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

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

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

the beginning – tenofovir in co-infection (TICO)

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

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

A second RCT: HIVNAT TCF / FTC / EFV AZT / FTC / EFV n=19 HIV/HBV Naïve to ART HIV NAT 023 PBMC Liver biopsy Anchalee Avihingsanon Kiat Ruxrungtham

Sub-studies of TICO and HIVNAT 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

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

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

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

the benefits of a long term cohort study

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

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

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)

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

contribution to a multi- site international cohort study

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

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

Suboptimal TDF response Gail Matthews

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

Frequency of TDF resistance Jen Audsley 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

outcomes and lessons learned

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)

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)

Grant success Funding bodyYearsCIs NIH R Lewin NIH R Thai supplement Thio / Locarnini Avihingsanon Gilead TICO qHBsAg TDF surveillance Dore Matthews Sasadeusz amfAR Crane NHMRC Lewin Matthews Torresi Crane Avihingsanon NHMRC (fellowship) Audsley

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

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

future directions

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

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

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

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