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1 Prevention of Cytomegalovirus infection following solid-organ transplantation: from guidelines to bedside Oriol Manuel, MD Infectious Diseases Service and Transplantation Center University Hospital and University of Lausanne Lausanne, Switzerland

2 Outline Introduction: the transplant troll Prevention of CMV disease: prophylaxis vs. preemptive Novel methods for risk stratification Conclusions

3 Cytomegalovirus in organ transplantation The transplant Troll in the 70 s 12/60 patients (20%) developed lethal CMV disease CMV disease was associated with a significantly increased incidence of transplant nephrectomy and death The only patients to die with serious bacterial, fungal or protozoan infection during the period of this study had concomitant overt CMV disease Peterson DK et al. Medicine 1980; 59: 283

4 Direct effects CMV infection Immunomodulatory effects CMV pneumonitis Pneumocystis Chronic dysfunction

5 Direct effects CMV infection Immunomodulatory effects CMV pneumonitis Pneumocystis Chronic dysfunction

6 Risk factors for CMV in solid-organ High transplant recipients Risk Category Intermediate* Low * D+/R+ generally at higher risk than D-/R+ Donor (D) or Recipient (R) Seropositivity (+/-) D+/R- D+/R+, D-/R+ D-/R-

7 CMV disease according to CMV Freedom of CMV disease serostatus in the STCS 1234 SOT recipients D-/R-: 0.8% R+: 3.6% D+/R-: 15% Time from transplant (years) Manuel O et al. ATC 2012 and submitted for publication

8 Prevention of CMV disease Antiviral prophylaxis Antiviral prophylaxis Transplantation Late-onset CMV disease Antiviral therapy ~20% in D+/R- < 5% in R+

9 Incidence of late-onset CMV disease in Patients with no investigatortreated CMV disease (%) Prophylactic period high-risk patients Time post-transplant (days) Ganciclovir, oral 3 g Valganciclovir, 900 mg Paya C et al. Am J Transplant 2004; 4:611

10 Event-free probability 50% reduction in CMV disease in the month prophylaxis arm 0.6 VGCV-100 days VGCV-200 days Study day Humar A et al. Am J Transplant 2010; 10: 1228

11 Proportion of patients with BPAR at 12 months (%) Rates of acute rejection and graft loss VGCV-100 days VGCV-200 days Proportion of patients with graft loss at 12 months (%) p = 0.11 p = VGCV-100 days VGCV-200 days Humar A et al. Am J Transplant 2010; 10; 1228

12 Creatinine levels in patients with/without late-onset CMV disease CMV disease free patients CMV disease patients Lamoth F et al. Transplantation 2008; 86: 1323

13 Prevention of CMV disease Preemptive therapy PCR / pp65 Transplantation CMV disease Antiviral therapy < 5% in R+

14 Prophylaxis/Preemptive and risk of CMV disease Prophylaxis Control Preemptive Control Kalil A et al. Ann Intern Med. 2005; 143: 870

15 CMV disease according to preventive strategy: the STCS D+/R- patients, n=236 R+ patients, n=719 p=0.06 p=0.08 Manuel O et al. ATC 2012 and submitted for publication

16 Direct effects CMV infection Immunomodulatory effects CMV pneumonitis Pneumocystis Chronic dysfunction

17 CMV replication and increased risk of cardiovascular disease in SOT recipients p= % 13.3% 18.2% Courrivaud C et al. J Infect Dis 2013

18 Prophylaxis Prophylaxis and risk of death / rejection Control Prophylaxis Control Khalil. Ann Intern Med. 2005; 143: 870

19 Preemptive vs. Prophylaxis n= 130 Better graft survival in the prophylactic group Long-Term Outcomes n= 70 Better graft survival in the preemptive group Kliem V, et al. Am J Transplant 2008;8:975 Reischig T, et al. J Am Soc Nephrol 2012;23:1588

20 Graft loss/death according to preventive 1239 SOT recipients (all) strategy 976 kidney or liver transplant recipients p=0.04 p=0.006 Manuel O et al. to be presented at ATC 2013

21 Prophylaxis vs. Preemptive Therapy Prophylaxis Pre-emptive Evidence of efficacy Indirect effects/mortality ++ + Costs Higher drug costs Higher lab costs Ease ++ +/- Late onset disease ++ (D+/R-) - Resistance Very Low Low Razonable R et al. Am J Transplant 2013; 13: s93

