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Ocular Immunology and Inflammation
ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: https://www.tandfonline.com/loi/ioii20
Management of Ganciclovir Resistant
Cytomegalovirus Retinitis in a Solid Organ
Transplant Recipient: A Review of Current Evidence
and Treatment Approaches
L. Fu, K. Santhanakrishnan, M. Al-Aloul, N. P. Jones & L. R. Steeples
To cite this article: L. Fu, K. Santhanakrishnan, M. Al-Aloul, N. P. Jones & L. R. Steeples (2019):
Management of Ganciclovir Resistant Cytomegalovirus Retinitis in a Solid Organ Transplant
Recipient: A Review of Current Evidence and Treatment Approaches, Ocular Immunology and
Inflammation, DOI: 10.1080/09273948.2019.1645188
To link to this article: https://doi.org/10.1080/09273948.2019.1645188
Published online: 17 Oct 2019.
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LETTER TO THE EDITOR
Management of Ganciclovir Resistant
Cytomegalovirus Retinitis in a Solid Organ
Transplant Recipient: A Review of Current Evidence
and Treatment Approaches
L. Fu, FRCOphth,
1,2
K. Santhanakrishnan, MRCP,
3
M. Al-Aloul, FRCP,
3
N. P. Jones, FRCOphth,
1,2
and
L. R. Steeples, FRCOphth
1,2
1
Manchester Royal Eye Hospital, Manchester University NHS Foundation Trust, Manchester Academic
Health Sciences Centre, Manchester, UK,
2
Centre for Ophthalmology and Vision Sciences, Faculty of Medical
and Human Sciences, University of Manchester, Manchester, UK, and
3
Department of Cardiothoracic
Transplant, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK
ABSTRACT
Purpose: Cytomegalovirus retinitis (CMVR) is a serious and potentially sight-threatening infection in immuno-
compromised individuals. Strategies for the management of drug-resistant CMVR are described.
Methods: A case of severe bilateral CMVR in a single lung transplant patient, with UL97 mutation conferring
ganciclovir-resistance, is presented. Treatment with standard antiviral agent and adjuvant leflunomide, immu-
nosuppression modifications (calcineurin inhibitors and corticosteroid), intravitreal antiviral therapy and novel
use of CMV-immunoglobulin is described. A literature review to support drug-resistant CMVR management is
presented.
Results: Severe and progressive CMV retinitis was refractory to intravitreal foscarnet and systemic leflunomide.
Drug-toxicity restricted systemic antiviral therapy options. The use of combined leflunomide and CMV-
immunoglobulins, in the absence of viremia, has not been previously reported. Loss of ganciclovir-resistance
was eventually observed permitting successful treatment with systemic and intravitreal ganciclovir.
Conclusions: Drug-resistant CMVR is a complex clinical challenge. Multiple systemic and local treatment
strategies may be necessary but toxicity, resistance, and co-morbidities may severely restrict available options.
Keywords: Cytomegalovirus (CMV) retinitis, drug-resistance, ganciclovir-resistance, immunoglobulins, UL97
Cytomegalovirus (CMV) is an ubiquitous human
herpes virus and causes significant morbidity and mor-
tality in immunocompromised hosts.
1
Cytomegalovirus
retinitis (CMVR) is severe and potentially blinding and
was commonly seen in patients with acquired immuno-
deficiency syndrome (AIDS) prior to modern highly
active antiretroviral therapy (HAART). Following the
introduction of HAART a dramatic reduction in the
incidence of CMVR in the HIV population was
observed.
2
In the non-HIV immunosuppressed popula-
tion, particularly solid organ transplant (SOT) or hemo-
poietic cell transplant (HCT) recipients, CMV infection
is common and tissue-invasive disease, including
CMVR, is important.
3
Treating viremia and tissue-
invasive disease may be challenging in the context of
systemic immunosuppression. Toxicity and emergence
of drug resistance are major concerns with currently
available antiviral therapies.
4
Current evidence for the management of drug-
resistant CMVR, particularly the use of novel therapies,
is limited and low-grade. Approaches are directed by
evidence for management of non-ocular drug-resistant
disease in transplant patients. We present a clinically
challenging case of ganciclovir (GCV)-resistant CMVR
Received 30 April 2019; revised 9 July 2019; accepted 15 July 2019
Correspondence: L. Fu, Manchester Royal Eye Hospital, Oxford Road, Manchester, M13 9Wl, UK. E-mail: Lana.Fu@mft.nhs.uk
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ioii.
