HIV-HBV co-infection

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