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1545
ISSN 1746- 0913
Future Microbiol. (2015) 10(10) , 1545 –1548
part of
10.2217/fmb.15.82 © 2015 Future Medicine Ltd
EDITORIAL
Cytomegalovirus antiviral drug
resistance: future prospects
for prevention, detection and
management
Kimberly E Hanson1,2 & Sankar Swaminathan*,1
Keywords
• adoptive immunotherapy
• antiviral drug resistance
•cytomegalovirus • human CMV
Human cytomegalovirus (CMV) is one
of the most important viral pathogens
affecting hematopoietic stem cell trans-
plant (HSCT) and solid organ transplant
(SOT) recipients, because infection is fre-
quent and it exerts short- and long-term
effects on host immunity. The direct
effects of active CMV infection include
fever, bone marrow suppression and inva-
sive end organ disease. Indirectly, CMV
increases risk for other infections and is
associated with increased rejection, graft
loss, mortality and transplant costs [1] .
Given the impact of CMV on transplant
outcomes, prevention of active infection
and aggressive treatment of invasive disease
are essential.
Prevention strategies include univer-
sal antiviral prophylaxis or pre-emptive
therapy that is based on sequential viral
load monitoring in blood. Both approaches
prevent CMV disease in at-risk patients,
but they are limited by the toxicities of
available anti-CMV drugs (i.e., cytopenias
from valganiclovir, ganciclovir and cidofo-
vir, and nephrotoxicity from foscarnet and
cidofovir) and the potential for the virus to
develop antiviral drug resistance (AVR).
Furthermore, optimal viral load thresholds
for the initiation of pre-emptive therapy
have not been defined and it is likely that
these cut-offs will vary based on host fac-
tors as well as the quantitative PCR assay
used for testing. Due to these complexi-
ties, an ideal preventative approach has
yet to be identified. Only prophylaxis
would be expected to prevent CMV indi-
rect effects, but early treatment of viremia
(i.e., pre-emptive therapy) may allow some
reconstitution of protective immunity.
Current approaches
HSCT programs generally apply pre-
emptive therapy to avoid the marrow sup-
pressive effects of valganciclovir (VGCV)
or ganciclovir (GCV). Some centers also
utilize prophylaxis for unrelated, HLA-
mismatched or cord blood transplants. SOT
programs also typically use prophylaxis for
the highest risk patients (CMV seroposi-
tive donor [D+]/CMV seronegative recipi-
ent [R-]), and may consider pre-emptive
approaches for moderate-risk R+ liver or
kidney recipients. The routine use of pro-
longed CMV prophylaxis (i.e., ≥6 months
of VGCV) has raised concern about AVR,
1Department o f Medicine, Division of Infec tious Diseases, Universit y of Utah, UT, USA
2Departm ent of Pathology, ARUP Laboratories, Universit y of Utah, UT, USA
*Author for correspondence: sankar.swaminathan@hsc.utah.edu
“Antiviral drug resistance is a
dreaded complication
because it makes treatment
more difficult, is associated
with poor clinical outcomes
and may lead to allograft loss
or death.”
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Future Microbiol. (2015) 10(10)
154 6
editorial Hanson & Swaminathan
future science group
with the potential to develop cross-resistance to
currently available drugs. A recent report also
described a high incidence of AVR among D+/R-
kidney recipients receiving pre-emptive ther-
apy [2] . AVR is a dreaded complication because
it makes treatment more difficult, is associated
with poor clinical outcomes and may lead to
allograft loss or death [3] .
GCV and its oral prodrug VGCV are the cur-
rent cornerstones of CMV therapy. These agents
are nucleoside analogs that require phosphoryla-
tion by the viral protein kinase (UL97 gene) in
order to inhibit the CMV DNA polymerase
(UL54 gene) that is required for viral replica-
tion. Certain mutations within the UL97 and/
or UL54 genes have been linked to GCV and
VGCV resistance (reviewed in [4]). Cidofovir
(CDV) and foscarnet (FOS) act at the level of
the DNA polymerase. Mutations in the UL54
gene can confer resistance to CDV, FOS or cross-
resistance to both CDV and GCV. CDV resist-
ance has been reported following GCV therapy,
while FOS resistance typically requires previous
exposure to that drug.
CMV AVR is suspected when viral load
increases or plateaus despite at least 2 weeks of
appropriate antiviral therapy. Drug resistance
is then confirmed by detecting specific gene
mutations or with phenotypic drug susceptibility
testing. Most laboratories use standard Sanger
DNA sequencing of known resistance loci to
detect drug resistance mutations. Confirmation
of genotypic resistance is preferred because host
factors or inadequate drug levels may also affect
treatment response, and empiric changes in anti-
viral therapy often have adverse side effects. A
limitation of current laboratory practice is that
standard DNA sequencing may not detect drug-
resistant heterogeneity (<20–30%) in a mixed
viral population. Minority CMV populations
can be clinically relevant and newer technolo-
gies such as next-generation sequencing [5] , that
can detect subpopulations on the order of 1–3%,
are being explored for the enhanced detection of
genotypic resistance.
Most AVR has been reported in the context
of long-term GCV or VGCV use, usually after
at least 6 weeks of drug exposure [6] . Precise esti-
mates of AVR prevalence and risk in an era of
VGCV prophylaxis and pre-emptive therapy are
limited by the paucity of large prospective stud-
ies. In general, CMV AVR appears to be rela-
tively uncommon after HSCT [7] but may affect
as many 5–27% of viremic SOT recipients, with
the highest incidence following lung transplan-
tation [8]. Risk factors for AVR include D+/R-
serostatus in SOT, lung transplantation, high
viral load, persistent viremia on therapy and sub-
optimal GCV concentrations [9] , as well as hap-
loidentical T-cell-depleted HSCT [10 ] . The exact
role, if any, that therapeutic drug monitoring
should have in detecting subtherapeutic GCV
drug concentrations needs to be better defined.