Ocular Immunology & Inflammation, 2019; 0(0): 1–7
© 2019 Taylor & Francis Group, LLC
ISSN: 0927-3948 print / 1744-5078 online
DOI: 10.1080/09273948.2019.1645188
1
in a SOT patient. Strategies for management are dis-
cussed including standard and adjuvant systemic anti-
viral agents, local antiviral therapy, modification of
immunosuppression and novel use of CMV immunoglo-
bulins (CMV IgG) for retinitis.
CASE REPORT
A 55-year-old male presented with bilateral CMVR 20
months after right single lung transplant for idio-
pathic pulmonary fibrosis. He had received standard
immunosuppression with rabbit antithymocyte glo-
bulin (RATG) induction (1.5 mg/Kg for 3 days) then
maintenance therapy with azathioprine, ciclosporin,
and prednisolone (15 mg/day). The CMV status was
both donor and recipient positive (D+/R+) and pro-
phylactic valganciclovir (VGCV) was administered
(450 mg daily) for 3 months.
Surveillance bronchoscopy and biopsy 3 weeks post-
transplant showed mild acute rejection. Intravenous (IV)
methylprednisolone was administered and ciclosporin
was switched to tacrolimus (2 mg twice daily). Three
months later, a further mild rejection episode was suc-
cessfully treated with IV methylprednisolone. Nine
months post-transplant, CMV viremia was detected for
the first time (log 4.89). Induction therapy with IV GCV
followed by oral VGCV achieved reduction in viral load
to undetectable levels. However, 3 weeks later rising
CMV viral load was observed (log 3.46) and complicated
by CMV pneumonitis. Resistance testing identified the
UL97 C670Y mutation, conferring resistance to GCV;
UL54 testing was negative. Intravenous foscarnet (FOS)
therapy replaced GCV but severe nephrotoxicity devel-
oped and it was discontinued. Systemic leflunomide and
weekly CMV immunoglobulin (CMV-IG, Cytotec®)
therapy achieved disease control with recovery of pul-
monary function and eventual resolution of viremia (18
months post transplant). Leflunomide was continued as
long-term antiviral therapy alongside oral tacrolimus
(2 mg twice daily) and prednisolone (5 mg daily).
Two months after resolution of viremia (20 months
post transplant) the patient presented with floaters
and reduced vision and was referred for tertiary uvei-
tis opinion. His vision was right (R) 1.0 and left (L) 0.6
logMAR. There was bilateral low-grade granuloma-
tous anterior uveitis and mild vitritis. Bilateral per-
ipheral necrotizing retinitis was seen with 4 and 2
clock-hours of retinitis in the R and L eyes, respec-
tively. The patient was pseudophakic. Aqueous sam-
pling was positive for CMV and negative for herpes
simplex, varicella zoster, and syphilis. HIV and syphi-
lis serology were negative. Blood PCR for CMV was
negative. Intravitreal FOS (2.4 mg/0.1 ml) was
initiated in the right then the left eye and repeated
at 1–2-week intervals.
Despite systemic leflunomide, and repeated intra-
vitreal FOS over 15 months (3 injections to the right,
and 16 to the left eye) bilateral persistent and progres-
sive retinitis was observed. Chorioretinal scarring
developed in previously necrotizing areas and cir-
cumferential spread of CMVR was seen (Figure 1).
Systemic immunosuppression was switched from
tacrolimus to sirolimus (1.5 mg daily) for secondary
antiviral properties. During the switch, increased pre-
dnisolone (8 mg daily) was given for 2 months.
Bilateral extension of retinitis to zone 2 was of signifi-
cant clinical concern. Serial aqueous sampling demon-
strated persistent high viral load and GCV-resistant
virus (UL97 C607Y mutation positive); UL54 mutation
testing was negative with no evidence of resistance to
FOS. Blood PCR remained negative for CMV.
Systemic FOS was contraindicated due to persistent
renal impairment.
Two-weekly CMV–IG (Cytotec®) was adminis-
tered alongside 1–2 weekly bilateral intravitreal FOS
over 2 months. A partial response was observed: in
the right eye retinitis remained active but progression
was halted; in the left eye reduction in serial aqueous
FIGURE 1. Wide-field retinal image (Optos ®) right (a) and left (b) eyes demonstrating active necrotizing retinitis, with circumfer-
ential progressive spread and extensive chorioretinal scarring in previously necrotizing areas.
2L. Fu et al.
Ocular Immunology & Inflammation
viral load and reduction in the area of retinitis was
observed after 3 weeks of treatment. The right eye
developed rhegmatogenous, macula-off, retinal
detachment with deterioration in vision to 1.0
logMAR. Pars plana vitrectomy, endolaser, and oil
tamponade was successfully performed. Under oil
tamponade retinitis resolved with no disease
recurrence.
