Lessons from a decade of collaboration in Thailand
Sharon R LewinProfessor and Head, Department of Infectious Diseases Alfred Hospital and Monash UniversityCo-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 / EFVn=36HIV/HBVNaïve to ART
AZT / LAM / EFV
0 24 48
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, 2008
2005
TICO (n=36)
2007
Anchalee Avihingsanon
A second RCT: HIVNAT023
2005
TCF / FTC / EFV
AZT / FTC / EFVn=19HIV/HBVNaïve to ART
0 24 48
HIV NAT 023
PBMC
Liver biopsy
+ + + + + + +
Anchalee Avihingsanon
Kiat Ruxrungtham
Sub-studies of TICO and HIVNAT023
2005
TICO (n=36)HIV NAT (n=19)
2007
Bx Bx
• HBV-specific T-cells• Hepatic flare• Immune restoration disease• Intrahepatic events
Judy ChangSunee
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)
2007 2013
Bx Bx
HIV NAT EXTENSION – TDF (n=48)
Bx
PBMC + + + + + + + + + +
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)
2007 2013
Immune activation and liver disease
Megan Crane
LPS, immune activation and liver abnormalities in HIV-HBV coinfected individuals on HBV-active combination antiretroviral therapyMegan Crane1,2, Anchalee Avihingsanon 3, Reena Rajasuriar 1,2,4, Pushparaj Velayudham 1,2, David Iser1, 5, Ajantha Solomon1,2, Baotuti Sebolao2,6, Andrew Tran2,6, 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)
2007 2013
Vitamin D deficiency
2005
TICO (n=36)HIV NAT (n=19)
HIV NAT EXTENSION – TDF (n=48)
2007 2013
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)
2007 2013
Bx Bx BxTHAI (n=47)
MACS (n=54)MEL/SYD (n=69)
2011
NIH COHORT (n=170)
Drug resistance and abnormal ALT
Jen AudsleyJoe Sasadeusz
2005 2007 2013
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)
2007 2013
Bx Bx Bx
NIH COHORTTHAI (n=47)
MACS (n=54)MEL/SYD (n=69)
2009
TDF SURVEILLANCE (n=92)
Frequency of TDF resistance
Jen Audsley
2005 2007TDF 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 body Years CIsNIH R21 2005-2007 Lewin
NIH R01 2005-2010+Thai supplement
Thio / LocarniniAvihingsanon
Gilead TICO qHBsAg TDF surveillance
2005-20072009-20112009-2013
DoreMatthewsSasadeusz
amfAR 2012-2013 Crane
NHMRC 2012-2016 LewinMatthewsTorresiCraneAvihingsanon
NHMRC (fellowship) 2009-2012 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
BxPBMCPlasma
Mel/Syd (n=30)Thailand (n=40)
Longitudinal (n=100)Mel/Syd (n=70)Thailand (n=30)
PBMCPlasma
PBMCPlasma
PBMCPlasma
PBMCPlasma
PBMCPlasma
PBMCPlasma
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 startJintanat
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
AcknowledgementsHIVNAT, Bangkok, ThailandKiat RuxrungthamAnchalee AvihingsanonSasiwimol UbolyamPraphan PhanuphakJintanat AnanworanichMonash University, MelbourneJudy ChangMegan CraneDavid IserJen Audsley Alfred Hospital, MelbourneJoe SadadeuszWill KempVIDRL, MelbourneStephen LocariniScott BwodenPeter RevillNadia WarnerKirby Institute, UNSW, SydneyGail MatthewsGreg DoreDavid Cooper
Johns Hopkins, Baltimore, MDChloe ThioEric SeabergSt Vincents Hospital, MelbournePaul DesmondAlex ThompsonAmsterdam Institute for Global Health and DevelopmentJoep Lange
