Roy F. Chemaly, MD, MPH, FIDSA, FACP, and Genovefa Papanicolaou, MD, FIDSA, prepared useful practice aids pertaining to cytomegalovirus for this CME activity titled "Changing the Paradigm of CMV Management: New Science and More Choices for Challenging Cases in the HCT Setting." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/38UNLwZ. CME credit will be available until March 19, 2021.

1. Phases of Opportunistic Infections
Among Allogeneic Hematopoietic
Cell Transplant Recipients1
Access the activity, “Changing the Paradigm of CMV Management: New Science and More Choices for
Challenging Cases in the HCT Setting,” at PeerView.com/ZXF40.
PRACTICE AID
CD: cluster of differentiation; EBV: Epstein-Barr virus; HHV6; human herpesvirus 6; NK: natural killer; PTLD: post-transplant lymphoproliferative disease.
1. Tomblyn M et al. Biol Blood Marrow Transplant. 2009;15:1143-1238.
Phase 1: Pre-Engraftment
BacterialViralFungal
Phase 2: Post-Engraftment Phase 3: Late Phase
Neutropenia, barrier breakdown
(mucositis, central venous access devices)
Gram-negative bacilli
Encapsulated bacteria
Varicella zoster virus
Aspergillus speciesAspergillus species
Candida species
Pneumocystis
Gastrointestinal Streptococcus species
Gram-positive organisms
Impaired cellular and humoral immunity;
NK cells recover first, CD8 T-cell numbers
increasing but restricted T-cell repertoire
Impaired cellular and humoral immunity;
B-cell and CD4 T-cell numbers recover
slowly and repertoire diversifies
Graft-versus-host disease:
Day 0 Day 15-45 Day 100
More common
Day 365
and beyond
Acute
Chronic
Less common
Herpes simplex virus
Respiratory and enteric viruses (seasonal/intermittent)
Other viruses (eg, HHV6)
Cytomegalovirus
EBV PTLD

2. PRACTICE AID
Access the activity, “Changing the Paradigm of CMV Management:
New Science and More Choices for Challenging Cases in the HCT Setting,”
at PeerView.com/ZXF40.
Preventing CMV infection and
Disease in HCT Recipients1
Comparison of Current CMV Prevention Strategies
The Newest FDA-Approved Drug for CMV Prophylaxis
in Allogeneic HCT Recipients: Key Characteristics of Letermovir
Prophylaxis
Antivirals administered to all at-risk
patients for a defined period of time
following transplantation
CMV DNA test (at least once weekly)
Antiviral therapy started when viral load
exceeds a certain threshold
Effectively prevents
early CMV reactivation
High rates of medication side effects
Increased drug cost
Risk for delayed-onset CMV disease
Preemptive Therapy
3,4-dihydro-quinazoline-4-yl-acetic acid derivative
Only active against CMV (no activity against HSV)
Uncommon, mainly GI (gastritis, nausea), dyspnea, hepatitis
93% in feces, mostly as unchanged drug
CMV prophylaxis in CMV-seropositive HCT recipients
Inhibits terminase complex subunit pUL56
94% healthy individuals; 35% in HCT (increased to 85% with cyclosporine)
Reduces exposure to voriconazole; increases exposure to tacrolimus,
cyclosporine, midazolam; letermovir exposure increased with cyclosporine
480 mg daily (240 mg if administered with cyclosporine) for prophylaxis in HCT;
no dose adjustment for renal dysfunction
Use of letermovir for CMV prophylaxis in
CMV-seronegative kidney transplant recipients
Principle
Advantages
Disadvantages
Reduced medication cost
Lower risk of drug toxicity
Allows immune reconstitution
DoesnotpreventearlyCMVreactivation
Escape CMV infections
(not detected by weekly CMV NAT)
Burden, logistics, cost of weekly
surveillance labs
Molecule
Mechanism
of action
Spectrum
of activity
Bioavailability
Excretion
Dosing
Side effects
Drug
interactions
Current FDA
approval indication
Ongoing
trials

