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Development of a Viral Removal Device to Prevent HCV Recurrence Following Liver Transplantation Michael G. Hughes, Jr., MD...
Overview <ul><li>Liver transplantation (LTx) for HCV  </li></ul><ul><ul><li>Removal of diseased, infected liver </li></ul>...
Impact of HCV Recurrence <ul><li>Large problem </li></ul><ul><ul><li>#1 indication for liver transplant in US and world-wi...
Inoculum Size Contributes to Severity of Recurrent HCV Disease <ul><li>Size of pretransplant viral load (inoculum amount) ...
HYPOTHESIS <ul><li>Viral  ELIMINATION  prior to reperfusion of the allograft would  PREVENT RECURRENCE  of HCV disease </l...
LIVER TRANSPLANT AS OPPORTUNITY <ul><li>PRIOR VIRAL REMOVAL DEVICES HAVE FAILED (double filtration plasmapheresis) </li></...
PROPOSED DEVICE:  BIOFILTER FOR HCV
HOW TO REMOVE VIRUS? <ul><li>Filtration based on size likely would not work </li></ul><ul><ul><li>Double filtration plasma...
HOW TO SELECTIVELY BIND AND REMOVE VIRUS? <ul><li>Antibodies </li></ul><ul><ul><li>Monoclonal (synthetic) </li></ul></ul><...
MONOCLONAL ANTIBODIES <ul><li>PRO </li></ul><ul><ul><li>Easy to make </li></ul></ul><ul><ul><ul><li>For others, not myself...
POLYCLONAL ANTIBODIES <ul><li>PRO </li></ul><ul><ul><li>Already available (CIVACIR, Biotest Pharma) </li></ul></ul><ul><ul...
PEPTIDES IDENTIFIED BY PHAGE DISPLAY <ul><li>PRO </li></ul><ul><ul><li>Synthesis should be straightforward </li></ul></ul>...
RECEPTORS FOR HCV <ul><li>PRO </li></ul><ul><ul><li>? </li></ul></ul><ul><li>CON </li></ul><ul><ul><li>Which receptor (8 k...
HEPATOCYTES <ul><li>PRO </li></ul><ul><ul><li>Contain all receptors  </li></ul></ul><ul><ul><li>Allografts have been shown...
HCV Biofilter <ul><li>SUMMARY:  </li></ul><ul><ul><li>Clearance of HCV during the anhepatic phase of liver transplant  cou...
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Development of a Viral Removal Device to Prevent HCV Recurrence Following Liver Transplantation, Michael Hughes, MD

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Transcript of "Development of a Viral Removal Device to Prevent HCV Recurrence Following Liver Transplantation, Michael Hughes, MD"

  1. 1. Development of a Viral Removal Device to Prevent HCV Recurrence Following Liver Transplantation Michael G. Hughes, Jr., MD March 24, 2010 Medical University of South Carolina
  2. 2. Overview <ul><li>Liver transplantation (LTx) for HCV </li></ul><ul><ul><li>Removal of diseased, infected liver </li></ul></ul><ul><ul><li>Persistence of circulating virus </li></ul></ul><ul><ul><li>Implantation of uninfected allograft </li></ul></ul><ul><ul><li>Reperfusion of allograft (restoration of blood flow) results in massive infection </li></ul></ul><ul><ul><li>More rapid HCV-induced disease after transplant compared with primary infection </li></ul></ul>
  3. 3. Impact of HCV Recurrence <ul><li>Large problem </li></ul><ul><ul><li>#1 indication for liver transplant in US and world-wide </li></ul></ul><ul><ul><li>1/3 of nearly 7,000 transplants performed in US </li></ul></ul><ul><li>HCV-positive recipients compared with HCV-negative recipients </li></ul><ul><ul><li>Increased rate of allograft failure </li></ul></ul><ul><ul><li>Increased rate of death </li></ul></ul><ul><li>33% severe graft damage by 5 years (36% graft loss) </li></ul>
  4. 4. Inoculum Size Contributes to Severity of Recurrent HCV Disease <ul><li>Size of pretransplant viral load (inoculum amount) predicts outcomes </li></ul><ul><li>Degree of post-transplant viral load rebound as early as POD#3 predicts severity of recurrent disease </li></ul><ul><li>Recurrence within first year carries at least a three-fold risk of death compared with recurrence at later times </li></ul><ul><li>Elimination of circulating virus prior to transplant prevents recurrence </li></ul>
  5. 5. HYPOTHESIS <ul><li>Viral ELIMINATION prior to reperfusion of the allograft would PREVENT RECURRENCE of HCV disease </li></ul><ul><li>Viral REDUCTION prior to reperfusion of the allograft would </li></ul><ul><ul><li>DIMINISH AND DELAY RECURRENCE of HCV disease </li></ul></ul><ul><ul><li>Or </li></ul></ul><ul><ul><li>PREVENT RECURRENCE of HCV disease when coupled with other interventions (pretreatment of allograft with anti-receptor antibodies) </li></ul></ul>
