Future Research agenda for Latin America Marcelo Silva MD Head of Liver and Transplant Units, Hospital Universitario Austral Board Member of the Clinical Research Unit, School of Biomedical Sciences Universidad Austral
Future Research agenda for Latin America
Marcelo Silva MDHead of Liver and Transplant Units, Hospital Universitario Austral
Board Member of the Clinical Research Unit, School of Biomedical SciencesUniversidad Austral
Future Research agenda for Latin America
Liver Research Fields:1. Viral Hepatitis
• (HAV, HBV, HCV, HDV, HEV)
2. NAFLD3. Alcohol‐induced liver disease4. Drug‐induced liver injury5. Autoimmune diseases6. Metabolic diseases7. Fibrosis and Cirrhosis8. Portal Hypertension9. Hepatocellular carcinoma10. Liver Transplantation
Types of Liver Research:1. Epidemiological2. Basic:
• Virology• Pathology• Immunology• Molecular biology• Fibrosis• Oncology
3. Translational4. Clinical5. Cost effectiveness
Where do we stand in Latin American Region ?
1. Good individual (KOL) efforts2. Low rate of collaborative studies within each country,
even less among different countries3. Lack of interdisciplinary research approaches4. Scanty federal budgets for basic scientists, few
translational research if any5. Most Government Health Offices don´t allocate funds
for clinical nor epidemiological research, and ususallyhave no “interest” to raise the field
6. Scientific Societies do not handle adequate budgets to support research and do not have professional organizations to help fund raising
Pharma companies like physicians, scientific societies and policy makers also have an opportunity to improve:
• They have prioritized: their own drug pipelines short term revenues Focused on battling for market share more than
it’s growth (strong marketing orientation with low research and awareness investment in the region)
• University Centers and their P.I./ opinion leaders, as key players, have been out of the game in this region
Where do we stand in Latin American Region ?
Where do we stand in Latin American Region ?
There is a great need for: enhance awarenessmultiply medical education expand research and develop local scientific data
Bottle neck: Low federal and private research resources Lack of tax deduction benefits to benefactors
Hep‐Net: a German Liver Foundation initiative as an example to follow
M Manns RC3 Conqueror Coalition, Panama 2010
12.06.2013
1. INCREASE PUBLIC AWARENESS and EDUCATION : Increase prevention, early identification of patients with hepatitis and optimization of therapies
2. Horizontal and vertical networking to optimize diagnosis and therapy of viral hepatitis
3. Transfer of knowledge: Fast transfer from “Bench to Bedside“
Aims of the Network
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Areas of Intervention
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HEALTHY LIVER
INFLAMMATION
CIRRHOSIS
HCC
InformationVaccination
Early diagnosisTreatment
12M Manns RC3 Conqueror Coalition, Panama 2010
Website German Liver Foundation • Information for Patients, e.g. Flyers
• Liver Tests
• Information for Health Care
Professionals
• Intranet for Associate Members
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Information
Home Page: Visits per month
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Information Information for patients and physicians
Telefone hotline
Homepage
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6/12/2013
Information Public Awareness Campaigns„Hepatitis B vaccination of German Olympic Team 2008“
Oliver Roggisch (World Champignon Handball 2007)„Vaccination is important“
Eike Onnen (German Champignon High Jump)„Now I feel safe“
16M Manns RC3 Conqueror Coalition, Panama 2010
www.hep‐net.de
2007
Cornberg et al, Z. Gastroenterol. 2007; J Viral. Hep, 2008 51M Manns RC3 Conqueror Coalition, Panama 2010
advanced liver fibrosisliver cirrhosis
testing of HBV‐DNA and ALT
every 3‐6 monthstherapy indication
HBV‐DNA ≥ 104 cop/ml (2x103 IU/ml)
no yes
detectable HBV‐DNA (PCR)
yes no
ALT > 2xtimes ULN or
histology >A1/F1
yes
no yes
Risk factors for HCCother indications
(i.e. extrahepatic manifestations)
no yes
testing of HBV‐DNA and ALT
every 3 (ALT elevated) otherwise
every 6 months
no
Cornberg et al., Z Gastroenterol. 2007 Jun;45(6):525‐74. Cornberg et al., Z Gastroenterol. 2007 Jun;45(6):525‐74.
