Review of Cytomegalovirus Prevention and Treatment Strategies

Erin K. McCreary, PharmD, BCPS, BCIDP Antimicrobial Stewardship/Infectious Diseases Clinical Pharmacist University of Pittsburgh Medical Center Pittsburgh, PA @erinmccreary Disclosures

• I have no disclosures or financial relationships relevant to the content of this activity. • I will discuss off-label and non-FDA approved treatments during this presentation.

2 Learning Objectives

1. Identify currently available diagnostics for cytomegalovirus (CMV) 2. Discuss strategies for prevention of clinically significant CMV infection 3. Describe available and emerging treatment options for CMV, including antiviral- resistant CMV

3 Let’s get this out of the way

• Cytomegalovirus (CMV) is common • CMV is VERY complex • Antivirals have helped, but we have a long way to go • No standardized, optimal prevention or treatment strategy exists

Image from: https://professionaldoctorate.wordpress.com/2014/11/17/sometimes-even-if-i-stand-in-the-middle-of-the-room- no-one-acknowledges-me/ 4 Cytomegalovirus

• Human betaherpesvirus • 60-70% of US adults infected —↑ globally • “Cured” by an immune system • Significant morbidity and mortality in immunocompromised hosts —Most common infection in HCT • Substantial genetic variation in strains Image from: https://researchfeatures.com/2018/01/31/human-cytomegalovirus-forgotten-herpesvirus/

Crumpacker CS. Cytomegalovirus. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th Edition. 2015:1738-53. Ljungman P, et al. Hematol Oncol Clin North Am. 2011;25:151-69. HCT = hematopoietic cell transplantation 5 Immune response to CMV

IL-6 TNF-α gB gH CD4+ IFNα T cells

Phagocytic cells CD8+ T cells g = glycoprotein NK = natural killer Neutrophils TNF = tumor necrosis factor NK IL = interleukin cells IFN = interferon Ljungman P, et al. Hematol Oncol Clin North Am. 2011;25:151-69. Crough T, Khanna R. Clin Microbiol Rev. 2009;22:76-98. 6 Risk factors for CMV infection

• Recipient (R) + —Increased if donor (D) -? • Cord blood • Haploidentical transplant • T-cell depleted graft • Unrelated/mismatched donor • Alemtuzumab or thymoglobulin (ATG) • Graft-versus-host disease (GVHD) • Systemic corticosteroid use

Table from: Marchesi F, et al. Hematological Oncology. 2018;36:381–391.

Camargo JF, Komanduri KV. Hematol Oncol Stem Cell Ther. 2017;10:233-8. Kalra A, et al. Biol Blood Marrow Transplant. 2016;22:1654-63. 7 • CMV infection —Viral isolation or detection of viral proteins or nucleic acid in any body fluid or tissue —Describe source and diagnostic method clearly • Primary infection —First detection of CMV in patient with no evidence of CMV exposure pre-transplant • Recurrent infection —New infection in patient with previous evidence of CMV infection —No virus detected for at least 4 weeks during active surveillance —Reactivation (latent, endogenous) v. reinfection (new strain, exogenous)

Ljungman P, et al. Clin Infect Dis. 2017;64(1):87–91. 8 • Proven CMV disease —Clinical symptoms and/or signs + tissue-proven* (*not required for CMV retinitis) • Histopathology, virus isolation, rapid culture, immunohistochemistry, DNA hybridization • Probable disease? • Some other rules —Response to therapy should not be used as a study endpoint —Report cases with co-pathogens separately • And remember…. —Detection of virus, antigen, or DNA in blood does not mean CMV is replicating in blood —Tissue-invasive disease can be present without viral replication in blood

Ljungman P, et al. Clin Infect Dis. 2017;64(1):87–91. 9 • Isolation of CMV by standard Viremia or rapid culture techniques

• pp65 antigen in peripheral Antigenemia blood leukocytes (PBLs)

