CMV in SOT

SARA AB O L G H ASE M I,M D

INF E CT IO US D ISE ASE S SP E CIA L IST
F E L L O W SH IP IN INF E CT IO N O F IM M UN O CO M P RO M ISE D PAT IE NT S
FACU LT Y M E M B E R O F SB M U
Case:
A 35 y/o female patient known case of cirrhosis due to autoimmune hepatitis, is a candidate for
liver transplantation. MELD score : 25

What screening tests do you request for recipient?

Screening tests (R&D)
HIV Ab, HBSAg, HBCAb, HBSAb,HCVAb,( NAT)
CMVIgG,EBV IgG, VZV IgG ?, HSV IgG? ,
Syphlis (EIA or RPR)
TB (PPD or IGRA)
Toxoplasma Ab IgG ?
SS Ab
The patient and her deceased donor were seropositive for CMV, EBV, HSV. And other tests were
negative
If the patient has received only childhood vaccination What is your
recommendation for patient’s vaccination?

Hepatitis B,
Pneumococus ( PCV13, 8 weeks later PPSV23)
Influenza
Hepatitis A, VZV ?
She received methylprednisolone and then tacrolimus, cellcept and
5mg prednisolone for prevention of graft rejection.
Which strategy for CMV prevention do you recommend?
Prophylaxis? 

Preemptive? 

Prophylaxis: Drugs: valganciclovir (note FDA caution) or intravenous

ganciclovir
Duration: 3 mo
CMV Prevention
Universal Prophylaxis

Preemptive Treatment
CMV Spectrum

CMV CMV CMV

Infection: All represent
Syndrome:
Fevers, Disease: replicating CMV
Organ Disease virus
Asymptomatic leukopenia
 Advantages:

–Minimizes drug exposure

–This may potentially decrease toxicity and drug costs
–Theoretically lowers risk of resistance
– Less late-onset disease: may allow development of
cell-mediated immune response
Disadvantages:

– Logistically more difficult to coordinate

– May be unsuccessful in preventing progression to
active disease in high-risk patients due to rapid
doubling time
– May not eliminate the indirect effects of CMV
Late CMV
Disease occurring after the discontinuation of prophylaxis:
– D+/R-
– Ongoing significant immunosuppression
– Allograft rejection
– Lack of development of significant CMV-specific,cell-mediated
immunity
– Immunologic/genetic factors
 Who Is at Risk?
•CMV serology status of donor/recipient (D+/R-)
•Organ transplanted : Lung/small bowel > pancreas, heart > liver, kidney
•Patient factors (age, comorbidities)
•Exogenous: Immunosuppression—Induction, routine, rejection
•High-volume transfusion of blood products
•Polymorphisms of Toll-like receptor-2 and Toll-like receptor-4
•Deficiencies of complement proteins and mannose-binding lectin
•Viral factors
GUIDELINES – Kidney, Liver,
Pancreas, and Heart
D+/R-
– Universal prophylaxis preferred (II/III)
– Valganciclovir (FDA caution in livers but some experts still use), oral
ganciclovir, IV ganciclovir, or valacyclovir (kidney)

Start by day 10 until 3-6 months

The duration of prophylaxis in D+/R- should be generally between 3-
6 months

6 months (minimum) is recommended for lung and small intestine

SOTs

Some centers add CMV immunoglobulin (CMV Ig) for heart, lung,
and bowel transplants
R+ Patients:

– Prophylaxis: ganciclovir, valganciclovir (FDA caution in livers),

valacyclovir (kidneys) (I/II)
or
– Preemptive therapy – pp65 antigen test or molecular diagnostic test
(II-2); IV ganciclovir or valganciclovir for positive test (I)
If you choose preemptive, How do you perform your surveillance for
CMV?
Viral load(PCR) or Antigen(PP65)?
Frequency?
Whole blood or Plasma
Cutoff
Duration?
Weekly CMV QNAT (or pp65 antigenemia) of
(whole blood or plasma) for 12 wk
Case (continue…)
After 2 month CMV viral load= 8000 of whole blood has been
reported What is your plan?
Drug?
Dosage?
How do you monitor response to treatment?
Duration of treatment?
Valganciclovir first line
IV ganciclovir first line
Foscarnet nephtotoxic
Cidofovir nephrotoxic
Brincidofovir GI toxic
Maribavir not approved
Letermovir not approved for treatment and prophylaxis of SOT
If a positive CMV threshold is reached (2000 to 4000 or 5/50000)

valganciclovir 900 mg po BID (preferred), or IV ganciclovir

5 mg/kg IV every 12 h until negative test

What is your recommendation about Maintenance therapy?

