Received Date : 15-Dec-2015

Accepted Article
Revised Date : 05-May-2016

Accepted Date : 16-May-2016

Article type : Case Report

Corresponding author mail id:- kmullane@medicine.bsd.uchicago.edu

Brincidofovir treatment of acyclovir-resistant disseminated varicella zoster

virus infection in an immunocompromised host

K.M. Mullane, C. Nuss, J. Ridgeway, M.N. Prichard, C.B. Hartline, J. Theusch, H. Mommeja-

Marin, R.A. Larson

K.M. Mullane1, C. Nuss1, J. Ridgeway1, M.N. Prichard2, C.B. Hartline2, J. Theusch1, H.

Mommeja-Marin3, R.A. Larson1

1
Medicine, University of Chicago, Chicago, Illinois, USA,
2
Pediatrics, University of Alabama at Birmingham, Birmingham Alabama, USA,
3
Chimerix, Inc., Durham, North Carolina, USA

Running title: Mullane et al: Brincidofovir varicella zoster treatment

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/tid.12583
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 Abstract: Brincidofovir (BCV) is a broad spectrum antiviral agent active in-vitro against
Accepted Article
double-stranded DNA viruses including herpesviruses, adenoviruses, polyomaviruses, and

poxviruses. We report successful BCV use in management of disseminated acyclovir- and

cidofovir-resistant varicella zoster virus in an immunocompromised hematopoietic stem cell

transplant patient with chronic graft-versus-host disease who was intolerant to foscarnet.

Key words: brincidofovir; disseminated varicella; acyclovir-resistant

Abbreviations: ACV, acyclovir; allo-HSCT, allogeneic hematopoietic stem cell transplantation;

BCV, brincidofovir; CDV, cidofovir; CDV-PP, CDV-diphosphate; CML, chronic myeloid

leukemia; CMV, cytomegalovirus; CMX001, former name of BCV; CTCAE, Common

Terminology Criteria for Adverse Events; EC50, 50% effective concentration; GI,

gastrointestinal; GVHD, graft-versus-host disease; PCR, polymerase chain reaction; PRA, plaque

reduction assays; TK, thymidine kinase; VACV, valacyclovir; VZV, varicella zoster virus.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with profound

immunosuppression and thus the risk of reactivation of latent herpesvirus infections such as

varicella zoster virus (VZV) (1–5). Prior to routine acyclovir (ACV) prophylaxis, the cumulative

incidence of VZV reactivation was reported to be approximately 50–60% (6–9). VZV disease

can lead to serious complications, including disseminated disease, post-herpetic neuralgia,

bacterial superinfection, visceral involvement, blindness, and death in the HSCT population.

ACV or valacyclovir (VACV) prophylaxis is recommended for at least 30 days and up to 1 year

after HSCT in VZV-seropositive recipients (6–8). Prophylaxis beyond 1 year is often continued

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 in those with chronic graft-versus-host disease (GVHD) or those requiring continued chronic
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immunosuppression. ACV resistance has been reported rarely (6).

Brincidofovir (BCV) (formerly CMX001) is an orally available, lipid conjugate of the

nucleotide analog cidofovir (CDV) with in-vitro antiviral activity against double-stranded DNA

viruses, including herpesviruses. We report a case of successful use of BCV in the management

of disseminated ACV and CDV-resistant VZV in a patient intolerant to foscarnet.

Case report

A 28-year-old woman, positive for cytomegalovirus (CMV), VZV, and herpes simplex virus,

with BCR/ABL1 chronic myeloid leukemia (CML) refractory to tyrosine kinase inhibitor

therapy underwent a second human leukocyte antigen-identical sibling allo-HSCT on February

13, 2015. Her past medical history included CML diagnosed April 2007. She was initially

cytoreduced with hydroxyurea followed by dasatinib treatment but, despite full adherence,

response was inadequate. This therapy was followed by nilotinib, without response. She next

received cladribine followed by fludarabine, melphalan, and alemtuzumab conditioning for her

first human leukocyte antigen-identical sibling allo-HSCT infused October 10, 2010. She

received ponatinib post-transplantation to suppress BCR/ABL1 transcription.

She remained in remission with her only post-transplant complication being mild skin

GVHD until a follow-up bone marrow biopsy November 14, 2014, showed relapse (CD34 and

CD117 positive blasts consistent with accelerated phase CML). She was treated with cytarabine

(HiDAC) and mitoxantrone complicated by neutropenic fever associated with Streptococcus

mitis bacteremia, a soft tissue abscess/cellulitis on her thigh, respiratory syncytial virus

pneumonia, and recurrent Clostridium difficile diarrhea. In January 2015, she received a second

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 induction chemotherapy course with HiDAC and cladribine followed by conditioning with
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busulfan and cyclophosphamide and second allo-HSCT from the same donor February 13, 2015.

