Improvement of acyclovir-resistant herpes zoster infection by amenamevir
Herpes zoster, a painful eruption of blisters, is the clinical manifestation of the reactivation of a latent varicella-zoster virus (VZV).1 Acyclovir (ACV) is the first-line drug for the management of VZV infections. However, ACV-resistant VZV is a problem for im- munocompromised patients that may pose therapeutic dilemmas.2 Foscarnet and cidofovir are therapeutic options in many of these cases,3,4 and amenamevir is now another treatment option in Japan. Amenamevir is a helicase-primase inhibitor with anti-VZV and anti- herpes simplex virus activity; it inhibits replication fork progression, an initial step in DNA synthesis that separates the double strand into two single strands.5 Here, we report the first case in which ame- namevir was administrated to a patient with severely disseminated herpes zoster caused by ACV-resistant VZV while the patient was receiving ACV treatment; after amenamevir treatment, the patient was successfully cured of the ACV-resistant lesions.
A 64-year-old male with adult T-cell lymphoma receiving stem cell
transplantation suffered a relapse and began chemotherapy. Initially, he was diagnosed with localized herpes zoster to the first branch of right trigeminal nerve, and rapidly disseminated. Although treat- ment with ACV was started, blisters rapidly increased (Figure 1a,b). Virus isolation and drug susceptibility tests were performed 14 days after ACV treatment. The administration of amenamevir quickly ter- minated the appearance of new vesicles and subsequently scabbed over 10 days later (Figure 1a,c). Despite the successful treatment of herpes zoster, the patient died from complications stemming from bacterial pneumonia.
Surprisingly, the virus was isolated from all vesicular fluid sam- ples and this indicated that ACV was not working in these vesicular lesions because the virus is not isolated during ACV administra- tion if it is not ACV-resistant. Half of the 12 isolates were less sensitive to ACV than the wild type (Figure 1d), and the isolated viruses were a mixture of ACV-susceptible and ACV-resistant vi- ruses, indicating that the viruses were isolated during the tran- sition of VZV from susceptible strain to resistant with different mutations in the thymidine kinase gene. The majority of drug re- sistance in VZV is caused by thymidine kinase gene mutations, which often result in premature stop codons that cause the virus to lose its thymidine kinase. There are two types of mutations: random mutations and ACV-induced mutations in the guanosine string, typically p.Try144Phefs*20 addition of thymine, and this mutation becomes truncated thymidine kinase at the 25th stop
codon. Amenamevir has a different mode of action than ACV, maintaining effective blood concentration with p.o. administra- tion once a day, and its exceptional pharmacokinetics might con- tribute to curing herpes zoster caused by ACV-resistant VZV. This is the first case to demonstrate the effectiveness of amenamevir therapy for ACV-resistant herpes zoster.
Although foscarnet is now the standard treatment for ACV- resistant VZV treatment, this successful course suggests amename- vir will become the standard drug for ACV-resistant VZV worldwide, in the future. The therapeutic efficacy of amenamevir for ACV- resistant VZV may require further clinical study.
CONFLIC T OF INTEREST
T.O. and A.Y. have no conflicts of interest, including specific finan- cial interests, relationships, and/or affiliations relevant to the subject matter or materials included. K.S. reports the receipt of a consulting fee from Maruho, lecture fees from Maruho, MSD, and Novartis, and research funding from MSD and Japan Blood Products Organization.
Takashi Onaka1 Kimiyasu Shiraki2 Akihito Yonezawa1
1Department of Hematology, Kokura Memorial Hospital,
2Senri Kinran University, Osaka, Japan
Correspondence Takashi Onaka, Department of Hematology, Kokura Memorial Hospital, 3-2-1 Asano, Kokura-kita, Kitakyushu,
Fukuoka 802-8555, Japan. Email: [email protected]
Takashi Onaka https://orcid.org/0000-0002-3149-2584
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Susceptibility (EC50) to Acyclovir (μg/mL)
0 0.05 0.1 0.15
Susceptibility (EC50) to Amenamevir (μg/mL)
F I G UR E 1 (a) Clinical course. Virus isolation and drug susceptibility tests were performed14 days after ACV treatment. The administration of amenamevir quicklyterminated the appearance of new vesicles and subsequently scabbed over 10 dayslater. (b)
Facial rash before the administration of amenamevir. The blisterswere broken and ulcerated, and new blistering was observed despite theadministration of acyclovir. (c) Facial rash after amenamevir administration. No new blister formation was observed, and the ulcerated regions showedimprovement. (d) Susceptibility of isolated viruses from different vesicles toacyclovir and amenamivir. Vesicular fluids taken before amenameviradministration were inoculated into human embryonic lung cells and isolatedviruses were preserved as cell-free virus. The cells in 60 mm plastic disheswere infected with 100 plaque-forming units/0.2 ml of cell-free VZV for 1 h andincubated in the presence of acyclovir at 0, 0.5, 1, 5, 10 μg/ml and amenamevirat 0.03, 0.01, and 0.3 μg/ml at 37°C for 5 days. The effective concentrationfor 50% plaque reduction (EC50) was determined and susceptibility to acyclovirand amenamevir were plotted. EC50 concentrations of acyclovir
in the wild typeare indicated by red line. Since the virus is in the transition phase fromacyclovir susceptibility to resistant virus, the susceptibility ranges from thesame as that of the wild strain to the resistant strain. The increased EC50 toacyclovir indicates the mixture of acyclovir-sensitive and resistant virusesand mutation in the thymidine kinase gene was different for the vesicles. p.Phe139Serfs*25:After the 139th Phenylalanine, frameshift starts from Serine and becomestruncated TK at the 25th stop codon. p.Try144Phefs*20:After the 144thTryptophan, frameshift starts from Phenylalanine and becomes truncated TK atthe 20th stop codon
zoster: report of a novel thymidine kinase mutation and review of the literature. Pediatr Infect Dis J. 2008;27(1):75–7.
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