• CMV DNA in plasma, serum, DNAemia whole blood, or isolated PBLs

• CMV RNA in plasma, serum, RNAemia whole blood, or isolated PBLs

Ljungman P, et al. Clin Infect Dis. 2017;64(1):87–91. 10 • Quantitative nucleic acid amplification Molecular • More sensitive than antigenemia • Turn around time ~3-4h PCR • Viral load recognized as appropriate surrogate endpoint

• Semiquantitative assay (# of CMV-infected PMNs per # cells evaluated) Antigenemia • Detects CMV antigens assay • Limited in patients with < 0.2 x 109 neutrophils/L • Cumbersome processing

• Detects monoclonal antibodies directed toward Rapid shell CMV IE proteins in cultured cells • Turn around time ~16h culture • Low sensitivity, high correlation with disease

Razonable RR, et al. J Clin Microbiol. 2002;40:746-52. Hodowanec AC, et al. J Clin Pharmacology. 2018. PMNs = polymorphonuclear cells 11 PCR has issues…

• Quantification —WHO International Standard to calibrate for CMV DNA NAT released 2010 (IU/mL) —Limit of detection/quantification still vary significantly • Lower: 34.5-159 IU/mL • Upper: 7.9-156 million IU/mL —Amplicon size, gene target, and extraction method also vary

Babady NE, et al. J Clin Microbiol. 2015;53:1252–1257. Dioverti MV, et al. Open Forum Infectious Diseases. 2017;4:ofx143. Natori Y, et al. Clin Infect Dis. 2018;66:617-31. Razonable RR, et al. J Clin Microbiol. 2002;40:746-52. Lisboa LF, et al. Transplantation. 2011;91:231 NAT = nucleic acid amplification technique 12 Lots of issues.

• Specimen type —Whole blood? Plasma? —Absolute value for individual viral load ~0.5- to 1.22-log higher in whole blood than plasma —Increased sensitivity with plasma at lower viral loads • Interpretation —No consensus on what threshold needs treated or leads to disease —Viral load of 1350 IU/mL proposed to distinguish asymptomatic infection from disease in HCT —Viral load ≥ 150 IU/mL = ↓ spontaneous clearance; ≥ 350 IU/mL = longer duration of viremia —Kinetics associated with response to therapy/progression of disease? —What is considered viral suppression?

Babady NE, et al. J Clin Microbiol. 2015;53:1252–1257. Dioverti MV, et al. Open Forum Infectious Diseases. 2017;4:ofx143. Razonable RR, et al. J Clin Microbiol. 2002;40:746-52. Natori Y, et al. Clin Infect Dis. 2018;66:617-31. Lisboa LF, et al. Transplantation. 2011;91:231. Camargo JF, et al. Biol Blood Marrow Transplant. 2018:806-814. Preiksaitis JK, et al. Clin Infect Dis. 2016;63:583-9. 13 Learning Question #1

Which of the following is the most sensitive and rapid method of detecting CMV infection with international calibration? a) CMV DNA Molecular PCR b) CMV RNA Molecular PCR c) CMV pp65 antigenemia assay d) CMV rapid shell culture

14 We know CMV is bad

Risk of death ↑: OR 1.76; 95% CI, 1.07 to 2.90; P = .025

Median post-transplantation survival ↓: 16 versus 36 months; P = .002

Biol Blood Marrow Transplant. 2014; 1958-1967. 15 How bad? Pretty bad.