German Guidelines: Chronic HBV TherapyChronic Hepatitis B
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Implementation of Guidelines
6/12/2013
Conferences, Seminars Short versions of the Guideline
Telephone Hotline, E‐Mail consulting, Homepage etc…
50M Manns RC3 Conqueror Coalition, Panama 2010
12.06.2013
1. INCREASE PUBLIC AWARENESS : Increase prevention, early identification of patients with hepatitis and optimization of therapies
2. Horizontal and vertical networking to optimize diagnosis and therapy of viral hepatitis
3. Transfer of knowledge: Fast transfer from „Bench to Bedside“
Aims of the Network
24M Manns RC3 Conqueror Coalition, Panama 2010
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Vertical Networking
> 12
00 associate m
embe
rs
Horizontal Networking (26 Universities, Research sites)
Municipal Hospitals
Private Practitioners
Patients (Advocacy Groups)
Universities
Public (i.e. pupils)
25M Manns RC3 Conqueror Coalition, Panama 2010
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• Acute Hepatitis B and C• Co‐infections (i.e. HBV/HCV, Delta Hepatitis)• Special patient groups
• … registration trials in these fields are not pushed by the industry
Investigators initiated trials only possible with a structure such as HEP‐NET
Unmet Need for Investigator initiated trials (IIT)
More than20 clinical trials since 2002
27M Manns RC3 Conqueror Coalition, Panama 2010
20
HEP‐NET Acute HCV‐II Study
P. Strohbach, C. Gartung, S. Matern (Aachen), U. Welter, H. Knechten (Aachen), K. Striepeke, M. Schüller (Bad Driburg), M. Seifert, E. Pape (Bad Driburg), J. Kröninger (Bad Sachsa), Dr. Zboril, H.J. Weis (Bamberg), A. See (Battenberg); A. Bergk, V. Weich, B. Wiedenmann (Berlin), A. Jansen, M. Zeitz (Berlin), U. Gottschalk (Berlin), C. John (Berlin), B. Hintsche (Berlin), A. Baumgarten (Berlin), B. Muckelbauer, M. Vogt (Breitengüßbach), B. Rühlmann (Bremen), B. Kohler (Bruchsal), H. Wietholtz(Darmstadt), U. Müller, J. Epping (Dortmund), E. Zehnter (Dortmund), H. Kinkel, PD Dr. Pauletzki (Düren), K. Koop, S. Bein, G. Gerken (Essen), B. Dürr, K. Haag (Frankfurt‐Höchst), L. Schneider (Fürth), P. Geyer (Fulda), J. Stadick, M. Keles, T. Schneider (Fürth), T. Heidenreich (Gevelsberg), R.D. Hanrath (Hagen), W.E. Fleig (Halle), B. Seegers, K. Wursthorn, H. Greten(Hamburg), K. Borchert, K. Deterding, A. Potthoff, H.L. Tillmann, C. Trautwein (Hannover), C.Maass, A. Tromm (Hattingen), W. Stremmel (Heidelberg), D. Hüppe (Herne), A. Wolf (Herrenberg), Dr. Becker (Herrenberg), M. v. Wagner, U. Mihm, J. Fischinger (Homburg), M. Wiese (Leipzig), C. Bernsmeier, H. Hinrichsen, U.R. Fölsch (Kiel), N. Hoffmann, T. Göser (Köln), W. Tekolf (Lemgo), A. Bühl, J.F. Riemann (Ludwigshafen), T. Hütteroth (Lübeck), H. Hillenbrand, F. Tieringer, P. Galle (Mainz), L. Kurtsiefer (Mönchengladbach), K. Zemke, R. Götz (Moers), H. Schuppan (Moers), O. Oehm (Niederwerrn), H. Gröpel, H. Schönekäs (Nürnberg), C. Niederau (Oberhausen), Dr. Endemann, Dr. Friedrich, Dr. Rockmann, J. Schölmerich (Regensburg), H. Pernice (Riedlingen), H. Burghardt (Rockenhausen), M. Lafrenz, E.C. Reisinger (Rostock), H. Schiel (Schwäbisch Hall), P. Steinbach, W. Koch (Schweinfurt), C. Meibaum (Schwelm), I. Rimbach (Schwerte), U. Tappe, R. Müller (Siegburg), E. Schnaitmann, A. Trein (Stuttgart), H. Ruppin (Tauberbischofsheim), S. Kaiser, M. Gregor (Tübingen), M. Fuchs, G. Adler (Ulm), J. Schmidt, W. Holtkamp (Westerstede), D. Schaps (Wilhelmshaven), C. Genters, P. Herzog (Wilhelmshaven), H. Klinker, K. Wilms (Würzburg), W. Stimming (Wuppertal)
89 Patients in 53 centers
18 Universities26 Community hospitals09 Private Practices
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Al‐Eryani (Arnsberg), Allescher (Garmisch Part.), Arbter (Mutlangen), Bästlein (Köln) Berthold (Wetzlar), Bey/Thießen (Lemgo), Böcher (Mainz), Buggisch (Hamburg), Cordes (Frankfurt), Dikopoulos (Ulm), Doberauer (Gelsenkirchen), Feyerabend (Hagen), Fleig (Halle), Frank
(Marburg), Franke (Hamminkeln), Frieling/Kreysel (Krefeld), Gerken (Essen), Geyer (Fulda), Göbel/Lößner (Cottbus), Günther/Kataev (Kiel), Gutberlet (Bremen), Haas (Frankfurt/Main), Hackenberg (Bergisch Gladbach), Haßkamp (Osterholz), Herzog (Wilhelmshaven), Heyer/Triller
(Düren), Hoffmann (Köln Kalk), Höhler (Recklinghausen), Hüppe (Herne), John (Berlin), Kaiser/Bissinger (Tübingen), Kehl (Wesel), Kern (München), Kirsch/Lehmann (Dresden), König
(Bautzen), Kordes (Emden), Krichbaum (Wittlich), Kröger (Bünde), Lippert (Hamburg), Lochs/Berg/Weich (Berlin), Lohnstein (Augsburg), Malfertheiner/Csepregi(Magdeburg),
Manns/Wedemeyer(Hannover), Muthwill (Düsseldorf), Pape/Grüner (München), Petrasch (Duisburg), Pfäffl (Nürnberg), Polzien (Braunschweig), Probst (Augsburg), Reiser (Bochum), Restrepo (Marburg), Rösch (Würzburg), Schäfer (Xanten), Schmidt/Schlenker (Heidelberg), Schubert/Göser (Köln), Schuppert/Krautheim (Bad Oeynhausen), Settele (Zirndorf), Singer (Mannheim), Spelter (Wuppertal), Spengler (Bonn), Sprung (Brühl), Stadick (Fürth), Stalter
(Landau), Stich (Würzburg), Theis (Witten), Tillmann/Wiegand (Leipzig), Többe (Ankum), Wehr (Coburg), Wiedmann (Regensburg), Witthöft (Lübeck), Zehnter (Dortmund),
Zeuzem/Kronenberger (Frankfurt M.)
