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Association between human herpesvirus-6 encephalitis and antiviral prophylaxis after allogeneic hematopoietic stem cell transplantation in the letermovir era

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Abstract

The impact of letermovir (LTV)—an anti-cytomegalovirus (CMV) drug—on human herpesvirus-6 (HHV-6) encephalitis is unclear. We hypothesized that LTV prophylaxis may increase the incidence of HHV-6 encephalitis by reducing anti-CMV therapies after allogeneic hematopoietic stem cell transplantation (HSCT). To evaluate the association between HHV-6 encephalitis and antiviral prophylaxis, 7985 adult patients from a nationwide registry who underwent their first HSCT between January 2019 and December 2021 were analyzed. The incidence of HHV-6 encephalitis on day 100 after HSCT was 3.6%; 11.5% for the broad-spectrum antiviral group (foscarnet, ganciclovir, or valganciclovir); 2.8% for the LTV group, and 3.8% for the other antiviral group (p < 0.001). These differences persisted when cord blood transplantation (CBT) was analyzed separately (14.1%, 5.9%, and 7.4%, p < 0.001). In the multivariate analysis, CBT (hazard ratio [HR]: 2.90), broad-spectrum antiviral prophylaxis (HR: 1.91), and grade II–IV acute graft-versus-host disease requiring systemic corticosteroids (HR: 2.42) were independent risk factors for encephalitis (all p < 0.001). The findings of this large modern database study indicate that broad-spectrum antiviral prophylaxis, rather than LTV prophylaxis, is paradoxically associated with HHV-6 encephalitis in the LTV era. This paradoxical finding needs to be further explored in future studies.

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Fig. 1: Cumulative incidence or overall survival of HHV-6 encephalitis development.
Fig. 2: Cumulative incidence of HHV-6 encephalitis in subgroup analysis.

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Data availability

The data in this study are not publicly available due to ethical restrictions that exceed the scope of the recipient/donor’s consent for research use in the registry. Data may be obtained from the corresponding author upon reasonable request and with permission from the JSTCT/JDCHCT.

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Acknowledgements

The authors are grateful for the work of all the physicians and data managers at the centers that contributed valuable data on transplantation to the JSTCT. We would also like to thank all of the members of the Transplant Registry Unified Management committees at JSTCT for their dedicated data management. We also thank Editage (https://www.editage.jp/) for English language editing. In addition, I, the first author, would like to thank Dr. Yoshimitsu Shimomura (Department of Hematology, Kobe City Hospital Organization Kobe City Medical Center General Hospital), Dr. Ayumi Fujimoto (Department of Hematology, Shimane University Hospital), and Dr. Kimimori Kamijo (Department of Hematology, Rinku General Medical Center) for giving me the technical advice to start this research. The authors did not receive financial support from any organization for the submitted work.

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Authors and Affiliations

  1. Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan

    Toshiki Terao & Ken-ichi Matsuoka

  2. Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Toshiki Terao & Ken-ichi Matsuoka

  3. Department of Hematology, Osaka International Cancer Institute, Osaka, Japan

    Shigeo Fuji & Jun Ishikawa

  4. Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan

    Shunto Kawamura, Yoshinobu Kanda & Hideki Nakasone

  5. Division of Emerging Medicine for Integrated Therapeutics, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Japan

    Shunto Kawamura & Hideki Nakasone

  6. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    Takashi Toya & Noriko Doki

  7. Department of Hematology, Federation of National Public Service Personnel Mutual Aid Associations TORANOMON HOSPITAL, Tokyo, Japan

    Naoyuki Uchida

  8. Department of Hematology, Kanagawa Cancer Center, Kanagawa, Japan

    Masatsugu Tanaka

  9. Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan

    Takahiro Fukuda

  10. Department of Hematology and Oncology, Anjo Kosei Hospital, Aichi, Japan

    Masashi Sawa

  11. Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Aichi, Japan

    Tetsuya Nishida

  12. Department of Hematology, Hokkaido University Hospital, Hokkaido, Japan

    Hiroyuki Ohigashi

  13. Department of Hematology, University of Tsukuba Hospital, Ibaraki, Japan

    Yumiko Maruyama

  14. Division of Hematology, Jichi Medical University, Tochigi, Japan

    Shin-ichiro Fujiwara & Yoshinobu Kanda

  15. Department of Hematology, Sapporo Hokuyu Hospital, Hokkaido, Japan

    Shuichi Ota

  16. Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan

    Fumihiko Ishimaru

  17. Japanese Data Center for Hematopoietic Cell Transplantation, Aichi, Japan

    Yoshiko Atsuta

  18. Department of Registry Science for Transplant and Cellular Therapy, Aichi Medical University School of Medicine, Aichi, Japan

    Yoshiko Atsuta

  19. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Junya Kanda

  20. Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Oita, Japan

    Masao Ogata

  21. Department of Medical Oncology and Hematology, Kobe University Hospital, Hyogo, Japan

    Kimikazu Yakushi**

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  1. Toshiki Terao
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  2. Ken-ichi Matsuoka
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Contributions

Toshiki T designed the study, analyzed the data, and wrote the draft of the paper. K-I M, Shigeo F, SK, Takashi T, JK, MO, and KY designed the study or advised on methods and wrote the manuscript. YK, FI, and TF collected data, revised the manuscript, and were responsible for data management at JSTCT. YA managed the unified registry database and revised the manuscript. HN designed the study, advised on the methods, revised the manuscript, and was responsible for the project of JSTCT Donor/Source Working Group. All the other authors contributed to data collection. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Toshiki Terao.

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Competing interests

The authors declare no competing interests.

Declaration of Generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the authors used ChatGPT (chat.openai.com), an AI language model developed by OpenAI, for English language proofreading and editing in order to improve the quality of the manuscript and to modify of statistical analysis code. After using ChatGPT, the authors reviewed and edited the content as needed to ensure accuracy and clarity and take full responsibility for the content of the publication.

Ethical approval

All procedures performed in the study were in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was designed by the Donor/Source Working Group and the Transplant Complications Working Group of the JSTCT and was approved by the Transplant Registry Unified Management Program Data Management Committee of the JSTCT and the Institutional Review Board of Okayama University Hospital (2401-004), where the study was conducted.

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All patients provided written informed consent for data reporting.

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Terao, T., Matsuoka, Ki., Fuji, S. et al. Association between human herpesvirus-6 encephalitis and antiviral prophylaxis after allogeneic hematopoietic stem cell transplantation in the letermovir era. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02313-3

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