JOURNAL CLUB

1. Use of Letermovir as Salvage Therapy for
Drug-Resistant Cytomegalovirus Retinitis:
A Case Series
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R.Anusha,
PharmD Intern,
170514882007.

2. INTRODUCTION
 Ganciclovir resistant CMV is a significant problem within
the transplant population.The incidence of resistance may be
as high as 45% among those previously exposed to
valganciclovir prophylaxis.
 There are few alternative treatment options, and nearly all
are limited by adverse effects.
 Letermovir, an oral antiviral agent highly specific for CMV,
was recently approved for CMV prophylaxis in
hematopoietic cell transplant (HCT) patients.
 Highly tolerable and orally bioavailable, letermovir also
shows many favorable characteristics as an alternative agent
for treating ganciclovir resistant CMV disease.
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3. METHODS
 This case series highlights a single-center experience with
off-label use of letermovir.
 Clinical data from all adult patients was analyzed at a
tertiary care hospital in North Carolina who received
letermovir for treatment of CMV disease between Nov-2017
and April-2018.
 Four patients received letermovir for treatment of
ganciclovir-resistant CMV disease after failing therapy with
ganciclovir/valganciclovir and developing nephrotoxicity
from foscarnet.
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4. RESULTS
 Letermovir was well-tolerated, with no adverse drug effects
observed for any of the four patients. Dose adjustments
were made for concomitant medications metabolized via the
Cyp3A4 pathway (e.g., tacrolimus, warfarin).
 All patients had retinoscopic improvement of their CMV
retinitis, however 3 of 4 failed to achieve viral suppression
raising concern for resistance emergent on treatment.
 Among the 3 with failed virologic suppression, 2 had
genotyping confirmed mutations in the viral terminase
(UL56) known to mediate resistance to letermovir.
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5.  Among patients with letermovir resistance, all three were
converted to a different anti-CMV agent.
 Two of the three demonstrated reversion of their prior
ganciclovir resistance. All three eventually achieved
virologic suppression on alternative therapies.
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6. Table.1: Patient characteristics and Clinical outcomes of 4 patients
with drug resistant CMV treated with Letermovir
A. 66 y.o. male B. 50 y.o. male C. 46 y.o. male D. 66 y.o. male
CMV risk factor(s) Lung txp Lung txp Heart txp Heart txp
Disease burden CMV syndrome
Retinitis
CMV syndrome
Retinitis
CMV syndrome
Retinitis
Colitis
Retinitis
Previous antivirals C, G/V, M, F G/V, F, M G/V, F C, G/V, F
Known CMV
mutations prior to
letermovir
initiation
M460V(UL97) Q578H(UL54) M460I(UL54) H520Q(UL97),
C603W(UL97),T5
03I(UL54)
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7. 7
LETERMOVIR
INITIATION
Patient A Patient B Patient C Patient D
Letermovir
dose(mg/dl)
720 960 720 720
Concomitant
therapies
CMV IgG,
Foscarnet
CMV IgG,
Foscarnet
n/a CMV
IgG,
Foscarnet
Virologic
suppression
Unsupressed Unsupressed Unsupressed Supressed
Management of
rebound viremia
and or
letermovir
resistance
Letermovir stopped,
changed to
valganciclovir and
CMV IgG;
subsequently achieved
viral suppression
Letermovir
stopped,changed to
valganciclovir;
subsequently
achieved viral
suppression
Letermovir
stopped,changed
to foscarnet;
subsequently
achieved viral
suppression
n/a
Clinical outcome Improved on
retinal exam
Improved on
retinal exam
Improved on
retinal exam
Improved
on retinal
exam

8. CONCLUSIONS
 Letermovir was an effective salvage agent for treatment and
suppression of retinitis from resistant CMV.
 Despite clinical improvement, 3 of 4 patients had rebound
DNAemia and required alternative therapies.
 The barrier to resistance appears low, both in the patient
cohort and in in vitro studies
 Letermovir should be used with caution in patients with
persistent CMV viremia.
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9. REFERENCES
 Nicholas Turner, Andrew Strand, Duke University School of
Medicine;Use of Letermovir as Salvage Therapy for Drug
Resistant Cytomegalovirus Retinitis; AMERICAN
SOCIETY FOR MICROBIOLOGY Antimicrobial Agents
and Chemotherapy,26TH Feb,2019;Page 1-6.
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