BK Virus Hans H Hirsch Transplantation & Clinical Virology Department Biomedicine (Haus Petersplatz) Division Infection Diagnostics Department Biomedicine (Haus Petersplatz) University of Basel Infectious Diseases & Hospital Epidemiology University Hospital Basel Switzerland Centre de Conf Centre de Conf ö ö rence rence 28 rue du Docteur Roux 28 rue du Docteur Roux - - 75015 75015 Paris Paris 22.04.2013 22.04.2013
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Egli A, Infanti L, Dumoulin A, Buser A, Samaridis J, Stebler C, Gosert R, Hirsch HH (2009) Prevalence of Polyomavirus BK and JC Infection and Replication in 400 Healthy Blood Donors J Infect Dis 199 : 837-846Dalianis T, Hirsch HH (2013) Human Polyomavirus and Cancer Virology 437: 63 - 72Background
� BK-VP1 and JC-VP1 expression in baculovirus SF9– Virus-like particles (BK-VLP, JC-VLP)
� N= 400 (100 per age decade from 20 – 59yrs) � IgG Seroprevalence
– BKV 82%– JCV 58%
� Viruria– BKV 7% (9%)– JCV 19% (33%)
� No viremia
BKV and JCV Infection and Replication BKV and JCV Infection and Replication in Healthy Blood Donorsin Healthy Blood Donors
Egli A, Infanti L, Dumoulin A, Buser A, Samaridis J, Stebler C, Gosert R, Hirsch HH (2009) Prevalence of Polyomavirus BK and JC Infection and Replication in 400 Healthy Blood Donors J Infect Dis 199 : 837-846
Hirsch HH, Randhawa P and the American Society of Transplantation IDCOP (2013) AST Infectious Disease Community of Practice Guidelines: BK Polyomavirus Update 2012 Am J Transpl 13 (in press)
� Incidence rate 5% (1% - 12%) after kidney transplantation– Functional deficits in ~90%, graft loss in ~50% (range 10% - 90%)
� (Multi-)focal disease, proceeds through histology stages A, B, C� No effective antiviral drug� Treatment by improving immune control = reducing immunosuppression
Large T-antigenAgnoproteinDecoy cell
BK PolyomavirusBK Polyomavirus --associated Nephropathyassociated Nephropathy
Background
The Issues of BKV in Kidney TransplantsThe Issues of BKV in Kidney Transplants
The problem�Irreversible functional decline�Heterogeneous histological presentation
– Refractory interstitial nephritis
�Chronic allograft nephropathy (IF/TA)�Graft loss
The challenge�Widespread viral infection�Complementing risk factors�Lack of early diagnosis�Uncertain response to modulating immunosuppression�No effective antivirals�Uncertainty about retransplantation
Refractory RejectionRefractory Rejection
0
100
200
300
400
500
600
0 20 40 60 80 100 120
Weeks posttransplantation
Ser
um C
reat
inin
e -
- -
(um
ol/L
)
100
1000
10000
100000
1000000
10000000
Pla
sma
BK
VLo
ad -
-
(GE
q/m
L)
AZACsA
AR ARPANAR
PAN Allograftremoval
PANAR
AZAMMFPRE
TAC CsA
Steroids i.v.
