudham 1,2, David Iser 1, 5, Ajantha Solomon 1,2, Baotuti Sebolao 2,6, Andrew Tran 2,6, Gail Matthews 7, Paul Cameron 1,2, 8, Pisit Tangkitvanich 3, Gregory J Dore 7, Kiat Ruxrungtham 3, Sharon R Lewin 1,2, 8. Under review JID 2005 TICO (n=36) HIV NAT (n=19) HIV NAT EXTENSION – TDF (n=48) 20072013

16. Vitamin D deficiency 2005 TICO (n=36) HIV NAT (n=19) HIV NAT EXTENSION – TDF (n=48) 20072013 Anchalee Avihingsanon

17. contribution to a multi- site international cohort study

18. An international HIV-HBV longitudinal cohort study 2005 TICO (n=36) HIV NAT (n=19) HIV NAT EXTENSION – TDF (n=48) 20072013 Bx THAI (n=47) MACS (n=54) MEL/SYD (n=69) 2011 NIH COHORT (n=170)

19. Drug resistance and abnormal ALT Jen Audsley Joe Sasadeusz 200520072013 NIH COHORT November 2011 | Volume 6 | Issue 11 | e26482

20. Suboptimal TDF response Gail Matthews

21. Understanding resistance to TDF 2005 TICO (n=36) HIV NAT (n=19) THAI PATIENTS (n=48) 20072013 Bx NIH COHORT THAI (n=47) MACS (n=54) MEL/SYD (n=69) 2009 TDF SURVEILLANCE (n=92)

22. Frequency of TDF resistance Jen Audsley 20052007 TDF SURVEILLANCE (n=92) 2011 IAS 2013 poster, abstract no: 3073 Frequencies: patterns of HBV viremia on-TDF % of samples with detectable HBV DNA – by study visit

23. outcomes and lessons learned

24. Capacity building  Immunology –Sunee Sirivichayakul Monash University, Melbourne (Judy Chang)  PBMC QC –Sasiwimol Ubolyam UNSW, Sydney (Philip Cunningham)  Clinical trials –Anchalee Avihingsanon Kirby Institute (Gail Matthews) University of Amsterdam (Joep Lange)

25. Capacity building  Real time PCR –Patcharin Eamyoungn Monash University, Melbourne (Ajantha Solomon)  Fibroscan –HIVNAT team Alfred Hospital (Will Kemp)  Education and training Conference presentations Scientific retreats (HIV NAT)

26. Grant success Funding bodyYearsCIs NIH R212005-2007Lewin NIH R012005-2010+Thai supplement Thio / Locarnini Avihingsanon Gilead TICO qHBsAg TDF surveillance 2005-2007 2009-2011 2009-2013 Dore Matthews Sasadeusz amfAR2012-2013Crane NHMRC2012-2016Lewin Matthews Torresi Crane Avihingsanon NHMRC (fellowship)2009-2012Audsley

27. Lessons learned  Excellent clinical research infrastructure from HIV NAT was critical  Well designed small RCTs with appropriate tissue and blood stored can have a significant impact  Significant natural history studies require long term investment  Capacity building and impacts on patient care should be a top priority

28. Challenges  Costs of training and infrastructure for basic science in low income countries are substantial  Opportunities for local funding in basic science and/or clinical research often limited which has an impact on sustainability

29. future directions

30. Study of Fibrosis and Immune Activation (SOFIA) 2013 X-sectional (n=70) 2016 Bx PBMC Plasma Mel/Syd (n=30) Thailand (n=40) Longitudinal (n=100) Mel/Syd (n=70) Thailand (n=30) PBMC Plasma PBMC Plasma PBMC Plasma PBMC Plasma PBMC Plasma PBMC Plasma

31. HIV Cure studies  Critical that these are also performed in low income countries –Different HIV genotypes –Different levels of immune activation –Community engagement  Thailand already a leader in the field –Early acute infection –Access to tissue  Intervention studies soon to start Jintanat Ananworanich

32. Conclusions  Well designed RCTs and cohort studies with stored tissue are a tremendous resource to ask new research questions as the clinical landscape changes  The investment pays off in publications, grants, training and clinical care  Multiple opportunities for capacity building but significant investment is needed to ensure sustainability

33. Acknowledgements HIVNAT, Bangkok, Thailand Kiat Ruxrungtham Anchalee Avihingsanon Sasiwimol Ubolyam Praphan Phanuphak Jintanat Ananworanich Monash University, Melbourne Judy Chang Megan Crane David Iser Jen Audsley Alfred Hospital, Melbourne Joe Sadadeusz Will Kemp VIDRL, Melbourne Stephen Locarini Scott Bwoden Peter Revill Nadia Warner Kirby Institute, UNSW, Sydney Gail Matthews Greg Dore David Cooper Johns Hopkins, Baltimore, MD Chloe Thio Eric Seaberg St Vincents Hospital, Melbourne Paul Desmond Alex Thompson Amsterdam Institute for Global Health and Development Joep Lange