Disclosures. CMV and EBV Infection in Pediatric Transplantation. Goals. Common Aspects CMV (Cytomegalovirus) and EBV (Epstein-Barr virus)

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1 Disclosures I have financial relationships with the following companies: CMV and EBV Infection in Pediatric Transplantation Elekta Inc Lucence Diagnostics Spouse employed Spouse employed I will not discuss radiotherapy or cancer diagnostic technology in this presentation Rachel Wattier, MD, MHS Assistant Professor, Department of Pediatrics, Division of Infectious Diseases and Global Health UCSF Immunocompromised Host Infectious Diseases Program I will discuss off-label use of valganciclovir (Valcyte) Goals Common Aspects CMV (Cytomegalovirus) and EBV (Epstein-Barr virus) Highlight pediatric issues in CMV and EBV infection - Biology and epidemiology in otherwise healthy children - Understanding risk stratification in pediatric SOT recipients - Antiviral dosing in pediatric SOT recipients Not a comprehensive review Double stranded DNA viruses in human herpesvirus family Ubiquitous in human populations Establish long term latency following primary infection Transmissible from organ donor to recipient - And easily transmitted through usual human to human contact Primary immune control by cytotoxic (CD8) T lymphocytes - Transplant immunosuppression increases vulnerability to disease

2 CMV Infection in Organ Transplantation CMV cytopathic effect CMV infection leads to death of infected cells Fishman JA, Rubin RH. NEJM CMV Infection in Pediatric SOT Recipients Why are pediatric recipients at higher risk for CMV infection & complications? High rates of CMV infection & disease in pre-prophylaxis era - Pediatric Liver: 40% had CMV infection, 32% had CMV disease - Pediatric Kidney: 40% had CMV infection, 15% had CMV disease Highest risk for complications in recipients who are seronegative receiving transplant from seropositive donor (D+R-) - No pre-existing CMV immunity - Primary infection acquired via transplanted organ - Primary infection occurs at time of maximal immunosuppression (1-3 months post-transplant) D+/R- more common in pediatric transplantation Bowman JS, et al. Clin Transplant 1991, Iragorri S, et al. Pediatr Nephrol 1993

3 CMV Seroprevalence by Age CMV Seroprevalence by Age, 1-17 Years (Germany) From US NHANES data CMV infection acquired via: Congenital transmission ~ 1% Perinatal transmission Breast milk feeding Contact with other children: 1-3 year old healthy children can shed CMV in urine & saliva for several months Staras SAS, et al. Clin Infect Dis 2006 Voigt S, et al. Open Forum Infect Dis 2015 Novola D, et al. Arch Med Res 2005 CMV Risk Stratification You are evaluating a 16 month old child for possible kidney transplantation. What test should you use to estimate CMV disease risk? Is it reliable at this age? 2018 International Consensus Guidelines on CMV in SOT recommend: - Use serologic (antibody) test with high sensitivity and specificity CMV IgG preferred CMV IgM avoid due to poor specificity Interpretation of antibody status is complicated in infants - Transplacental IgG from mother may make CMV IgG test positive, even if infant has not been exposed - At what age is CMV IgG considered to reflect the child s own immune response? vs. mother s due to transplacental antibody? At 12 months and up, positive CMV IgG reflects true CMV status this is recommended cutoff in CMV consensus guidelines CMV Risk Stratification You are evaluating a 6 month old child with biliary atresia for possible liver transplantation. Her CMV IgG result is positive. How should you interpret the test? At < 12 months of age, positive CMV IgG could reflect either maternal antibody or the infant s own immune status CMV consensus guidelines recommend stratifying to the highest possible risk category for the purposes of planning CMV prevention strategy Donor CMV IgG Infant < 12 month Risk Category Recipient CMV IgG Positive Positive High (= D+R-) Positive Negative High Negative Positive Intermediate Negative Negative Low Kotton CN, et al. Transplantation 2018, Chen J, et al. Virol Journal 2012 Kotton CN, et al. Transplantation 2018