• ↑ nonrelapse and overall mortality • ↑ $$$ • ↑ length of stay • ↑ severity of GVHD • ↑ bacterial, fungal, opportunistic infections —Even after adjusting for conditioning & acute GVHD, CMV reactivation = only independent risk factor for proven/probable invasive fungal infection (OR 2.3; 95% CI, 1 to 5.1; P = .049) —Peak viral load not associated with outcomes • CMV disease can affect most organs

Robin C, et al. BMC Infect Dis. 2017;17:747 Takenaka K, et al. Biol Blood Marrow Transplant. 2015;21:2008-16. Yong MK, et al. Biol Blood Marrow Transplant. 2017;23:1961-7. Bhutani D, et al. Biol Blood Marrow Transplant. 2015;21:159-64. Simanek AM, et al. PLoS ne. 2011;6:e16103. 16 Prevention

Successful strategies and current practice recommendations

17 Non-pharmacologic prevention

• Avoid body fluids of CMV-seropositive individuals • Wash hands following any form of human secretion exposure • Standard precautions for medical professionals —Risk of acquiring infection through patient contact low • Use of leukocyte-depleted blood products or from CMV-seronegative donors for R- recipients

Zaia J, et al. Bone Marrow Transplantation. 2009;44:471-82. Tomblyn M, et al. Biol Blood Marrow Transplant. 2009;15:1143-238. www.cdc.gov/cmv Accessed December 2018. 18 Pharmacologic prevention (per the guidelines)

• “HCT recipients at risk should be placed on a CMV disease prevention program from time of engraftment until at least 100 days after HCT” (AI)

• “Physicians should use either prophylaxis or preemptive treatment for allogeneic recipients” (AI) —Preemptive strategy preferred for D+/R- patients (BII)

Zaia J, et al. Bone Marrow Transplantation. 2009;44:471-82. Tomblyn M, et al. Biol Blood Marrow Transplant. 2009;15:1143-238. 19 Pharmacologic prevention

Universal prophylaxis Preemptive treatment

No one Everyone gets an gets an antiviral antiviral (at first)

+ PCR monitoring ~1x/week from day 10 to at 100 days after HCT for at-risk allos (AIII)

Zaia J, et al. Bone Marrow Transplantation. 2009;44:471-82. Tomblyn M, et al. Biol Blood Marrow Transplant. 2009;15:1143-238. 20 What about autologous HCT?

• Guidelines —High-risk patients may benefit from preemptive monitoring until 60 days after HCT (BII) —Patients transplanted with CD34+ selected grafts should be treated at any level of antigenemia (BII) —No prevention strategy necessary for R+ recipients (DII) • Real-world data —~17-41% develop CMV infection when monitoring used; 3-12% when clinically-driven —Disease is rare (up to 4%), but just as bad as in allos if it happens —8-16% of patients with no risk-factors may develop DNAemia; 1-2% disease —Monitoring has limited usefulness  mortality similar regardless of diagnostic strategy —New high risks? • Age ≥ 50 • MM > NHL and HL • Progressive disease at transplant • Rituximab?

Zaia J, et al. Bone Marrow Transplantation. 2009;44:471-82. Marchesi F, et al. Hematological Oncology. 2018;36:381-91. Kaya AH, et al. Transplantation Proceedings. 2017;49:1911-5. Massoud R, et al. J Clin Virol. 2017;95:36-41. 21 HCMV = human cytomegalovirus FDA Approval

1989 GCV

1991 FOS

1996 CDV

2001 VGC

Cidofovir (CDV) 2017 LTV Foscarnet (FOS) Ganciclovir (GCV) Letermovir (LTV) Maribavir (MBV) Foolad F, et al. Expert Review of Clinical Pharmacology, 11:10, 931-941 Valganciclovir (VGC) 22 Antiviral therapy P T Drug Dose IV PO Active against ADRs FDA-Indication for HCT P, PO: 400-800 mg BID Headache, rash, renal tubular ACV HSV, VZV P, IV: 200 mg Q8-12H damage/SCr ↑

VCV P: 500 mg BID HSV, VZV Headache, rash T: 5 mg/kg Q12H GCV HSV, VZV, CMV Hematologic toxicity, P/M: 5 mg/kg Q24H carcinogenic, impaired T: 900 mg Q12H fertility, impaired renal VGC HSV, VZV, CMV P/M: 900 mg Q24H function T: 60 mg/kg Q8-Q12H Nephrotoxicity, electrolyte FOS T: 90 mg/kg Q12H HSV, VZV, CMV disturbances, seizures, QTc P/M: 60-90 mg/kg Q24H prolongation T: 5 mg/kg weekly x 2 HSV*, VZV*, Nephrotoxicity, neutropenia, CDV M: 5 mg/kg Q2 weeks CMV carcinogenic, teratogenic LTV P: 480** mg Q24H CMV Nausea, vomiting, edema