Subsequently, left eye retinitis progressed cir-
cumferentially, threatening the macula with sequen-
tial extensive peripheral scarring. (Figure 2)Despite
regular intravitreal FOS (1–2 weekly), rising left eye
aqueous viral load (peak log 6.4) and persistent
activity was observed. There was no CMV viremia
even after temporary withdrawal of leflunomide.
Further UL97 and UL54 mutation analysis testing
was negative, indicating loss of resistance.
Induction therapy, adjusted for renal function, was
recommenced with intravenous GCV (2.5 mg/kg,
daily for 4 weeks) plus weekly CMV-IG (2 mg/kg
for 4 weeks). Weekly left eye intravitreal GCV
(2 mg/0.1 ml) for 4 weeks was given and a rapid
drop in ocular viral load and full resolution of CMV
retinitis was observed. (Figure 3)
Sirolimus and VGCV (450 mg daily) therapy were
continued with no recurrence of retinitis during 12
months follow-up and with stable renal function.
Right eye silicone oil removal and epiretinal mem-
brane peel was performed 6 months post-
detachment repair and the retina has remained
attached. The vision remains 0.4 LogMAR in both
eyes.
DISCUSSION
This case demonstrates the complexities of drug-
resistant CMV retinitis in immunocompromised
patients. In transplant recipients, mandatory immu-
nosuppression for transplant survival restricts oppor-
tunity for immune reconstitution and permits the
possibility of viral reactivation and tissue-invasive
disease. Incomplete suppression of viral replication
risks the eventual development of drug-resistant dis-
ease adding to the challenge of treatment.
5,6
In this
population, co-morbidities are frequent and further
restrict treatment options.
Antiviral resistance can manifest from true viral
resistance secondary to one or more genetic mutations
or as a result of “clinical resistance”in the absence of
any detectable mutations. The latter is attributable to
host or viral factors. In general, CMV drug-resistance
FIGURE 2. Sequential wide-field retinal images (Optos ®) of left eye demonstrates persistent and progressive CMV retinitis. CMV
retinitis was refractory to treatment and circumferential disease progression was observed from baseline (a) with retinitis advancing
superiorly and temporally (b, c) and threatening the macula (d). Resultant extensive chorioretinal scarring is observed involving
zones 1–3.
Management of Ganciclovir CMV Retinitis in SOT 3
© 2019 Taylor & Francis Group, LLC
should be suspected in patients who have received
several weeks of full dose antiviral therapies and have
rising or persistent CMV viral load or tissue
disease.
5,7
Resistance is unusual in the first 6 weeks
of therapy.
8
Other causes for sub-optimal response
should always be considered and confirmation of
drug resistance is desirable because empirical treat-
ment changes may cause drug toxicity.
5
Drug resistance is caused by mutations either in the
phosphotransferase-gene (UL97) or in the viral poly-
merase gene (UL54). Mutations emerge first in UL97,
conferring high- or low-grade GCV resistance. Later,
UL54 mutations may emerge with cross-resistance to
GCV-cidofovir (CDV), GCV-FOS, GCV-CDV-FOS, or
FOS alone even without prior exposure to CDV or
FOS.
9
There are many known mutations, with new
mutations detected continuously. Different levels of
resistance are conferred with individual mutations.
Prolonged drug exposure (>3 months) and incom-
plete suppression of viral replication with sub-
therapeutic drug activity (resulting from inadequate
dosing, absorption or prodrug conversion and varia-
tion in drug clearance) are major risk factors for drug
resistance.
5,7,10
Other risks are high peak viral load,
recurrent infection, T-cell depletion, delayed immune
reconstitution and prior drug exposure, although pre-
emptive therapy in HCT has been shown to be
protective.
11
In renal impairment, absorption during
adjusted dosing is uncertain. In our patient, signifi-
cant immunosuppression with high-dose corticoster-
oid during transplant rejection episodes and T-cell
inhibition immunomodulation therapy (IMT) were
significant risks for emergence of drug resistance.
There may be no detectable CMV in blood or other
tissue at the time of presentation with CMVR. Active
ocular disease, including persistent or progressive reti-
nitis, with persistent or rising intraocular viral load,
may be the only indicator of drug resistance. This high-
lights the utility of ocular sampling for PCR, further to
diagnostic purposes, for serial quantification of viral
load and/or resistance testing. However, the small
volume typically obtained (~0.1 ml from the anterior
chamber) may restrict the number of tests and clinical
priority must be considered. Antivirals in high concen-
tration interferes with PCR analysis, and sampling
should always be performed prior to intravitreal
injection.