4 Antiviral Drugs for CMV First line agents Ganciclovir (IV) Neonatal Dose Pediatric Dose Adult Dose 6mg/kg 5 mg/kg 5 mg/kg (age 0-3 months) (age >= 3months) Valganciclovir (PO, prodrug) 16 mg/kg Based on congenital CMV studies 7 x BSA x CrCl (max 900mg) 900mg Prophylaxis giving antiviral medications to prevent CMV replication Pre-emptive therapy monitoring for CMV viremia and treating based on viral load threshold, regardless of symptoms Hybrid or surveillance after prophylaxis combination of approaches BSA = body surface area, calculated from height & weight (Mosteller formula) CrCl = creatinine clearance (modified Schwartz formula)* *use maximum CrCl 150 ml/min/1.73m 2 Frequency: once daily for prophylaxis, twice daily for treatment Kotton CN, et al. Transplantation 2018 Lexi-Comp Valganciclovir Pediatric Dosing Basis for current dosing algorithm Target ganciclovir exposure (AUC; area under concentrationtime curve) = μg*h/ml - Based on population pharmacokinetic modeling, understanding of relationship between CMV viremia and ganciclovir pharmacokinetics - Similar to adult ganciclovir exposure on valganciclovir 900mg daily and IV ganciclovir 5mg/kg q24h - AUC in this range showed good safety and efficacy profile in clinical trial including adults & adolescents > 13 years What is the ideal dose in children to achieve goal exposure? Clearance of drugs (via renal elimination or hepatic metabolism) varies based on body size and maturation Options to approximate relationship between body size and clearance: Dosing by body weight simple to calculate, but likely to under-dose in younger age groups Dosing by body surface area closer match to actual relationship between body size and clearance, but more complicated to calculate, may over-dose at younger ages Paya C, et al. Am J Transplant

5 Younger children have larger BSA in proportion to body weight BSA-based dose will be higher than weight-based dose in younger kids Weight-based dosing at 17mg/kg daily in 13 SOT (kidney, liver) recipients All but 3 had below target exposure (40-60μg*h/mL) Ursing J, et al. PLOS One 2014 Peled O, et al. Pediatr Infect Dis J 2017 Valganciclovir Pediatric Dosing Studies Dosing Algorithm & Population 520 mg/m 2 Ganciclovir Exposure (AUC 0-24, μg*h/ml) Age 4 mo-5 yo Age 6-11 yo Age yo (N = 4) Median (Range) (N = 7) (N = 14) Kidney (Pescovitz, et al) 520 mg/m ( ) (N = 13) ( ) (N = 2) ( ) (N = 3) Liver (Pescovitz, et al) 7 x BSA x CrCl Kidney, Liver, Heart (Vaudry, et al) 23.4 ( ) (N = 17) / ( ) Mean +/- SD (N = 21) / ( ) (N = 25) / Study evaluating 7 x BSA x CrCl valganciclovir dosing in 0-4 month old infant heart transplant recipients (N=17) Median AUC μg*h/ml Two alternative dosing strategies evaluated had median AUC well below target range Pescovitz MD, et al. Transplant Infect Dis 2010, Vaudry W, et al. Am J Transplant 2009 Bradley D, et al. Pediatr Infect Dis J 2016