*Active in-vitro but breakthrough infections have been documented ACV = acyclovir; VCV = valacyclovir **240 mg Q24H if co-administered with cyclosporine P: Prevention; M: Maintenance; T: Treatment and/or Induction 23 Wait… which weight??

Drug Dose TBW < IBW Non-obese Obese T: 5 mg/kg Q12H No data GCV TBW TBW P/M: 5 mg/kg Q24H AdjBW? T: 900 mg Q12H VGC Non-weight based in adults P/M: 900 mg Q24H T: 60 mg/kg Q8-Q12H No data FOS T: 90 mg/kg Q12H TBW TBW “May be prudent to utilize IBW or P/M: 60-90 mg/kg Q24H AdjBW” No data PK in non-obese suggest limited T: 5 mg/kg weekly x 2 CDV TBW TBW distribution into adipose tissue M: 5 mg/kg Q2 weeks “…case by case basis… risk v. benefit” P: Prevention; M: Maintenance; T: Treatment and/or Induction TBW: total body weight; AdjBW = adjusted body weight

Polso AK, et al. J Clin Pharm Ther. 2014;39:584-608 24 • R+ or D+ patients • Weekly cultures  ganciclovir or placebo if + —Ganciclovir: N= 37 —Placebo: N=35 • ↓ CMV disease (3% v 43%!!!!!!!!!!!) • ↓ CMV-disease related deaths —0 (0%) ganciclovir —6 (17%) placebo

Goodrich JM, et al. N Engl J Med. 1991;325:1601-67. 25 • R+ patients: 33 ganciclovir, 31 placebo • CMV assessed by viral culture

Outcome GCV Placebo P value

CMV infection 3% 45% P < 0.001 CMV disease 0% 29% P < 0.001 Neutropenia 30% 0% P = 0.001 Bacterial or fungal infections 45% 29% P > 0.2 Mortality at day 100 12% 19% P > 0.2

Goodrich JM, et al. Ann Intern Med. 1993;118:173-8. 26 • 226 patients

• GCV group = ↓ disease before day 100 but no difference at day 180 ↑ fungal infection and late CMV disease • Survival similar • Authors say: preemptive treatment appropriate, but treat any positive and continue GCV until day 100 even if repeat antigenemia negative

Boeckh M, et al. Blood. 1996;88:4063-71. 27 • Trial conducted to assess late-onset disease (day 100-270) • Patients received 6 months of valganciclovir (N=95) or placebo (N=89) —R+ or D+: treated CMV infection between day 80-120 (before randomization) —R+ also included if GVHD or receiving CMV-active prophylaxis since engraftment • No difference in composite outcome: death, CMV disease, or other invasive infection • No difference in any secondary outcome —Notably: no difference in immune reconstitution or virus-specific T-cell recovery

Boeckh M, et al. Ann Intern Med. 2015;162:1-10. 28 Preemptive treatment in solid organ transplantation (SOT), too!

Singh N, et al. Oral Abstract. IDWeek 2018. ClinicalTrials.gov: NCT01552369 29 Preemptive treatment Transplant

CMV Monitoring

CMV CMV Not CMV Detected Treatment Detected

30 A possible strategy • Initial monitoring • Continued monitoring —Autos: Day 0-10 thru 40-60 —Monitor through day 100, at least —Allos: Day 0-10 thru Day 100 —Continue as long as “substantial —1-2 x weekly (↑ frequency as risk ↑) immunocompromise persists” —“Lead-in” or hybrid GCV/VGC for high-risk • Chronic GVHD patients? • Steroid use • Treat anything detectable • CD4 < 50 cells/mm3 • —Consider higher thresholds for lower risk D-/R+ patients • Unrelated, haplo, cord, and/or T- —Valganciclovir if GI tract works and no cell depleted grafts evidence of disease, otherwise ganciclovir —Treat until undetectable or “low positive” x 2 —Reinitiate monitoring post-treatment