22 High-risk (D+/R-, lung transplant, thymoglobulin): prophylaxis R+: prophylaxis /preemptive approach Kotton CN et al. Transplantation 2010; 89:779 Razonable R et al. Am J Transplant 2013; 13: S93

23 CMV in 2013 Prevention strategies have reduced CMV-associated morbidity and mortality Life-threatening CMV disease rarely seen Similar efficacy of prophylaxis and preemptive Controversial data on the significance of indirect effects in the current era More evidence for a better protection with antiviral prophylaxis

24 Other strategies to decrease late-onset CMV disease Prediction of late-onset CMV disease by analyzing cell-mediated immunity CMV vaccine Genetic markers of susceptibility

25 Host response to CMV Innate immunity TLR-2, TLR-4 Mannose-binding lectin deficiency NK activation Host response to CMV Production of neutralizing antibodies Adaptive immunity TNF-α Il-2 IFN-γ Helper CD4+ lymphocytes Cytotoxic CD8+ lymphocytes

26 Cell-mediated immunity assays MHC-peptide tetramer and/or ELISPOT Quantiferon-CMV ICS-assisted analysis Khanna R. Clin Microbiol Rev 2009; 22: 76

27 Cell mediated immunity and the prediction of CMV disease in SOT recipients: a multicenter study 127 D+/R- SOT recipients from 13 centers in US, Canada and Europe CMI CMI CMI Transplant 3 months 4 months 5 months 12 m D+ / R- Prophylaxis CMV disease Assessment Manuel O et al. Clin Infect Dis 2013; 56: 817

28 CMV disease according to Quantiferon- CMV assay Positive vs. Non-reactive p=0.024 Quantiferon positive Quantiferon non-reactive Manuel O et al. Clin Infect Dis 2013; 56: 817

29 CMV disease according to Quantiferon- CMV assay Positive vs. Negative vs. Indeterminate p<0.001 Quantiferon positive Quantiferon negative Quantiferon indeterminate Manuel O et al. Clin Infect Dis 2013; 56: 817

30 Performance of the Quantiferon-CMV Sensitivity (95% CI) 0.30 ( ) Specificity (95% CI) 0.93 ( ) assay Positive vs. non-reactive PPV (95% CI) 0.93 ( ) NPV (95% CI) 0.27 ( ) Patients with a positive Quantiferon can safely stop antiviral prophylaxis Manuel O et al. Clin Infect Dis 2013; 56: 817

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32 CMV vaccine: MF59-adjuvanted Griffiths PD et al. Lancet 2011: 377: 1256

33 CMV vaccine: DNA vaccine Kharfan-Dabaja MA et al. Lancet Infect Dis 2012; 12: 290

34 IL28B and HCV Predictors of chronic vs. spontaneously cleared HCV infection Rauch et al. Gastroenterology 2010; 138: 1338

35 CMV replication in patients with IL28B (A) Probability of CMV replication Months from transplant AA/AC, N=1047,Ev=313 CC, N=48,Ev=23, lgrk P=0.03 polymorphism All patients, n=1095 Patients without prophylaxis, n=704 (B) Probability of CMV replication Months from transplant AA/AC, N=685,Ev=205 CC, N=29,Ev=17, lgrk P=0.006 Manuel O, Bochud PY et al. To be presented at the ATC 2013

36 Take-home messages Preventive strategies against CMV have greatly reduced CMVassociated morbidity and mortality after transplantation Both prophylaxis and preemptive therapy appropriately prevent CMV disease Antiviral prophylaxis may have greater impact in preventing CMV indirect effects CMV specific cell-mediated immunity assays can predict the risk for the development of subsequent CMV disease This assays may be useful in tailoring duration of antiviral prophylaxis Novel vaccines may play a role in reducing the burden of CMV disease after transplantation

37 Acknowledgements Infectious Diseases Service, Lausanne: T. Calandra, PY. Bochud, S. Giulieri Transplantation Center, Lausanne: M. Pascual Institute of Microbiology, Lausanne: P. Meylan STCS: G. Kralidis, N. Müller, H. Hirsch, C. Van Delden, C. Garzoni, A. Cusini, K. Boggian, C. Berger, M. Weisser University of Alberta, Edmonton, Canada: A. Humar, D. Kumar ESGICH: José M Aguado