6 Valganciclovir Pediatric Safety Data From studies using current 7 x BSA x CrCl dosing algorithm Study Population 63 patients (17 < 2 years old) Kidney, liver, heart (Vaudry, et al) 56 patients (6 < 2 years old) Kidney (Varela-Fascinetto, et al) Exposure Period Treatment- Related Adverse Events 100 days 29 events Diarrhea Leukopenia Neutropenia 200 days 27 patients (48%) experienced drugrelated AE Leukopenia Anemia Neutropenia Tremor Treatment- Related Serious Adverse Events 7 events Hematologic abnormalities Diarrhea 14 SAEs in 9 patients Neutropenia Leukopenia Pancytopenia Valganciclovir Pediatric Dosing Summary & literature gaps The currently recommended 7 x BSA x CrCl dosing of valganciclovir - Achieves mean exposure within target range (40-60 μg*h/ml) in children > 5 years of age - Achieves above target exposure in infants and younger children Outstanding issues - Though safety profile has been deemed comparable to adults, there is limited safety data especially in younger children - Anecdotally, greater hematologic toxicity seen in younger children - Need more study and optimization of dosing in younger children Vaudry W, et al. Am J Transplant 2009, Varela-Fascinetto Pediatr Transplant 2017 Treatment of Active CMV Infection You are following a 3 year old patient who is being monitored for CMV after recently coming off prophylaxis. He is asymptomatic but now with CMV detected in plasma at 3500 IU/mL. In most respects, diagnosis and treatment of active CMV infection are similar in children vs. adults Older guidelines (2013) recommended therapy with IV ganciclovir in - Children < 12 years with CMV disease, regardless of severity - Children < 5 years with asymptomatic CMV DNAemia Current recommendations (2018): - PO valganciclovir for asymptomatic CMV DNAemia - Initial treatment with IV ganciclovir for children with severe CMV disease - Individualized management (IV or PO) for children with mild or moderate CMV disease Kotton CN, et al. Transplantation 2013; Kotton CN, et al. Transplantation 2018; Höcker B, et al. Transplantation 2016 EBV (Epstein-Barr Virus) Infection Major manifestations in solid organ transplant recipients Primary concern is potential for development of posttransplant lymphoproliferative disorder (PTLD) - Uncontrolled proliferation of B lymphocytes in the setting of transplant immunosuppression Other manifestations - Asymptomatic viremia - Infectious mononucleosis (similar to immunocompetent hosts) - Direct viral infection syndromes e.g. hepatitis - Trigger for hemophagocytic lymphohistiocytosis (HLH) - Development of other malignant neoplasms Allen UD, et al. Am J Transplant 2013

7 Odumade OA, et al. Clin Microbiol Rev 2011 Heslop HE. Blood 2009 PTLD Cumulative Incidence Pediatric vs. adult, by transplanted organ Organ Pediatric Adult 1 year 5 year 1 year 5 year Kidney 1.3% 2.4% < 0.2% 0.6% Liver 2.1% 4.7% 0.25% 1.1% Heart 1.6% 5.7% 0.3% 0.7% Lung/Heart-Lung 4% 16% 1.0% 1.5% Data for intestinal transplant recipients not reported by age: 5% at 1 year 9% at 5 years Thorley-Lawson, DA, Gross, A. NEJM 2004 Green M, Michaels MG. Am J Transplant 2013 Based on data from 2010 UNOS/SRTR report

8 EBV Seroprevalence by Age PTLD Risk in Pediatric SOT Elevated risk not completely explained by more EBV-naïve recipients Adult Liver, Pediatric Liver, Adult Heart, Pediatric Heart, From study of Minnesota children age 18 months 19 years Condon LM, et al. Clin Infect Dis 2014 OPTN/SRTR Annual Report 2016 EBV and PTLD: Prevention Approaches Approach Minimize immunosuppression where appropriate EBV viral load monitoring for EBV D+/R- recipients, some sources recommend for all infants Reduce immunosuppression for increasing viral load Guidelines/Supporting Data Recommended (American Society of Transplantaion ID Community of Practice [ID-COP] Guidelines, moderate quality evidence) Recommended (ID-COP, moderate quality evidence, Kidney transplant [KDIGO] guidelines, level 2 rec, low quality evidence) Considered first line approach (ID-COP, moderate quality evidence; KDIGO, level 2 rec, low quality evidence) Antivirals for increasing viral load Commonly used, no official recommendation IVIG for increasing viral load Sometimes used, no official recommendation Pre-emptive rituximab, adoptive Insufficient evidence to recommend immunotherapy, other strategies (ID-COP, low quality) Antiviral prophylaxis No official recommendation (ID-COP, low quality evidence, differing results) CMV IgG No official recommendation (ID-COP, low quality evidence, differing results) Take Home Points Pediatric solid organ transplant recipients are more likely to be CMV and EBV-naïve at transplant - Higher risk for CMV infection and complications - Higher risk for PTLD, not solely based on EBV-naïve status Valganciclovir dosing in pediatrics - Based on BSA and CrCl to approximate adult exposure - May still not be ideal and needs further evaluation of safety Suggested further reading: - Kotton CN, et al. CMV International Consensus Guidelines. Transplantation Green M, Michaels MG. EBV and PTLD. Am J Transplant 2013 Allen U, et al. Am J Transplant 2013; Kasiske BL, et al. Kidney Intl 2009