Biopsy
Intensified Immunosuppression
Nickeleit V, Hirsch HH, Binet I, Gudat F, Prince O, Dalquen P, Thiel G, Mihatsch MJ (1999) Polyomavirus infection in renal allograft recipients: from latent infection to manifest disease J Am Soc Nephrol 10: 1080Hirsch & Steiger (2003) Polyomavirus BK Lancet Infect Dis 3: 611
Nickeleit V, Hirsch HH, Binet I, Gudat F, Prince O, Dalquen P, Thiel G, Mihatsch MJ (1999) Polyomavirus infection in renal allograft recipients: from latent infection to manifest disease J Am Soc Nephrol 10: 1080Hirsch & Steiger (2003) Polyomavirus BK Lancet Infect Dis 3: 611
Heterogenous HistologyHeterogenous Histology
Courtesy of M.J. Mihatsch & H.Hopfer, Basel
Immunohistochemistry for SV40 large TImmunohistochemistry for SV40 large T --antigenantigen
Courtesy of M.J. Mihatsch & H.Hopfer, Basel
Purighalla et al. 1995 Am J Kid Dis 26: 671
PyVAN without PyVAN without →→→→→→→→ with significant inflammationwith significant inflammation
Gosert R, Rinaldo CH, Funk GA, Egli A, Ramos E, Drachenberg CB Hirsch HH (2008) Polyomavirus BK with rearranged Non-CodingControl Region emerge in vivo in Renal Transplant Patients and increase Viral Replication and Cytopathology J Exp Med 205: 841
BK PyVAN and Plasma BKV loadBK PyVAN and Plasma BKV load
100
1000
10000
100000
1000000
10000000
0
100
200
300
400
500
600
0 20 40 60 80 100 120
Pla
sma
BK
VLo
ad -
-
(GE
q/m
L)
Ser
um C
reat
inin
e -
- -
(um
ol/L
)
Weeks posttransplantation
AZA CsA
AR AR PyVAN
AR PyVAN
Allograft removal
PyVAN AR
AZA MMF PRE
TAC CsA
Steroids i.v.
Biopsy A B C
Nickeleit V, Hirsch HH, Binet I, Gudat F, Prince O, Dalquen P, Thiel G, Mihatsch MJ (1999) Polyomavirus infection in renal allograft recipients: from latent infection to manifest disease J Am Soc Nephrol 10: 1080Hirsch & Steiger (2003) Polyomavirus BK Lancet Infect Dis 3: 611
� BKV plasma viral half-life t 1/2 ~1-2h� Steady-state: High viral turnover ~99% per day� Renal tubular epithelial cell loss ~106 to ~107 /day� In silico model to predict viral cytopathology and clearance
BKV Dynamics after Transplant NephrectomyBKV Dynamics after Transplant Nephrectomy
BK
V lo
ad lo
g10
Funk GA, Gosert R, Comoli P, Ginevri F, Hirsch HH (2008) Polyomavirus BK Replication Dynamics in vivo and in silico to predict Cytopathology and Viral Clearance in Kidney Transplants Am J Transplant 8: 2368Funk GA, Steiger J, Hirsch HH (2006) Rapid dynamics of Polyomavirus BK in Renal Transplant Recipients J Infect Dis 193: 80
[S-Crea]
Weeks post transplant
Nephrectomy
PyVAN pathology and risk of graft lossPyVAN pathology and risk of graft loss
Graft function
Baseline
Slightly impaired
Significantly impaired,progressive failure
False-negativebiopsy, %
PyVANstages
A
B1B2B3
C
Risk ofgraft loss, %
<10
50
>80
10–30
Drachenberg et al. 2004 Am J Transplant 4:2082-92Drachenberg, Papadimitriou 2006 Transpl Inf Dis 8: 68
high-level
Viruria
Viruria
Viremia
NephropathyPyVAN
BKV Viruria and Viremia precedes BKV Viruria and Viremia precedes provenproven PyVANPyVAN
Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, Steiger J (2002) Prospective Study of Polyomavirus type BK Replication and Nephropathy in Renal Transplant Recipients N Engl J Med 2002; 347: 488
Screening for BKV replication
Viremia 78%
www.kdigo.org
1. Schold et al. Transpl Int 20092. Dharnidharka et al. Transplantation 20093. Hirsch et al. NEJM 20024. Bohl Am J Transplant 2007;2:S36–46;5. Brennan et al. Am J Transplant 2005;5:582–94
