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Development of a Viral Removal Device to Prevent HCV Recurrence
Following Liver Transplantation
Michael G. Hughes, Jr., MDMarch 24, 2010
Medical University of South Carolina
Overview
• Liver transplantation (LTx) for HCV –Removal of diseased, infected liver–Persistence of circulating virus– Implantation of uninfected allograft–Reperfusion of allograft (restoration of
blood flow) results in massive infection–More rapid HCV-induced disease after
transplant compared with primary infection
Impact of HCV Recurrence
• Large problem– #1 indication for liver transplant in US and world-wide– 1/3 of nearly 7,000 transplants performed in US
• HCV-positive recipients compared with HCV-negative recipients– Increased rate of allograft failure– Increased rate of death
• 33% severe graft damage by 5 years (36% graft loss)
Inoculum Size Contributes to Severity of Recurrent HCV Disease
• Size of pretransplant viral load (inoculum amount) predicts outcomes
• Degree of post-transplant viral load rebound as early as POD#3 predicts severity of recurrent disease
• Recurrence within first year carries at least a three-fold risk of death compared with recurrence at later times
• Elimination of circulating virus prior to transplant prevents recurrence
HYPOTHESIS
1. Viral ELIMINATION prior to reperfusion of the allograft would PREVENT RECURRENCE of HCV disease
2. Viral REDUCTION prior to reperfusion of the allograft would – DIMINISH AND DELAY RECURRENCE of HCV disease
Or– PREVENT RECURRENCE of HCV disease when coupled
with other interventions (pretreatment of allograft with anti-receptor antibodies)
LIVER TRANSPLANT AS OPPORTUNITY
• PRIOR VIRAL REMOVAL DEVICES HAVE FAILED (double filtration plasmapheresis)– Highly efficient viral removal – Did not impact circulating viral amount
• Diseased liver still producing virus• Low flow rates (<200 cc/min)
• PROPOSED DEVICE SHOULD SUCCEED BECAUSE– It would be implemented during during anhepatic phase of
liver transplant• No liver in patient for approximately 60-120 minutes• No active viral replication
– It would achieve flow rates of 1-2 L/min
PROPOSED DEVICE: BIOFILTER FOR HCV
HOW TO REMOVE VIRUS?
• Filtration based on size likely would not work– Double filtration plasmapheresis removed all
components of acellular blood >50nm• Flow rates very limited• Other blood components essential for safe
performance of transplant (fibrinogen) were completely removed
• Biofilter should – Selectively bind and remove virus – Leave behind all other blood components
HOW TO SELECTIVELY BIND AND REMOVE VIRUS?
1) Antibodies– Monoclonal (synthetic)– Polyclonal (pooled donors)
2) Synthetic Peptides– Synthetic peptides (identified by phage display)– Known protein receptors for virus
3) Human hepatocytes– Only human and chimpanzee hepatocytes are
infected by HCV
MONOCLONAL ANTIBODIES
1) PRO– Easy to make• For others, not myself
2) CON– Unlikely to work• High error rate of RNA dependent RNA polymerase (9
million mutations per day)• No conserved regions in viral envelope proteins
across all individuals (hence no HCV vaccine)
POLYCLONAL ANTIBODIES
1) PRO– Already available (CIVACIR, Biotest Pharma)• Anti-HCV antibodies from pooled HCV infected donor
serum– Straightforward to attach to filter (Dr. Xuejun Wen)
2) CON– Not necessarily accessible• Awaiting response from Biotest
– Unknown whether donors have cleared virus• May not represent neutralizing antibody
PEPTIDES IDENTIFIED BY PHAGE DISPLAY
1) PRO– Synthesis should be straightforward• Again, by others
– May identify new receptor for HCV by BLAST search of HCV binding peptides
2) CON– I have not performed phage display and have not
found anyone to collaborate with to figure it out
RECEPTORS FOR HCV
1) PRO– ?
2) CON– Which receptor (8 known)?– Harder to manufacture?
HEPATOCYTES1) PRO– Contain all receptors – Allografts have been shown to bind all circulating virus – Liver bio-filters have already been made
• Liver replacement devices• This is simpler:
– Structure, not function is important– Only needs to work for 120 minutes
2) CON– Complexity of manufacture– Ultimate product needs to be available on short notice– More FDA hurdles?
HCV Biofilter1) SUMMARY: – Clearance of HCV during the anhepatic phase of liver
transplant could cure HCV2) KEY POINT:– Implementation would have little impact on existing surgeon
practice3) PROBLEMS TO RESOLVE: – Best way to bind virus (CIVACIR, phage display, hepatocytes)– Human Hepatocyte Biofilter manufacture
4) COLLABORATIONS TO MAKE:– CIVACIR bound filter: Dr. Xuejun Wen– Phage display– Human Hepatocyte Biofilter manufacture