She was discharged February 25, 2015, on prophylaxis with posaconazole, VACV (2 gm every 6

h), trimethoprim/sulfamethoxazole, and tacrolimus.

She initially did well after transplantation. Her day 30 post-HSCT bone marrow biopsy

showed exuberant marrow regeneration without evidence of CML by morphology or reverse

transcription polymerase chain reaction (PCR) assay. In March, she was hospitalized with a new

skin rash, consistent with GVHD, and diarrhea. Plasma CMV and repeat C. difficile testing were

negative. Endoscopic biopsies showed no evidence of an infectious process, but were consistent

with grade 2 acute GVHD of the gastric and colonic mucosa. She was started on high-dose

intravenous methylprednisolone followed by tapering doses of oral prednisone and budesonide.

On June 14, 2015, she developed an erythematous vesicular rash starting around her right

ear that extended posteriorly across the back of her head and anteriorly to her cheek and into her

mouth in a dermatomal pattern consistent with C2–C5 involvement (Fig. 1 A and B). Her rash

rapidly disseminated to her trunk and extremities over the next 24 h. Swabs for VZV were

positive by PCR assay. Because the patient developed this rash on high-dose VACV prophylaxis,

she was admitted for suspected ACV-resistant disseminated VZV and was initiated on

intravenous foscarnet dosed at 90 mg/kg and administered every 12 h on June 16, 2015.The

varicella virus isolate was sent out for phenotypic drug resistance testing (University of Alabama

Health Services Foundation Diagnostic Virology Laboratory).

The rash showed no further progression or development of new lesions by June 19, 2015

and she was discharged home continuing on induction intravenous foscarnet. On post-discharge

return visit to the outpatient clinic on June 22, 2015 no new vesicles were noted and there was

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 scant crusting on the superior margin of the pinna of her right ear, with the remaining lesions still
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open and weeping. When she presented for follow-up on June 25, 2015, no new varicella

vesicles were present, but she had onset of new exquisitely painful ulcers in her mouth and vulva

consistent with foscarnet toxicity. An emergency investigational new drug application for BCV

was requested and granted. The patient started BCV 100 mg given orally twice weekly with her

first dose administered on June 26, 2015. Baseline VZV quantitative plasma PCR was

significant for 13,000 copies/mL (Viracor-IBT Laboratory Headquarters, Lee’s Summit,

Missouri USA).

On July 6, the patient returned for evaluation. The vulvar ulcers had resolved; the oral

ulcers, although improved, persisted with swelling and irritation of the buccal mucosa. VZV was

undetectable by repeat quantitative VZV PCR on plasma. The zoster lesions from dermatomes

C2–C5 were now crusted and those on her trunk and extremities were resolving. Skin GVHD

was noted to have flared and she was restarted on topical triamcinolone 1% cream.

On July 17, 2015, the results of the varicella susceptibility results returned (see Table 1).

By July 27, all lesions were healed and crusting had resolved. Repeat plasma quantitative PCR

for VZV was again not detectable. The patient remained on secondary prophylaxis with BCV

100 mg orally twice weekly.

In August, the patient’s course was complicated by GVHD of the liver associated with

elevated hepatic transaminase levels, hyperbilirubinemia, and ascites as well as a partial small

bowel obstruction. She was admitted and treated with high-dose methylprednisolone followed

by tapering doses of prednisone. She also developed grade IV GVHD of the corneas.

She completed 12 weeks of BCV and on September 22, and was transitioned to

valganciclovir 900 mg orally given twice daily for CMV and VZV prophylaxis. The patient had

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 no recurrence of varicella during the 12 weeks on BCV and had no adverse effects attributable to
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the drug (see Timeline, Fig. 2).

Discussion

Reactivation of latent herpesviruses including VZV is common after HSCT (1–10). VZV has

been reported to occur in 30–50% of HSCT patients who are not on antiviral prophylaxis and is

associated with significant morbidity and mortality, with fatality reported to be as high as 20%

(2, 5, 11). Factors associated with VZV reactivation in this population include treatment with

mesenchymal stromal cells, total body irradiation ≥ 6 Gy as part of conditioning, engraftment

later than day 16, cord blood HSCT, low CD4+ lymphocyte count, GVHD, continued

immunosuppression, diagnosis other than CML, and age >10 years (1, 5, 11, 12–15). Before

routine VZV prophylaxis, the incidence of VZV in this population ranged from 50–60% (6–10,

16) Use of ACV prophylaxis until the CD4 count was >200 cells/uL reduced VZV reactivation

to 2% at 1 year and 34% at 5 years post transplantation (16). One year of ACV or VACV

prophylaxis was shown to effectively reduce VZV reactivation to 4–7% without evidence of

rebound after discontinuation of the drug (8).