3. PRACTICE AID
Access the activity, “Changing the Paradigm of CMV Management:
New Science and More Choices for Challenging Cases in the HCT Setting,”
at PeerView.com/ZXF40.
CMV: cytomegalovirus; GCV: ganciclovir; HCT: hematopoietic stem cell transplantation; NAT: nucleic acid testing; QTc: corrected QT interval; SOT: solid organ transplantation; VGCV: valganciclovir.
1. El Helou G, Razonable RR. Infect Drug Resist. 2019;12:1481-1491.
Mechanism
of action
• 2ʹ-deoxyguanosine
analog
• Competitive binding
to UL54
• DNA polymerase
• Needs phosphorylation
by CMV (UL97 encoded)
and host kinases
• Virostatic agent
• Pyrophosphate analog
• Noncompetitive inhibitor
of many RNA and DNA
polymerases (UL54 DNA
polymerase in CMV)
• Virostatic agent
• Acyclic monophosphate
deoxycytidine analog
• Competitive substrate of
UL54 DNA polymerase
leads to inhibition of viral
DNA synthesis through
incorporation into
growing viral DNA chain
• Virostatic agent
• Inhibits viral terminase
complex, encoded by
genes UL56, UL51, and
UL89
• Virostatic agent
Indications/
uses
• CMV retinitis
• CMV prophylaxis SOT
Non-FDA uses
• CMV disease
• CMV preemptive strategy
• CMV prophylaxis in HCT
• CMV retinitis
Non-FDA uses
• Second line for GCV-
resistant CMV disease
therapy, prophylaxis, or
preemptive therapy
• CMV retinitis
Non-FDA uses
• Second line for GCV-
resistant CMV disease
therapy, prophylaxis, or
preemptive therapy
• CMV prophylaxis in
CMV-seropositive HCT
recipients
Formulations
• GCV IV only
• VGCV oral
• IV only
• IV only
• Lipid conjugate not yet
approved (brincidofovir)
• IV and oral
Adverse effects
• Pancytopenia and
myelosuppression
(leukopenia/
neutropenia++)
• Renal injury
• Diarrhea
• Less common: pruritus,
nausea, fever, torsade de
pointe
• Renal injury
• Electrolytes wasting
• Neutropenia
• Less common: headache,
diarrhea, fever, QTc
prolongation
• Renal injury
• Proteinuria
• Neutropenia
• Ocular toxicity (iritis,
uveitis, amblyopia)
• Less common: headaches,
shivering, rash, alopecia,
dyspnea
• Uncommon, mainly
GI (gastritis, nausea),
dyspnea, hepatitis
Resistance
mechanism
• Mutations in UL97 gene
prevent activation of drug
• Mutations in UL54 gene
prevent binding to DNA
polymerase (may confer
cross-resistance with all
DNA-polymerase active
antivirals)
• Mutations in UL54 gene
prevent binding to DNA
polymerase (may confer
cross-resistance with all
DNA-polymerase active
antivirals)
• Mutations in UL54 gene
prevent binding to DNA
polymerase (may confer
cross-resistance with all
DNA-polymerase active
antivirals)
• Mutations in UL56 gene
• Less commonly,
mutations in UL51 or UL89
genes
Characteristics of Antiviral Drugs Approved for CMV
Ganciclovir and
Valganciclovir
Foscarnet Cidofovir Letermovir
Preventing CMV infection and
Disease in HCT Recipients1

