Assessment of patients' characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease

Yasumasa Kakei; Ichiro Morioka; Takumi Imai; Kotaro Itohara; Ikuko Yano; Naoto Takahashi; Tetsushi Yoshikawa; Hiroyuki Moriuchi; Yoshinori Ito; Kazumichi Fujioka; Akira Oka; Japanese Congenital Cytomegalovirus Study Group

doi:10.1016/j.jiac.2024.03.006

Assessment of patients' characteristics associated with the efficacy and safety of oral valganciclovir treatment for infants with symptomatic congenital cytomegalovirus disease

J Infect Chemother. 2024 Mar 13:S1341-321X(24)00081-3. doi: 10.1016/j.jiac.2024.03.006. Online ahead of print.

Collaborators

Japanese Congenital Cytomegalovirus Study Group:
Aya Okahashi¹², Nobuhiko Nagano¹², Midori Hijikata¹², Kazumasa Fuwa¹², Ryoji Aoki¹², Ayako Seimiya¹², Takayuki Imaizumi¹², Takuya Akimoto¹², Koichiro Hara¹², Daichi Katayama¹², Shinya Abe¹³, Mariko Ashina¹³, Ruka Nakasone¹³, Yuki Kyouno¹³, Kido Takumi¹³, Satoshi Takenaka¹⁴, Satsuki Kakiuchi¹⁴, Yu Kakimoto¹⁴, Kei Kozawa¹⁵, Yusuke Funato¹⁵, Hiroki Miura¹⁵, Yoshiki Kawamura¹⁵, Tsutomu Ogata¹⁶, Yumiko Nakashima¹⁶, Jun-Ichi Kawada¹⁷, Yuka Torii¹⁷, Takako Suzuki¹⁷, Yuto Fukuda¹⁷, Kazunori Haruta¹⁷, Makoto Yamaguchi¹⁷, Teranishi Masaaki¹⁸

Affiliations

¹ Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan; Clinical and Translational Research Center, Kobe University Hospital, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. Electronic address: ykakei@med.kobe-u.ac.jp.
² Department of Pediatrics and Child Health, Nihon University School of Medicine, 30-1 Oyaguchi, Kami-cho, Itabashi-ku, Tokyo, 173-8610, Japan. Electronic address: morioka.ichiro@nihon-u.ac.jp.
³ Clinical and Translational Research Center, Kobe University Hospital, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. Electronic address: imai@med.kobe-u.ac.jp.
⁴ Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. Electronic address: kitohara@med.kobe-u.ac.jp.
⁵ Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. Electronic address: iyano@med.kobe-u.ac.jp.
⁶ Department of Pediatrics, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Electronic address: ntakahashi@m.u-tokyo.ac.jp.
⁷ Department of Pediatrics, Fujita Health University School of Medicine, 1-98 Kutsukake-cho, Dengakugakubo, Toyoake, Aichi, 470-1192, Japan. Electronic address: tetsushi@fujita-hu.ac.jp.
⁸ Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan. Electronic address: hiromori@nagasaki-u.ac.jp.
⁹ Department of Pediatrics, Aichi Medical University Graduate School of Medicine, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan. Electronic address: yoshi-i@med.nagoya-u.ac.jp.
¹⁰ Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. Electronic address: fujiokak@med.kobe-u.ac.jp.
¹¹ Department of Pediatrics, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan; Saitama Prefectural Children's Medical Center, 1-2 Shin-toshin, Chuo-ku, Saitama, Saitama, 330-8777, Japan. Electronic address: oka.akira@saitama-pho.jp.
¹² Department of Pediatrics and Child Health, Nihon University School of Medicine, Japan.
¹³ Department of Pediatrics, Kobe University Graduate School of Medicine, Japan.
¹⁴ Department of Pediatrics, The University of Tokyo, Japan.
¹⁵ Department of Pediatrics, Fujita Health University School of Medicine, Japan.
¹⁶ Department of Pediatrics, Nagasaki University Graduate School of Medicine, Japan.
¹⁷ Department of Pediatrics, Nagoya University Graduate School of Medicine, Japan.
¹⁸ Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Japan.

PMID: 38484931
DOI: 10.1016/j.jiac.2024.03.006

Abstract

Introduction: Insurance coverage for oral valganciclovir (VGCV) began in Japan in April 2023 on the basis of results, including our clinical trials for symptomatic congenital cytomegalovirus (CMV) disease. The VGCV treatment is available throughout Japan, so clinicians must consider the likelihood of hearing improvement and the possibility of neutropenia before dosing.

Materials and methods: We performed a substudy of an investigator-initiated, single-arm, prospective, multicenter, clinical trial in which 24 infants with symptomatic congenital CMV disease were orally administered 16 mg/kg VGCV twice daily for 6 months as an intervention. We examined the infants' baseline characteristics associated with improved hearing impairment or a severely reduced neutrophil count.

Results: Of the 24 patients, 4 had normal hearing on assessment of their ear with the best hearing. Hearing impairment improved in 14 patients and did not respond to VGCV treatment in 6 patients at the 6-month hearing assessment. CMV DNA levels in plasma at baseline were higher in patients in whom hearing did not respond to treatment. A neutrophil count <500/mm³ occurred in 5 (21%) patients for the first 6 weeks and in 8 (33%) patients for the first 6 months. A neutrophil count at screening and the lowest neutrophil count over the 6 months showed the highest correlation (r = 0.477, p = 0.019).

Conclusions: Infants with a low plasma viral load at screening tend to have an improvement in hearing impairment. Clinicians should be aware of neutropenia during VGCV treatment particularly in patients with a low neutrophil count during screening.

Keywords: Auditory brainstem response; Clinical trial; Cytomegalovirus; Neutropenia; Valganciclovir.

Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.