Not routinely recommended
Valgancyclovir 900 mg BD was started with weekly monitoring of CMV NAT

After 2 weeks the viral load was undetectable and the valcyte was discontinued
but 1 month later the viral load became positive again: at load of 12,000.
Gancyclovir 5mg/Kg BD was started,
1 week later : CMV viral load=12,800, What do you do?
After 2 weeks CMV viral load=100,000, what do you do ?
Definitions of resistance

Antiviral drug resistance can manifest as true virological

resistance secondary to one or a combination of clinically
significant mutations or as “clinical resistance” in the absence of
these mutations.
The distinction between these two entities is important, as
clinical resistance is mainly secondary to host or viral factors
rather than genotypic mutations, and altering antiviral therapy
without addressing the host factors could be detrimental to the
patients in many instances.
Antiviral drug resistance should be suspected when CMV viremia
(DNAemia or antigenemia) fails to improve (ie, >1 log10 increase
in CMV DNA levels in blood or serum) after 2 weeks of
appropriately dosed and delivered antiviral therapy.

Antiviral drug resistance should also be suspected when CMV

end-organ disease occurs during prolonged antiviral therapy
(>6 weeks of antiviral drug exposure, including 2 weeks of full-
dose therapy) in the presence of risk factors.
UL97
CMV UL97 is the gene that encodes for a viral kinase that catalyzes the initial
mono‐phosphorylation and activation of ganciclovir. leads to the active
ganciclovir‐triphosphate (a nucleoside analogue)
UL54
ganciclovir‐triphosphate serves as a competitive substrate for incorporation
into the elongating CMV DNA chain, a process that is catalyzed by CMV DNA
polymerase (an enzyme encoded by CMV UL54 gene).
Mechanism of action of antiviral drugs for CMV. In
the CMV-infected cell, GCV and valganciclovir
(VGCV) undergo phosphorylation by UL97 kinase
(pUL97) and cellular kinases. CDV
phosphorylation is independent of pUL97; cellular
kinases add an additional phosphate. GCV, VGCV,
and CDV compete with deoxynucleotide
triphosphate (dNTP) for the binding site on pUL54
(CMV DNA polymerase [pol]). FOS does not
require phosphorylation. Once inside the CMV-
infected cell, FOS directly inhibits CMV DNA
replication by binding to the pyrophosphate (ppi)
site of pUL54. Alterations in the substrate binding
or phosphate transfer sites of pUL97 confer UL97
resistance to GCV and VGCV. Alterations in the
catalytic site or relative increases in the
exonuclease activity of pUL54 confer UL54
resistance to GCV, VGCV, and CDV. Alterations of
the ppi binding site of pUL54 confer UL54
resistance to FOS.
IC50 = 50% inhibitory concentration, the concentration at which
there is a 50% reduction in the number of plaques on a phenotypic
plaque reduction assay

GCV ratio = IC50 of mutant/IC50 of wild-type

GCV IC50 values≤ 6 indicate sensitivity, and values ˃6 indicate

resistance
For GCV:
IC50 increases of twofold to fivefold may be considered low-grade
IC50 fivefold to 15-fold considered moderate (a level that may result
from a single UL97 mutation),
IC50 greater than 15-fold considered a high level that suggests the
combined effect of UL97 and UL54 mutations
foscarnet and cidofovir also act to inhibit UL54‐encoded CMV DNA
polymerase,
mutations in UL54 gene may confer cross‐resistance to ganciclovir,
foscarnet, and cidofovir
A ganciclovir‐resistant CMV with UL54 mutation is more likely to be
cross‐resistant to cidofovir
foscarnet is the empiric choice for treatment of ganciclovir-resistant
CMV infection
 +

Failing to respond after at least two weeks of appropriately dosed antiviral treatment should be suspected of
having drug‐resistant virus
Genotypic assays to detect UL97 mutation should be performed among patients suspected to have resistance
to ganciclovir, and UL54 mutation analysis should be performed among patients suspected to have resistance
to ganciclovir, foscarnet, and cidofovir
reduction in immunosuppression
Maybe switch to sirolimus‐containing regimen
Options for empiric treatment :
high‐dose intravenous ganciclovir (up to 10 mg/kg q 12 hours, renally adjusted)
or foscarnet ( unavailable, nephrotoxic)
Cidofovir, Maribavir, Letermovir, IVIG
Leflunamide, Artesunate