Future possibilities
Given the safety profile of traditional drugs in
conjunction with the problem of AVR, better-
tolerated anti-CMV agents with different
mechanisms of action are needed. The primary
risk for active infection after transplantation is a
reduced number and function of CMV-reactive
T cells. Therefore, reduction in immunosuppres-
sion when feasible is an essential component of
CMV management.
Adoptive transfer of donor-derived or third
party T cells is being explored as a way to pro-
mote immune reconstitution and reduce viral
burden. Perhaps the most exciting approach is
the generation and expansion of broad-spectrum,
cytotoxic donor T lymphocytes in vitro which
recognize virus-specific epitopes, persist and pro-
liferate in vivo [1 1] . These strategies have been
used in prophylactic and pre-emptive regimens
as well as for the treatment of clinically resist-
ant infection. Despite significant heterogeneity,
most studies have observed that CMV-specific
T-cell immunity can be restored without induc-
ing graft-versus-host disease or other significant
toxicity [12–14]. It is possible that adoptive T-cell
therapy could be used in combination with
shorter course antiviral prophylaxis to enhance
cellular immune protection while minimizing
antiviral drug side effects, cost and AVR.
Three experimental CMV antivirals have
entered Phase II and III clinical trials. Maribavir
(MBV) and letermovir (LTV) have unique
mechanisms of action. MBV is an oral UL97
protein kinase inhibitor that initially failed
Phase III prophylaxis trials possibly due to
inappropriate dose selection [15] . More recently,
two as of yet unpublished Phase II dose-rang-
ing studies have been completed that examined
higher doses of MBV as pre-emptive therapy
(EuraCT: 2010-024247-32) and for refractory
or resistant CMV (ClinicalTrials.gov identi-
fier: NCT01611974). Since UL97 is needed to
phosphorylate GCV, therapy with MBV and
GCV would be expected to be antagonistic.
“Three experimental
human cytomegalovirus
antivirals have entered
Phase II and III clinical
trials.”
1547
Cytomegalovirus antiviral drug resistance editorial
future science group www.futuremedicine.com
However, the UL97 mutations elicited by MBV
and GCV are different and MBV retains in vitro
activity against most GCV- and CDV-resistant
viruses [16 ] . Of note, there is a single p-loop
mutation (F342S) that has been shown to confer
dual cross-resistance between MBV and GCV,
but does not affect kinase activity or growth in
cell culture [17 ] . The F342S mutation has not yet
been observed in vivo.
LTV (formerly AIC-246) is a CMV-specific
viral terminase inhibitor with potent in vitro
activity against wild-type and drug-resistant
virus. Oral and intravenous formulations have
been developed, which is of potential ben-
efit for patients unable to tolerate or absorb
oral therapy. LTV recently entered Phase III
prophylaxis studies (ClinicalTrials.gov iden-
tifier: NCT02137772) after successful com-
pletion of an HSCT Phase II dose-escalation
trial [18]. No AVR information was provided in
the Phase II report. However, high-grade resist-
ance mutations in the UL56 terminase gene are
readily selected in vitro and await clinical cor-
relation [19] . The potentially low barrier to LTV
resistance may limit the utility of this agent as
monotherapy for severe disease or high-grade
viremia.
Brincidofovir (formerly CMX-001) is a broad-
spectrum, orally bioavailable lipid conjugate of
CDV. Unlike CDV, brincidofovir (BCV) is not
a substrate for human organic anion transport-
ers (hOATs) and therefore has reduced potential
to cause renal impairment. A Phase II prophy-
laxis study in HSCT was completed wherein no
development of AVR was noted [2 0] . Phase III
trials are currently underway (ClinicalTrials.gov
identifier: NCT0176170). Despite overlapping
resistance mechanisms, BCV may have a role in
treating genotypically resistant infection because
the drug has potent in vitro activity and achieves
high intracellular concentrations.
Combination antiviral therapy is the standard
of care for other viral infections, such as HIV
and HCV. Dual DNA polymerase inhibitor
treatment for CMV, however, has been limited
by additive toxicity, cross-resistance and a lack
of evidence to support effectiveness. We have
now entered an exciting time of late-phase drug
development for several anti-CMV agents with
novel drug targets, potent activity and reduced
toxicity. Additionally, CMV-specific immuno-
therapies are under active investigation. These
agents used alone or in combination, create new
opportunities to refine our management strate-
gies and potentially provide therapeutic alterna-
tives for drug-resistant CMV. Studies are now
needed to determine whether combinations of
the new agents with different mechanisms of
action can improve treatment efficacy and/or
reduce the risk for AVR. Additionally, stud-
ies comparing prophylactic versus pre-emptive
approaches, that utilize standardized CMV
assays and are powered to assess both the direct
as well as indirect effects of CMV, will better
inform clinical practice in the future.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial
involvement with any organization or entity with a finan-
cial interest in or financial conflict with the subject matter
or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or
pending, or royalties.
No writing assistance was utilized in the production of
this manuscript.
“We have now entered
an exciting time of late-
phase drug
development for several
anti-cytomegalovirus
agents with novel drug
targets, potent activity and
reduced toxicity.”
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