Several challenging factors and unusual virus beha-
viors were evident in this case. Firstly, the patient
rapidly developed true GCV resistance following short
exposure to a high GCV dose. This was deemed highly
atypical by transplant physicians. Concurrent immuno-
suppression undoubtedly accelerated the development
of resistance. Secondly, eye disease was diagnosed and
persisted when there was no systemic viremia and other
end-organ disease was controlled, indicating seques-
tered intraocular virus. Thirdly, the detected UL97
mutation conferred resistance to ganciclovir but not
FOS. UL54 mutation testing was repeatedly negative,
with no evidence of foscarnet resistance. However,
CMVR remained refractory to intensive intravitreal
FOS suggesting additional clinical resistance. Systemic
leflunomide therapy was ongoing during refractory
ocular disease and prevented viremia; however,
whether the dose was achieving sufficient intraocular
concentration to limit viral replication is uncertain.
Finally and exceptionally, after months of treatment,
loss of detectable resistance mutations was observed
and permitted re-introduction of systemic and local
GCV therapy with complete clinical resolution. This
may be explained by heterogeneous intraocular virus
populations with mixed ganciclovir sensitivities.
The outcome of CMVR is influenced by several
factors including immune function, co-morbidities,
toxicity, virulence, previous therapy and the develop-
ment of drug resistance. The site, extent and respon-
siveness of CMVR alongside complications determine
long-term visual outcomes, with high risk of signifi-
cant vision loss. Complications can be severe and
include retinal detachment (up to one third of eyes),
FIGURE 3. Wide-field retinal images (Optos ®) left eye before (a) and (b) 4 weeks post induction therapy with systemic ganciclovir
and intravitreal ganciclovir plus CMV-IG after identification of loss of resistance. Complete resolution of CMV retinitis was observed.
4L. Fu et al.
Ocular Immunology & Inflammation
macular edema and ischemia, optic atrophy, glau-
coma, and cataract.
12
Treatment
Standard Antiviral Therapy
Systemic Therapy. There are four established anti-
viral drugs for CMV infection: ganciclovir, valganci-
clovir, foscarnet, and cidofovir (CDV); all target DNA
polymerase. Oral or intravenous GCV is standard
first-line therapy. In patients with renal impairment
or impaired absorption, IV therapy is favored.
9
All
available antivirals are associated with significant
toxicity and emergence of drug resistance. Foscarnet
is second-line for resistant or refractory disease. If
UL97 resistance is diagnosed during GCV or VGCV
therapy the principal approach is to switch to IV FOS
and reduce systemic immunosuppression if possible.
Alternatively, for mutations conferring low-level GCV
resistance, dose escalation or combined GCV/FOS,
with monitoring for hematological toxicity, is an alter-
native approach.
12
Systemic adjuvant therapy may be
used alongside FOS, particularly leflunomide. Use of
cidofovir is limited by toxicity, particularly severe
nephrotoxicity and especially with concurrent calci-
neurin inhibitor therapy.
9
If there is inadequate clin-
ical response or toxicity with FOS, one or more
investigational medicines must be considered.
5
UL54
mutation resistance is treated according to cross-
resistance, with FOS, CDV and GCV used according
to sensitivity and tolerance. Drug level monitoring is
encouraged, particularly in renal-adjusted dosing.
13
Intravitreal Therapy. Currently available treatments
are foscarnet (2.4 mg/0.1 ml) and ganciclovir (1–2mg/
0.1 ml). Foscarnet is used first-line in our service with
reported lower risk of retinal toxicity.
14
Intensive induc-
tion therapy once- to twice-weekly is used in addition to
systemic therapy. In refractory disease, switching
between the two agents should be considered, with test-
ing for resistance. As seen in our case, local treatment
may need to be intense and prolonged to halt disease
progression where standard systemic treatment options
are severely restricted by toxicity and resistance.
Adjuvant Therapies
Leflunomide. Leflunomide, an immunosuppres-
sive drug approved for use in rheumatoid arthritis,
has in-vivo coincident anti-CMV activity, either
alone or in combination in CMV treatment and sec-
ondary prophylaxis.
9,15
It has variable efficacy in
multi-drug resistant and refractory disease.
9,14–16
It
may also interfere with CMV virion assembly.
15,16
There are few reports of its use in CMVR. Rifkin
et al. reported successful control of CMVR with
adjuvant leflunomide alongside other antiviral
therapy in two SOT recipients with UL-97
mutation.