Hep‐Net Acute HCV‐III Study
12.06.2013
72 centers in Germany recruited 108 patients from 2004 to 2008
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HBV/HCV CoinfectionSofar limited studies for therapy of HBV / HCV coinfection
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The Hep‐Net/International Delta Hepatitis Intervention Trial (HIDIT‐1)
91 patients in 6 monthsWedemeyer, Yurdaydin, …….Manns, EASL 2007 45
M Manns RC3 Conqueror Coalition, Panama 2010
Hep ‐ Net Research´s output
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National and International Recommendations for Therapy of
- Acute Hepatitis C- Hepatitis B/Hepatitis C Coinfection- Hepatitis Delta- Chronic Hepatitis C
Are based on Hep-Net Study results
Worldwide largest Study on the efficacy of Amantadin in chronic hepatitis C results in recommendation not to use Amantadin in HCV(PRAMA Study, von Wagner et al., Hepatology 2008)
48M Manns RC3 Conqueror Coalition, Panama 2010
12.06.2013
1. INCREASE PUBLIC AWARENESS : Increase prevention, early identification of patients with hepatitis and optimization of therapies
2. Horizontal and vertical networking to optimize diagnosis and therapy of viral hepatitis
3. Transfer of knowledge: Fast transfer from “Bench to Bedside“
Aims of the Network
58M Manns RC3 Conqueror Coalition, Panama 2010
From Bench to Bedside Translational Research
12.06.2013
Nature Biotechnology 26, 335 - 341 (2008)
Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope proteinJoerg Petersen1,7, Maura Dandri1,7, Walter Mier2, Marc Lütgehetmann1, Tassilo Volz1, Fritz von Weizsäcker3,6, Uwe Haberkorn2, Lutz Fischer4, Joerg-Matthias Pollok4, Berit Erbes5, Stefan Seitz5 & Stephan Urban5
Journal of Virology, February 2005, p. 1613-1622, Vol. 79, No. 3Efficient Inhibition of Hepatitis B Virus Infection by Acylated Peptides Derived from the Large Viral Surface ProteinPhilippe Gripon,1 Isabelle Cannie,1 and Stephan Urban2*
Phase I‐Study 2010
Hep-NetStart-Up Fund
Journal of Hepatology 2005, Volume 42, Issue 1, Pages 54-60Chronic infection with hepatitis B viruses and antiviral drug evaluation in uPA mice after liver repopulation with tupaia hepatocytesMaura Dandria†, Martin R. Burdaa†, David M. Zuckermanb, Karsten Wursthorna, Urte Matschla, Joerg M. Pollokc, Xavier Rogiersc, Andreas Gochtd, Josef Köcke, Hubert E. Blume, Fritz von Weizsäcker, Joerg Petersen
59M Manns RC3 Conqueror Coalition, Panama 2010
The Research Network Virtuous Cycle: Integrated Research
Basic Research
Epidemilogic and Clinical Research
Development
Patient Care Medicine Medical Education
Community Applied Research
Why such a network should be developed in the Region ?
• Public policy makers in most of Latin American countries demonstrated at least lack of interest in the impact of chronic liver diseases
• Pharmaceutical industry “messages” are usually not well taken nor understood due to their bias
• An academic network has a “neutral” profile which favors acting as bridge among different health‐care players: policy makers, community physicians, scientists, patients, general population and pharma companies
• Locally produced data published in peer review journals have greater upon policy makers and colleagues
• Need for local data, eg: 1) prevalence data adjusted to local risk factors,
gender and age2) cost effectiveness of different treatments strategies3) local host genetic resistance factors: genomics &
proteomics
Why such a network should be developed in the Region ?
Liver Latin American Research Education and Awareness Network
Processes
Supportive Systems
AgreementsDesired Results Guideliness
Resources Accountability Consequences
Relationships
CharacterIntegrity maturity Abundance Mentality
Key players and the five dimensions of win‐win
Health Policy Makers
Who should come on board ?
A strong and committed group of KOL and researchers with the same strategic vision:
• “ Integrated, Clinical & Epidemiological Research is associated to a better health related system”
• A network which shall:
– Improve medical education– Enhance awareness of liver diseases– Expand access to therapy– Serve as a bridge between patients, health care policy
makers, physicians, pharmaceutical industry and non profit organizations