4. Access the activity, “Changing the Paradigm of CMV Management: New Science and More Choices for
Challenging Cases in the HCT Setting,” at PeerView.com/ZXF40.
PRACTICE AID
A Closer Look at Resistant and Refractory CMV
Infection and Disease in HCT Recipients1,2
Risk Factors for CMV Resistance
in HCT Recipientsa
Summary of the Definitions of Refractory
CMV Infection and Disease and Antiviral Drug
Resistance for Use in Clinical Trials
Host
factors
Host
factors
Viral
factors
• Prolonged antiviral CMV drug exposure (>3 mo)
• Previous antiviral CMV drug exposure
• Recurrent CMV infection
• Inadequate antiviral CMV drug absorption
and bioavailability
• Inadequate antiviral CMV oral prodrug conversion
• Variation in antiviral CMV drug clearance
• Subtherapeutic antiviral CMV drug level
• Poor patient compliance with antiviral drug regimen
• T-cell depletion
• Haploidentical, allogeneic, or cord blood HCT
• Delayed immune reconstitution
• CMV-seropositive recipient and CMV-seronegative donor
• Treatment with antithymocyte antibodies
• Active GVHD
• Young age
• Congenital immunodeficiency syndromes
Refractory CMV
infection
Probable
refractory CMV
infection
Refractory CMV
end-organ disease
Probable
refractory CMV
end-organ
disease
Antiviral drug
resistance
• CMV viral load rise while receiving treatment
(after >2 wk of adequate dosing)
• Failure of CMV viral load to fall despite appropriate
treatment
• Rise in CMV viral load after initial decline
while receiving appropriate treatment
• Intermittent low-level CMV viremia
• High CMV viral loads
Host
factors
CMV viremia that
increasesb
after
at least 2 wk of
appropriately dosed
antiviral therapy
Worsening in signs and
symptoms or progression
into end-organ disease
after at least 2 wk of
appropriately
dosed antiviral therapy
Viral genetic alteration
that decreases
susceptibility to one
or more antiviral drugsd
Persistent viral loadc
after at least 2 wk of
appropriately dosed
antiviral therapy
Lack of improvement
in signs and symptoms
after at least 2 wk
of appropriately dosed
antiviral drugs

5. Access the activity, “Changing the Paradigm of CMV Management: New Science and More Choices for
Challenging Cases in the HCT Setting,” at PeerView.com/ZXF40.
PRACTICE AID
A Closer Look at Resistant and Refractory CMV
Infection and Disease in HCT Recipients1,2
a
Most of the risk factors for CMV resistance pertain to solid organ transplant recipients as well, in addition to graft rejection (instead of GVHD) and CMV-seropositive donor and CMV-seronegative recipient. b
More than 1 log10
increase in CMV DNA levels in
blood or serum and determined by log10
change from the peak viral load within the first week to the peak viral load at ≥2 weeks as measured in the same laboratory with the same assay. c
CMV viral load at the same level or higher than the peak viral load
within 1 week but <1 log10
increase in CMV DNA titers done in the same laboratory and with the same assay. d
Known examples involve genes involved in antiviral drug anabolism (eg, UL97-mediated phosphorylation of ganciclovir), the antiviral drug target
(eg, UL54, UL97, UL56/89/51), or compensation for antiviral inhibition of biological function (eg, UL27).
CMV: cytomegalovirus; GVHD: graft-vs-host disease; HCT: hematopoietic cell transplantation; SOT: solid organ transplantation.
1. Chemaly RF et al. Clin Infect Dis. 2019;68:1420-1426. 2. Papanicolaou GA et al. Clin Infect Dis. 2019;68:1255-1264.
Maribavir for Refractory or Resistant CMV Infections
Cl N
N
N
H
HO
O
O
O H
H
Cl
A Phase 3, Multicenter, Randomized, Open-Label,
Active-Controlled Study to Assess the Efficacy
and Safety of Maribavir Treatment Compared to
Investigator-Assigned Treatment in Transplant
Recipients With Cytomegalovirus (CMV) Infections
That Are Refractory or Resistant to Treatment With
Ganciclovir, Valganciclovir, Foscarnet, or Cidofovir
• Clinicaltrials.gov/NCT02931539
• Status: recruiting
HCT + SOT
Side effects: dysgeusia and nausea, vomiting
Phase 3
trial
Completed
phase 3
trial
Within 6 weeks, 67% of patients
had undetectable plasma CMV DNA
Refractory or resistant CMV infection