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HIV-HBV co-infection

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  1. Lessons from a decade of collaboration in ThailandSharon R LewinProfessor and Head, Department of Infectious Diseases Alfred Hospital and Monash UniversityCo-head, Centre for Biomedical Research, Burnet Institute, Melbourne, AustraliaTrack A Workshop Linking Clinical Cohorts and Basic/ Clinical Science, IAS2013, Kuala Lumpur, Malaysia

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

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

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

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

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

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

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

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

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

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

  12. the benefits of a long term cohort study

  13. TICO and HIVNAT extension study Bx Bx Bx HIV NAT (n=19) HIV NAT EXTENSION – TDF (n=48) TICO (n=36) 2005 2007 2013 + + + + + + + + + + PBMC

  14. Understanding HBV seroconv Gail Matthews 1 April 2013 | Volume 8 | Issue 4 | e61297 HIV NAT (n=19) HIV NAT EXTENSION – TDF(n=48) TICO (n=36) 2005 2007 2013

  15. Immune activation and liver disease LPS, immune activation and liver abnormalities in HIV-HBV coinfected individuals on HBV-active combination antiretroviral therapy Megan 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 Megan Crane HIV NAT (n=19) HIV NAT EXTENSION – TDF (n=48) TICO (n=36) 2005 2007 2013

  16. Vitamin D deficiency Anchalee Avihingsanon HIV NAT (n=19) HIV NAT EXTENSION – TDF (n=48) TICO (n=36) 2005 2007 2013

  17. contribution to a multi-site international cohort study

  18. An international HIV-HBV longitudinal cohort study NIH COHORT (n=170) MACS (n=54) MEL/SYD (n=69) THAI (n=47) Bx Bx Bx HIV NAT (n=19) HIV NAT EXTENSION – TDF (n=48) TICO (n=36) 2005 2007 2011 2013

  19. Drug resistance and abnormal ALT Joe Sasadeusz Jen Audsley November 2011 | Volume 6 | Issue 11 | e26482 NIH COHORT 2005 2007 2013

  20. Suboptimal TDF response Gail Matthews

  21. Understanding resistance to TDF NIH COHORT THAI (n=47) MACS (n=54) MEL/SYD (n=69) Bx Bx Bx HIV NAT (n=19) THAI PATIENTS (n=48) TICO (n=36) 2005 2007 2013 2009 TDF SURVEILLANCE (n=92)

  22. Frequency of TDF resistance IAS 2013 poster, abstract no: 3073 Jen Audsley Frequencies: patterns of HBV viremia on-TDF % of samples with detectable HBV DNA – by study visit 2005 2007 2011 TDF SURVEILLANCE (n=92)

  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

  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) X-sectional (n=70) Mel/Syd (n=30) Thailand (n=40) Longitudinal (n=100) Mel/Syd (n=70) Thailand (n=30) Bx PBMC Plasma PBMC Plasma PBMC Plasma PBMC Plasma PBMC Plasma PBMC Plasma PBMC Plasma 2013 2016

  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. 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 Acknowledgements 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