Hammerstrom AE, et al. Biol Blood Marrow Transplant. 2018;24:353-8. Milano F, et al. Blood. 2011;118:5689-96. 31 And then… a game changer

Marty FM, et al. N Engl J Med. 2017;377:2433-2444 32 Marty FM, et al. N Engl J Med. 2017;377:2433-2444 33 Letermovir: too good to be true?

• Remember to monitor voriconazole (and tac, and warfarin…) • ↑ cardiac events? • In vitro data suggest low genetic barrier to resistance —Rapid development with drug exposure —Breakthrough CMV disease with resistance mutation has been described (selective pressure?) • Exercise caution with off-label use (at this point) —Especially in setting of high viral burden —Treatment data limited to case-studies • Doses up to 960mg/day are well-tolerated • No way to monitor treatment response with current assays —Watch for these registered clinical trials • Refractory or resistant disease • Prophylaxis in kidney transplantation

Knoll BM, et al. Bone Marrow Transplantation. 2018. Deleenheer B, et al. Expert Opin Drug Metab Toxicol. 2018;14:1197-1207. Clinicaltrials.gov: NCT03728426 Turner N, et al. Antimicrob Agents Chemother. 2019. pii: AAC.02337-18 Clinicaltrials.gov: NCT03443869 34 Letermovir: what else do we want to know?

• Role for secondary prophylaxis? • Is 100 days enough? • Can we delay initiation? Should we start during conditioning? —Caution with cyclophosphamide • Dosing if CrCl ≤ 10? —Patients excluded from trials —Eliminated by OATP1B and UGT1A (minor) —Phase 1 trial data showed mild increase in exposure with no increase in ADR (120 mg dose) —My opinion = do not dose adjust for renal impairment • Is there bang for your buck in low-risk patients? Probably…

Kropeit D, et al. Br J Clin Pharmacol. 2017;83:1944-195 Solano C, et al. Bone Marrow Transplant. 2018. doi: 10.1038/s41409-018-0251-0 Chen K, et al. Blood Adv. 2018;2:2159-2175 Chong PP, et al. Transpl Infect Dis. 2018;10:e12965 35 Preemptive treatment ? Transplant

? CMV Monitoring

? ? ? CMV CMV Not CMV Detected Treatment Detected

36 We have so much to learn (research opportunities galore!) • Initial Monitoring —Risk stratification by disease, conditioning, D/R status, GVHD prophylaxis —Role of letermovir and when to initiate? —CMV PCR: when to initiate? how frequently to check? which assay? —Is preemptive monitoring logistically possible for all patients? —What threshold needs treated? —Is the rate of rise predictive for disease? • Treatment —What drug? What dose? For how long? • Continued monitoring —How long post transplant? —Does GVHD treatment change things? —Role for secondary prophylaxis? —Hybrid or “surveillance after prophylaxis” strategy? • CMV-specific cell-mediated immunity

37 Learning Question #2

Which of the following is the most appropriate prophylaxis strategy for CMV-seropositive recipient of a haploidentical HCT? a) Preemptive treatment with CMV DNA PCR monitoring every two weeks b) Letermovir 480mg PO daily, initiated on day 30 c) Preemptive treatment with CMV DNA PCR monitoring twice weekly d) Valganciclovir 900mg PO daily, initiated on day 0

38 Prevention

Clinical Failures, Unanswered Questions, and Emerging Data

39 IVIG and CMV-IVIG…not the answer

• "For CMV disease prophylaxis, intravenous Ig is not recommended" (EIII)