ACV is phosphorylated first by viral thymidine kinase (TK) followed by human cellular

kinases to its active form, ACV triphosphate, which is a competitive inhibitor of viral DNA

polymerase and causes chain termination of viral DNA. Mechanisms of VZV resistance to

antiviral agents are primarily related to reduced or altered viral TK or altered TK substrates

specificity, and infrequently to altered viral DNA polymerase (6, 17). VZV resistance is usually

associated with mutations in VZV TK with inability to phosphorylate ACV or, less frequently, to

mutations in viral DNA polymerase (18, 19). While ACV-resistant VZV is rare in

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 immunocompetent individuals, it has been described primarily in those with acquired human
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immunodeficiency syndrome, where prolonged exposure to sub-therapeutic dosages in the face

of ongoing viral replication are key risk factors (20). Clinically, ACV-resistant infection should

be suspected when zosteriform lesions persist despite 10 days of appropriately dosed therapy.

ACV resistance has broad consequences from drug toxicities associated with second and third

line agents (foscarnet and CDV), progressive disease, and death when alternative treatments are

not available.

Assays to measure resistance include phenotypic (plaque reduction assays [PRA]) and

genotypic methods. In PRA, cells are infected with a constant viral inoculum and virus is

allowed to grow in the presence of serial drug dilutions for 10 days before fixing and staining the

cells (21). The drug concentration that reduces the number of plaques by 50% compared to

controls (no antiviral agent added) is defined as the 50% effective concentration (EC50). An

increase in the EC50 values ≥4 times that of a susceptible reference strain is generally accepted to

define VZV resistance to ACV (22). The low rate of VZV isolation from vesicle samples (20–

43%) and its slow growth in cell culture (≥ 5–6 days) markedly limits the use of PRA in clinical

situations (23). Genotypic testing is based upon amplification of VZV genes known to be

involved in drug resistance (ORF36 for TK and ORF28 for DNA polymerase) by PCR and is

more rapid and sensitive than phenotypic assays, allowing detection of resistant virus present in

low numbers within a mixed population (19). Resistance to foscarnet and CDV are conferred by

DNA polymerase point mutations. Because foscarnet and CDV do not require viral TK for

activation, they often retain activity against viruses resistant to ACV and ganciclovir. While the

primary adverse event associated with ganciclovir is neutropenia, both foscarnet and CDV are

associated with significant renal toxicities and are only available as intravenous products (6).

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 Foscarnet therapy is associated with renal wasting of electrolytes requiring frequent laboratory
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evaluations and replacement of potassium and magnesium, and rarely mucosal ulcerations as

seen in our case. CDV therapy is associated with bone marrow suppression and uveitis.

BCV (previously known as CMX-001) is a broad spectrum antiviral agent with in vitro

activity against herpesviruses, polyomaviruses, adenoviruses, papillomaviruses, and poxviruses

(6). It is a lipid-conjugated nucleotide analog of CDV that has a high oral bioavailability and a

long intracellular half-life, allowing twice weekly oral dosing. In contrast to its parent

compound, BCV is not a substrate for the human organic anion transporters and, therefore, has

significantly reduced potential to cause renal toxicity. Once inside the cell, the lipid phosphate

ester linkage of BCV is cleaved by intracellular phospholipases to release CDV, which is then

converted to CDV-diphosphate (CDV-PP) by cellular kinases. Viral TK is not needed for

activation of this compound. CDV-PP is a cytidine triphosphate analog and is incorporated into

the nascent viral DNA chain by DNA-polymerases, thereby resulting in a reduction in the overall

rate of viral DNA synthesis. In cell culture, BCV results in >100-fold higher concentrations of

CDV-PP when compared to CDV (24). BCV is typically 300–400-fold more active against

herpes simplex virus-1 and CMV than CDV. It has potent in-vitro activity against most

ganciclovir, foscarnet, and CDV-resistant CMV, the latter potentially due to higher intracellular

concentrations of the active antiviral (CDV-PP). Because the EC50 for VZV is approximately

1000-fold lower than the corresponding EC50 values of CDV, it is likely that the intracellular

CDV-PP concentrations were able to overcome the baseline CDV resistance reported in the

phenotypic assay. Reduced viral fitness from foscarnet therapy may also have played a role in

the response seen in this patient. Replication of other herpesviruses isolates including VZV,

Epstein–Barr virus, human herpesvirus-6 (HHV), and HHV-8, is markedly inhibited by BCV,

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 with EC50 values inhibiting VZV and Epstein-Barr virus replication being at least 1000-fold
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lower than the corresponding EC50 values of CDV. BCV has potent activity against adenovirus

with EC50 values for different serotypes being 5- to 200-fold lower than those obtained for CDV.