17
In a further case report of leflunomide
in multi-drug-resistant CMVR the authors reported
detection of the drug in vitreous samples.
18
However, the ocular penetration and necessary
intra-ocular therapeutic concentration is unknown.
Toxicity can occur including abnormal liver
enzymes and impaired bone marrow function.
7
Immune Function
Reconstitution of immune function and host defenses is
an important aspect of the management of CMV infec-
tion. Return of CMV-specific T-cell immunity results in
control of and/or cessation of infection recurrences.
Consideration should be given to reducing immuno-
suppression where feasible. Adjusting immunosup-
pression to a mammalian Target Of Rapamycin
(mTOR) inhibitor may have a particular role.
mTOR Inhibitors. Cytomegalovirus uses the mTOR
pathway for viral replication. The mTOR inhibitors sir-
olimus and everolimus, used primarily as immunomo-
dulatory (IMT) agents, have been associated with
reduced incidence of CMV infections in transplant
recipients.
19
Switching is established in guidelines for
management of non-ocular drug-resistant CMV where
possible and requires expert physician management.
20
Temporary increases in systemic corticosteroid dose
may be necessary during switches in IMT agents, with
potential for increased viral replication/activity.
Adoptive Immunotherapy. With demonstration of the
importance of T-cell immune function, use of T-cell
adoptive treatment is of interest and described as
beneficial.
21
There is however no current evidence
for use in CMV retinitis.
CMV Intravenous Immune Immunoglobulin (CMV-IVIG).
IVIG is FDA-approved for prophylaxis of CMV disease
and is used as rescue treatment, alongside antivirals, in
refractory CMV disease.
22
A role in combination with
standard antivirals is uncertain with no evidence for
superiority of combined use with GCV/VGCV versus
appropriate antiviral therapy alone.
23
In addition, renal-
adjusted dosing is necessary. Specifically for CMVR dos-
ing, ocular penetration and clinical efficacy are uncertain.
Our case is the first documented use of Cytotec® IVIG in
the absence of systemic viremia to treat ocular tissue
disease. Overall there is a lack of evidence for use in
CMVR.
Novel Therapies
Letermovir. Letermovir is a novel CMV-terminase
inhibitor, blocking cleaving and packaging of viral
DNA. It is FDA approved for prophylaxis in HCT reci-
pients. It maintains high potency against GCV, FOS,
and CDV-resistant CMV and may be promising in
Management of Ganciclovir CMV Retinitis in SOT 5
© 2019 Taylor & Francis Group, LLC
multi-drug-resistant CMV disease.
7,24
However, there is
in-vitro evidence of rapid emergence of resistance and
recent experience of in-vivo resistance. This included
off-label use in a lung-transplant recipient conferring
letermovir resistance primarily mapping to the UL56
component of the terminase complex.
24,25
In clinical
trials, a favorable side-effect profile was reported with
no nephrotoxicity or myelosuppression.
11,26
Arolein
treatment of CMVR is not established.
Maribavir and Brincidofovir. Brincidofovir, an oral
lipid conjugate of CDV, and maribavir, an oral benzi-
midazole L-riboside that inhibits the UL97 viral pro-
tein kinase of CMV, are new treatments with potential
in the prophylaxis of CMV and treatment of refrac-
tory/resistant CMV.
9
Brincidofovir is more potent
and less nephrotoxic than CDV but associated with
increased gastrointestinal toxicity.
27,28
There is no evi-
dence of use of either agent in CMV retinitis.
CONCLUSION
Treatment of drug-resistant CMV retinitis can be extre-
mely challenging and must consider host factors,
including immune function and organ toxicity and
virus factors particularly clinical and genetic resistance.
Ganciclovir resistance and previous FOS toxicity pre-
vented use of standard systemic antivirals, and the risk
of renal failure with cidofovir or foscarnet was deemed
unacceptable. Immunomodulation was switched to an
mTOR inhibition regime with lowest possible mainte-
nance corticosteroid dose. With limited therapeutic
options, a strategy of virustatic therapy (systemic leflu-
nomide and intravitreal FOS (>50 total injections in
eyes) was used in parallel with Cytotec® IVIG to ame-
liorate tissue invasive disease. The response was limited
with partial efficacy. Identification of loss of resistance
provided a fortuitous opportunity for a major therapeu-
tic switch with an excellent outcome. Further research
on novel therapies with different antiviral mechanisms
in drug-resistant CMV retinitis is necessary.
DECLARATION OF INTEREST
The authors report no conflicts of interest. The authors
alone are responsible for the content and writing of the
paper.
ORCID
L. Fu http://orcid.org/0000-0003-1959-9749
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