Risk factors for BKV replication and PyVANRisk factors for BKV replication and PyVAN
� Prospective single-center study of 78 kidney transplants in Basel� Multiple logistic regression analysis for independent risk factors
Hirsch HH et al. N Engl J Med 2002;347:488–96
Risk of BKV and ImmunosuppressionRisk of BKV and Immunosuppression
Adapted from Dharnidharka VR, et al. Transplantation 2009;87:1019–26
Induction: IL2 vs none
Induction: thymoglobulin vs none
CsA based vs tacrolimus based
Azathioprine based vs MMF based
No anti-metabolites vs MMF based
mTORi: yes vs no
Low risk
Adjusted hazard ratio
High risk
0.0 0.5 1.0 1.5 2.0 2.5
Retrospective analysis of BKV treatment within 24 m onths Retrospective analysis of BKV treatment within 24 m onths Organ Procurement and Transplantation Network data Organ Procurement and Transplantation Network data
Risk Factors of BKV ViremiaRisk Factors of BKV Viremia
Hirsch HH, Vincenti F, Friman S, Tuncer M, Citterio F, Wiecek A, Scheuermann E, Klinger M, Pecovitz MD, Prestele H (2013)Polyomavirus BK Replication in De Novo Kidney Transplant Patients Receiving Tacrolimus or Cyclosporine: A Prospective, Randomized, Multicenter Study Am J Transplant 13: 136
1 2 3 6 120
5
10
15
20
BK
vire
mia
(%
)
p=0.048
p=0.004
Tacrolimus
Cyclosporin
p=0.494
p=0.279
p=0.095
Univariate
� International prospective multicenter study >600 de novo kidney transplant patients receiving basiliximab, mycophenolate, prednisone and randomized 1:1 to Cyclosporine (C2) vs Tacrolimus (C0)
� International prospective multicenter study >600 de novo kidney transplant patients randomized 1:1 to Cyclosporine vs Tacrolimus
DIRECT Study: Multivariate at 6 MonthsDIRECT Study: Multivariate at 6 Months
Hirsch HH, Vincenti F, Friman S, Tuncer M, Citterio F, Wiecek A, Scheuermann E, Klinger M, Pecovitz MD, Prestele H (2013)Polyomavirus BK Replication in De Novo Kidney Transplant Patients Receiving Tacrolimus or Cyclosporine: A Prospective, Randomized, Multicenter Study Am J Transplant 13: 136
Risk Factors of BKV ViremiaRisk Factors of BKV Viremia
Hirsch HH, Vincenti F, Friman S, Tuncer M, Citterio F, Wiecek A, Scheuermann E, Klinger M, Pecovitz MD, Prestele H (2013)Polyomavirus BK Replication in De Novo Kidney Transplant Patients Receiving Tacrolimus or Cyclosporine: A Prospective, Randomized, Multicenter Study Am J Transplant 13: 136
Steroids TacrolimusSteroids
TacrolimusMaleAge
1 2 3 6 120
5
10
15
20
BK
vire
mia
(%
)
p=0.048
p=0.004
Tacrolimus
Cyclosporin
p=0.494
p=0.279
p=0.095
Multivariate
Univariate
� International prospective multicenter study >600 de novo kidney transplant patients randomized 1:1 to Cyclosporine vs Tacrolimus
Alemtuzumab Induction in 666 Kidney TransplantsAlemtuzumab Induction in 666 Kidney Transplants
25
Theodoropoulos et al. (2013) Am J Transplant 13: 197
Risk Factors for BKPyVANRisk Factors for BKPyVAN
26
Theodoropoulos et al. (2013) Am J Transplant 13: 197
Graft Survival of 666 Kidney TransplantsGraft Survival of 666 Kidney Transplants
27
Theodoropoulos et al. (2013) Am J Transplant 13: 197
Schaub S, Hirsch HH, Dickenmann M, Steiger J, Mihatsch MJ, Hopfer H, Mayr M (2010) Reducing immunosuppression preserves allograft function in presumptive and definitive polyomavirus-associated nephropathy Am J Transplant 10: 2615