  6. 6. LIVER TRANSPLANT AS OPPORTUNITY <ul><li>PRIOR VIRAL REMOVAL DEVICES HAVE FAILED (double filtration plasmapheresis) </li></ul><ul><ul><li>Highly efficient viral removal </li></ul></ul><ul><ul><li>Did not impact circulating viral amount </li></ul></ul><ul><ul><ul><li>Diseased liver still producing virus </li></ul></ul></ul><ul><ul><ul><li>Low flow rates (<200 cc/min) </li></ul></ul></ul><ul><li>PROPOSED DEVICE SHOULD SUCCEED BECAUSE </li></ul><ul><ul><li>It would be implemented during during anhepatic phase of liver transplant </li></ul></ul><ul><ul><ul><li>No liver in patient for approximately 60-120 minutes </li></ul></ul></ul><ul><ul><ul><li>No active viral replication </li></ul></ul></ul><ul><ul><li>It would achieve flow rates of 1-2 L/min </li></ul></ul>
  7. 7. PROPOSED DEVICE: BIOFILTER FOR HCV
  8. 8. HOW TO REMOVE VIRUS? <ul><li>Filtration based on size likely would not work </li></ul><ul><ul><li>Double filtration plasmapheresis removed all components of acellular blood >50nm </li></ul></ul><ul><ul><ul><li>Flow rates very limited </li></ul></ul></ul><ul><ul><ul><li>Other blood components essential for safe performance of transplant (fibrinogen) were completely removed </li></ul></ul></ul><ul><li>Biofilter should </li></ul><ul><ul><li>Selectively bind and remove virus </li></ul></ul><ul><ul><li>Leave behind all other blood components </li></ul></ul>
  9. 9. HOW TO SELECTIVELY BIND AND REMOVE VIRUS? <ul><li>Antibodies </li></ul><ul><ul><li>Monoclonal (synthetic) </li></ul></ul><ul><ul><li>Polyclonal (pooled donors) </li></ul></ul><ul><li>Synthetic Peptides </li></ul><ul><ul><li>Synthetic peptides (identified by phage display) </li></ul></ul><ul><ul><li>Known protein receptors for virus </li></ul></ul><ul><li>Human hepatocytes </li></ul><ul><ul><li>Only human and chimpanzee hepatocytes are infected by HCV </li></ul></ul>
  10. 10. MONOCLONAL ANTIBODIES <ul><li>PRO </li></ul><ul><ul><li>Easy to make </li></ul></ul><ul><ul><ul><li>For others, not myself </li></ul></ul></ul><ul><li>CON </li></ul><ul><ul><li>Unlikely to work </li></ul></ul><ul><ul><ul><li>High error rate of RNA dependent RNA polymerase (9 million mutations per day) </li></ul></ul></ul><ul><ul><ul><li>No conserved regions in viral envelope proteins across all individuals (hence no HCV vaccine) </li></ul></ul></ul>
  11. 11. POLYCLONAL ANTIBODIES <ul><li>PRO </li></ul><ul><ul><li>Already available (CIVACIR, Biotest Pharma) </li></ul></ul><ul><ul><ul><li>Anti-HCV antibodies from pooled HCV infected donor serum </li></ul></ul></ul><ul><ul><li>Straightforward to attach to filter (Dr. Xuejun Wen) </li></ul></ul><ul><li>CON </li></ul><ul><ul><li>Not necessarily accessible </li></ul></ul><ul><ul><ul><li>Awaiting response from Biotest </li></ul></ul></ul><ul><ul><li>Unknown whether donors have cleared virus </li></ul></ul><ul><ul><ul><li>May not represent neutralizing antibody </li></ul></ul></ul>
  12. 12. PEPTIDES IDENTIFIED BY PHAGE DISPLAY <ul><li>PRO </li></ul><ul><ul><li>Synthesis should be straightforward </li></ul></ul><ul><ul><ul><li>Again, by others </li></ul></ul></ul><ul><ul><li>May identify new receptor for HCV by BLAST search of HCV binding peptides </li></ul></ul><ul><li>CON </li></ul><ul><ul><li>I have not performed phage display and have not found anyone to collaborate with to figure it out </li></ul></ul>
  13. 13. RECEPTORS FOR HCV <ul><li>PRO </li></ul><ul><ul><li>? </li></ul></ul><ul><li>CON </li></ul><ul><ul><li>Which receptor (8 known)? </li></ul></ul><ul><ul><li>Harder to manufacture? </li></ul></ul>
  14. 14. HEPATOCYTES <ul><li>PRO </li></ul><ul><ul><li>Contain all receptors </li></ul></ul><ul><ul><li>Allografts have been shown to bind all circulating virus </li></ul></ul><ul><ul><li>Liver bio-filters have already been made </li></ul></ul><ul><ul><ul><li>Liver replacement devices </li></ul></ul></ul><ul><ul><ul><li>This is simpler: </li></ul></ul></ul><ul><ul><ul><ul><li>Structure, not function is important </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Only needs to work for 120 minutes </li></ul></ul></ul></ul><ul><li>CON </li></ul><ul><ul><li>Complexity of manufacture </li></ul></ul><ul><ul><li>Ultimate product needs to be available on short notice </li></ul></ul><ul><ul><li>More FDA hurdles? </li></ul></ul>
  15. 15. HCV Biofilter <ul><li>SUMMARY: </li></ul><ul><ul><li>Clearance of HCV during the anhepatic phase of liver transplant could cure HCV </li></ul></ul><ul><li>KEY POINT: </li></ul><ul><ul><li>Implementation would have little impact on existing surgeon practice </li></ul></ul><ul><li>PROBLEMS TO RESOLVE: </li></ul><ul><ul><li>Best way to bind virus (CIVACIR, phage display, hepatocytes) </li></ul></ul><ul><ul><li>Human Hepatocyte Biofilter manufacture </li></ul></ul><ul><li>COLLABORATIONS TO MAKE: </li></ul><ul><ul><li>CIVACIR bound filter: Dr. Xuejun Wen </li></ul></ul><ul><ul><li>Phage display </li></ul></ul><ul><ul><li>Human Hepatocyte Biofilter manufacture </li></ul></ul>
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