Raanami P, et al. J Clin Oncol. 2008;27:770-81. 40 Non-FDA approved antivirals

Brincidofovir Maribavir (MBV)

Foolad F, et al. Expert Review of Clinical Pharmacology, 11:10, 931-941 41 Brincidofovir (CMX001)

• Oral lipid-conjugated nucleotide analogue Brincidofovir —Converted into cidofovir in the target cells —No nephrotoxicity! • Enhanced in vitro activity against CMV and HSV —Retains activity against ganciclovir-resistant CMV strains • Dose-limiting GI toxicities • SUPPRESS Trial failed to meet primary endpoint —100mg twice weekly through week 14 vs placebo —Median start = day 15 —No difference in clinically significant CMV infection at week 24 but ↑ GI toxicity • Currently only case studies of off-label emergency investigational protocols — Company only providing drug for adenovirus Cidofovir

Marty FM, et al. Biol Blood Marrow Transplant. 2018. 42 Maribavir (SHP620)

• Phase 1 —Doses > 800 mg/day = taste disturbance

—Dosed at 400 mg BID = maintain concentrations above CMV IC50 • Phase 2 —Started after engraftment for prophylaxis in HCT —Not able to assess statistical difference between dosing strategies • Phase 3 —No difference in CMV disease for 100 mg BID v placebo —No difference in DNAemia or initiation of antiviral therapy —Need higher dose? —CMV disease no longer the right end-point?

Marty FM and Boeckh M. Current Opinion in Virology. 2011;1:555-562. 43 How about a vaccine?

• DNA vaccine ASP0113 • Multi-antigen CMV-MVA vaccine (Triplex) —Contains two plasmids encoding gB and pp65 —Composed of 3 CMV antigens inserted into • Most frequently recognized CMV antigens by weakened modified vaccinia Ankara (MVA) both CD4+ and CD8+ T cells vector —Novel delivery system —Prolifically expressed, highly immunogenic, • ↑ gene expression in vivo and immune response robust expansion of CD4+ and CD8+ T-cells • Good news and bad news specific for each immuno-dominant CMV protein —Phase 2: well tolerated, ↓ DNAemia occurrence, —Phase 1: increased CMV pp65-, IE1- and IE2- ↑ time to DNAemia episode specific T-cells post-vaccination —No difference in antiviral initiation (?testing issue, —Antibodies may persist for ~75 years!! HCT) • —No difference in DNAemia from day 100 through 1 Ongoing Phase 2 study in R+ HCT patients year (?timing issue, SOT patients) —Phase 3 HELIOS trial (N=514) found no difference in…. anything (HCT)

Vincenti F, et al. Am J Transplant. 2018;18:2945-54. Kharfan-Dabaja MA, et al. Lancet Infect Dis. 2012;12:290-299. Clinicaltrials.gov identifier NCT01877655 Mori T, et al. Int J Hematol. 2017;105:206-212. Clinicaltrials.gov Identifier NCT02506933 La Rosa C, et al. Blood. 2017;129:114-125 Walsh SR, et al. J Infect Dis. 2013;207:1888-97 44 And we can’t forget to ask the sirolimus question

• Protective effect… how? —mTOR pathway role in CMV protein synthesis/replication —Immunomodulatory effects —Lower degree of immunosuppression • Data mostly in SOT, HCT less explored —Significant ↓ in CMV reactivation when sirolimus/tacrolimus used as GHVD prophylaxis • aHR 0.46 (95% CI, 0.27-0.78; P = .004) —Sirolimus associated with exposure-dependent anti-CMV activity • Concentrations 8-18 ng/mL = maximal effect • More prolonged exposure also beneficial? —Would we see more benefit without tacrolimus?

Pinana JL, et al. Am J Transplant. 2018;18:2885-2894. Marty FM, et al. Blood. 2007;110:490-500. 45 Best for last?!