AST Guidelines 2013AST Guidelines 2013
Hirsch HH & Randhawa P (2013) American Society of Transplantation Infectious Disease Community of Practice Guideline: BK Polyomavirus Update 2012 Am J Transplant 13: 179
BKV Viremia and SV40 + HistologyBKV Viremia and SV40 + Histology
Menter T, Mayr M, Schaub S, Mihatsch MJ, Hirsch HH, Hopfer H (2013) Pathology of resolving polyomavirusAssociated nephropathy Am J Transplant 13: in press
Clearance of BKV viremiaClearance of BKV viremia
DefinitivePyVAN(n=13)
PresumptivePyVAN(n=17)
Low BKV viremia(n=18) P value
Clearance of BKV viremia, n (%) 12 (92) 15 (88) 8 (100) 0.60
Months from first BKV viremia to BKV clearance
8.8(2.8–18.5)
4.6(1.2–23.3)
2.9(0.9–4.6)
0.001
Reduction of immunosuppressionto achieve BKV clearance, n (%)
Step 1 2 (17) 8 (53) 8 (100) 0.001
Step 2 6 (50) 7 (47)
Step 3 4 (33) ‒
Schaub S, Hirsch HH, Dickenmann M, Steiger J, Mihatsch MJ, Hopfer H, Mayr M (2010) Reducing immunosuppression preserves allograft function in presumptive and definitive polyomavirus-associated nephropathy Am J Transplant 10: 2615
Challenges persistChallenges persist ……
� Standardizing BKV load measurement– WHO Standard for calibrating in international units– Establishing BKV load as clinical endpoint (“10’000 copies”?)
• Sood et al. (Abstract 1103); Eyileten et al. (Abstract 1093) ATC 2012
� PyVAN histological diagnosis– Quality control Randhawa et al. (Abstract 1096) ATC 2012
– 10th Banff proposal on staging (fibrosis vs inflammation)• Matsutani et al. (Abstract 287) ATC 2012
� Role of BKV-specific immunity as surrogate marker– BKV-specific T-cells and antibody responses
• Hariharan et al. (Abstract 284) ATC 2012
• Dziubianau et al. (Abstract 288) ATC 2012
� Differentiating PyVAN and acute rejection� Diagnosis and treatment of advanced PyVAN
Clearing BKV viremia parallels increasing BKVClearing BKV viremia parallels increasing BKV --specific Tspecific T --cells in bloodcells in blood
RisingBKV viremia
ClearingBKV viremia
RisingBKV viremia
ClearingBKV viremia
Key Results 4
Binggeli S, Egli A, Schaub S, Binet I, Mayr M, Steiger J, Hirsch HH (2007) Polyomavirus BK-Specific Cellular Immune Response to VP1 and Large T-Antigen in Kidney Transplant Recipients Am J Transplant 7: 1131
Large T antigen-spec. T-cells VP1- spec. T-cells
BKVBKV --specific Tspecific T --cells in blood cells in blood afterafter declining viremiadeclining viremia(= not predicting)(= not predicting)
Schachter et al. 2012 Am J Transplant 11: 2443Schachter et al. (Abstract 289) ATC 2012 Interferon-g induced protein 10 (IP10) in Serum.
LT-specific T-cells
VP1-specific T-cells
VP1-specific IgM
BKV viral load
Clearing BKV viremia is linked to selfClearing BKV viremia is linked to self --limiting acute limiting acute interstitial nephritisinterstitial nephritis
Menter T, Mayr M, Schaub S, Mihatsch MJ, Hirsch HH, Hopfer H (2013) Pathology of resolving polyomavirusAssociated nephropathy Am J Transplant 13: in press
Residualinflammation
“Plasma-cellRich” infiltrate
InterstitialInflammatoryinfiltrate
Clearing BKV viremia, graft function, and HLAClearing BKV viremia, graft function, and HLA --DRDR
Menter T, Mayr M, Schaub S, Mihatsch MJ, Hirsch HH, Hopfer H (2013) Pathology of resolving polyomavirusAssociated nephropathy Am J Transplant 13: in press
PyVAN Course PyVAN Course versus versus Acute RejectionAcute Rejection