In a phase II dose-escalation study in HSCT recipients, BCV showed a reduction in the

incidence of CMV infection or disease in patients receiving doses of 100 mg, 200 mg, or 400 mg

dosed twice weekly for prophylaxis when the drug was started at engraftment (24). The most

common side effect was diarrhea in patients receiving CMX001 at doses of 200 mg or higher.

No significant differences in renal or hematologic adverse effects were observed between BCV

and placebo recipients (25).

A phase III randomized multicenter trial of BCV at a dose of 100 mg twice weekly to

week 14 post stem cell transplantation in CMV-positive recipients did not meet its primary

endpoint for prevention of clinically significant CMV disease through week 24 after

transplantation. During the on-treatment period through week 14, significantly more CMV

infections were seen in the placebo group; however, during the 10 week follow-up period, an

increased incidence of CMV infections was seen in the BCV arm that appears to be driven by an

8-fold higher corticosteroid use, attributed to a higher incidence of GVHD in that arm (26). The

BCV arm saw 16.5% of subjects with ≥ Common Terminology Criteria for Adverse Events

(CTCAE) grade 3 treatment emergent adverse gastrointestinal (GI) effects including diarrhea,

abdominal pain and/or nausea, which lead to discontinuation of study medication in 10% of

individuals. This result compares with 3.4% of subjects in the placebo arm developing ≥

CTCAE grade 3 treatment-emergent adverse GI effects and none of the subjects discontinuing

study medication because of GI adverse events. BCV use was associated with GI toxicity in

previous studies, but these findings were dose-related and occurred in those treated with oral

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 BCV ≥200 mg twice weekly for more than 2–4 weeks. Noteworthy was the fact that these
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toxicities, when treated with increasing doses of corticosteroids, did not improve. It appears that

biopsy of the GI tract is not likely to be able to discern between GVHD and BCV toxicity. The

etiology of this finding is currently under investigation, but may be related to known GI toxicity

associated previously with use of oral CDV. BCV use has not been associated with ocular or

skin GVHD.

Elevated liver enzymes have also been noted in individuals treated with BCV. In

preclinical studies, no histopathologic changes were noted with these elevations. In the phase 3

trial, as noted above, any hepatobiliary event occurred in 7.6% of individuals on BCV compared

to 3.4% of those in the placebo group with ≥ CTCAE grade 3 treatment-emergent events

reported in 3% vs. 1%, respectively. The most common event was hyperbilirubinemia. These

events led to discontinuation of study medication in 7% of those on BCV vs. 2% in the placebo

group.

This patient was on BCV at the time of the presentation of elevated liver enzymes and

ocular/skin GVHD. At the time, she did not have increased complaints of symptoms associated

with her known GVHD. Given that this patient had significant issues with skin and GI GVHD in

the past, her dose of prednisone was increased and she was initiated on ocular steroids and

tacrolimus with marked improvement of both her elevated liver enzymes and her eye findings.

That this patient had a complete clinical and virological response to BCV despite CDV resistance

is likely a result of the higher potency of BCV and a reduced fitness of the resistant virus.

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 Conclusion
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Disseminated VZV infection has serious consequences in immunocompromised individuals,

particularly in the HSCT population. ACV-resistant VZV is a concern in those who have

received prolonged ACV prophylaxis. BCV is a lipid-conjugated nucleotide analog of CDV with

high oral bioavailability that delivers high intracellular concentrations of CDV-PP. BCV has a

long intracellular half-life allowing twice weekly administration and has broad spectrum in-vitro

activity against double-stranded DNA viruses including VZV. We report here the first

successful case, to our knowledge, using BCV in the treatment and post-treatment prophylaxis of

a profoundly immunocompromised patient with ACV-resistant disseminated varicella and

intolerable toxicity from foscarnet.

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 Figure legends
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Fig. 1. A and B. Erythematous vesicular rash starting around her right ear that extended

posteriorly across the back of her head and anteriorly to her cheek and into her mouth in a

dermatomal pattern consistent with C2–C5 involvement.

Fig. 2. Timeline. Onset of varicella zoster through completion of brincidofovir treatment. PCR,

polymerase chain reaction assay.

Susceptibility of virus isolate

Virus Isolate
Drug VZV Subject
Acyclovir 5.7 29.1 (resistant)
Cidofovir 2.4 14.7 (resistant)
Foscarnet 107 287 (sensitive)
Values shown represent the concentration of the
drugs (µM) sufficient to reduce plaque formation
by 50% (EC50) in a control isolate.
VZV, varicella zoster virus.
Table 1

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