Camargo JF. Hematol Oncol Stem Cell Ther. 2017;10:233-8. 46 Treatment

47 Audience poll…not an assessment question 

Your patient, SA, is a low-risk R+ allogenic HST recipient. He has CMV DNAemia without disease and is receiving ganciclovir 5 mg/kg Q12H. His most recent CMV DNA PCRs result as < 137 IU/mL and undetectable on days 8 and 13 of treatment, respectively. What do you recommend? a) Continue ganciclovir treatment until at least two tests are negative. b) Stop ganciclovir treatment. The patient has two negative tests. c) Stop ganciclovir treatment. The patient has one negative test. d) Continue ganciclovir treatment but switch to maintenance dosing for 8 more days. e) Continue ganciclovir treatment for one more day, then stop. f) Continue ganciclovir treatment for one more day, then give one week maintenance dosing.

48 Guidelines recommend:

• Begin preemptive treatment if CMV detected —Allo: • Induction x 7-14 days • Maintenance until indicator test negative • Minimum duration: 2 weeks if 14-day induction, 3 weeks if only 7-day induction course —Auto: • Induction x 7 days • Maintenance until indicator test negative • Minimum duration: 2 weeks • If CMV still detected after 2 weeks of therapy, maintenance therapy can be given until CMV is undetectable, or it can be continued up to day 100

Zaia J, et al. Bone Marrow Transplantation. 2009;44:471-82. Tomblyn M, et al. Biol Blood Marrow Transplant. 2009;15:1143-238. 49 Treatment considerations

• What is a negative test? — “Undetectable” v “below quantification” • Vary by risk? • Is one enough, or do you need 2+ “negatives” —Blood tests may be negative with ongoing tissue-invasive disease • Which drug? —Usually VGC/GCV unless profound neutropenia, then foscarnet • Role for TDM? —GCV if CMV disease —Combination therapy? • Maintenance therapy —Use the same drugs, but at prophylaxis dosing —Duration if early response?

Gimenez E, et al. Antimicrob Agents Chemother. 2014;58:5602-5. Peled O, et al. Pediatr Infect Dis J. 2017;36:745-50. Tangden T, et al. Clin Pharmacokinet. 2018;57:1399-1405. Ritchie BM, et al. Antimicrob Agents Chemother. 2019. pii: AAC.01855-18 50 • Refractory CMV infection

—CMV viremia ↑ > 1log10 after at least 2 weeks of appropriately-dosed antiviral therapy

• < 1log10 increase during first 2 weeks of therapy may occur… this is okay —Must have at least weekly viral load monitoring—SAME LAB, SAME ASSAY! —Persistent CMV DNA titers <1000 IU/mL, and in particular detected but not quantifiable (<137 IU/mL), should not be considered refractory CMV infection • Antiviral drug resistance —Viral genetic alteration that ↓ susceptibility to one or more antiviral drugs

51 Learning Question #3

Which patient has refractory CMV disease? a) SA, CMV DNAemia ↑ > 1log10 after 16 days of valganciclovir 450mg BID, CrCl ~90 mL/min, with his most recent PCR checked at the same laboratory b) RS, CMV DNAemia ↑ > 1log10 after 12 days of valganciclovir 900mg BID, CrCl ~75 mL/min, , with his most recent PCR checked at a new laboratory c) JP, CMV DNAemia ↑ > 1log10 after 14 days of valganciclovir 900mg BID, CrCl ~80 mL/min, with his most recent PCR checked at a new laboratory d) JG, CMV DNAemia ↑ > 1log10 after 18 days of ganciclovir 5 mg/kg Q12H, CrCl ~75 mL/min, with his most recent PCR checked at the same laboratory

52 CMV Resistance

CMV Gene Role Associated Drug Resistance

UL97 Kinase Ganciclovir, valganciclovir, maribavir

Ganciclovir, valganciclovir, cidofovir, UL54 Polymerase foscarnet, brincidofovir

UL27 Cell cycle regulation Maribavir (low level)

Cleavage and UL51, UL56, UL89 Letermovir packaging

Table adapted from: Chemaly RF, et al. Clin Infect Dis. 2018. 53 Foscarnet +/- GCV

High-dose Cidofovir GCV Resistant CMV Treatment Options IVIG Maribavir

Leflunomide

El Chaer F, et al. Blood. 2016;128:2624-263. Papanicolaou GA, et al. Clin Infect Dis. 2018. doi: 10.1093/cid/ciy706 Wang E, et al. J Oncol Pharm Practice. 2018. Erard V, et al. Clin Infect Dis. 2015;61:31-9. Clinicaltrials.gov NCT: 02927067 54 Figure 5 from: El Chaer F, et al. Blood. 2016;128:2624-263 55 Figure 6 from: El Chaer F, et al. Blood. 2016;128:2624-263 56 CMV-specific T-cell therapy

Bao L, et al. J Immunother. 2012;35:293–298. Pegg KS, et al. Clin Infect Dis. 2009. Camargo JF and Komanduri KV. Hematol Oncol Stem Cell Ther. 2017;10:233-8. Lilleri D, et al. Haematologica. 2008;93:248-56. Images from: Pei X, et al. J Infect Dis. 2017;216:945-956. Pelak O, et al. Cytometry B Clin Cytom. 2017. 57 Key Takeaways

• CMV is incredibly intricate • Antiviral therapy is effective, but not without risk • Optimal prevention and treatment strategies remain unknown • Antiviral stewardship is important • Precision medicine is the future —Immunologic monitoring —Adoptive CMV-specific T-cell immunotherapy —Vaccination

58 Recommended references

• Meesing A, Razonable RR. Drugs. 2018;78:1085–1103. • Ljungman P, et al. Clin Infect Dis. 2017;64:87–91. • Tomblyn M, et al. Biol Blood Marrow Transplant. 2009;15:1143-238. • El Chaer F, et al. Blood. 2016;128:2624-263. • Marty FM, et al. N Engl J Med. 2017;377:2433-2444.

59 Some additional thoughts and interesting facts 

60 Is CMV always bad?

• Conflicting data, but signal that CMV reactivation associated with decreased risk of AML relapse • Does not seem to hold true for other malignancies • Not observed with delayed immune reconstitution? • Nullified by increased nonrelapse mortality?

Image from: Elmaagacli AH, Koldehoff M. Blood. 2016;128:456-9. Lonnqvist B, et al. Br J Haematol. 1986;63:671-679. Elmaagacli AH, et al. Blood. 2011;118:1402-1412. Takenaka K, et al. Biol Blood Marrow Transplant. 2015;21(11):2008-16. Teira P, et al. Blood. 2016;127:2427-38. AML = acute myeloid leukemia 61 • Exploratory study of 37 patients in Taiwan • Nilotinib 200 mg/day —Prevent CMV infection by inhibiting platelet-derived growth factor receptor-alpha • 25 (80.6%) of patients had successful prophylaxis —12 (38.7%) undetectable —13 (41.9%) DNAemia < 10,000 copies/mL (all resolved without antiviral therapy) —Success rate highest in patients without ATG exposure • Failures occurred before day 40 • No increased myelosuppression or graft failure  ongoing RCT using imatinib

Lin CT, et al. Biol Blood Marrow Transplant. 2018;24:2310-5. Clinicaltrials.gov identifier NCT03343600 62 But wait…

• 109 HCT patients for CML or Ph+ ALL • 21 patients received post-HCT dasatinib • Dasatinib use independent risk factor for CMV reactivation —aHR, 7.65; 95% CI, 1.84–31.7 • SRC and TEC kinase blockage = suppressed effector memory T-cell function

Prestes DP, et al. Clin Infect Dis. 2017;65:510-3. 63 Cytomegalovirus Prevention and Treatment Strategies

Erin K. McCreary, PharmD, BCPS, BCIDP Antimicrobial Stewardship/Infectious Diseases Clinical Pharmacist University of Pittsburgh Medical Center Pittsburgh, PA @erinmccreary