Refractory and Resistant Herpes Simplex Virus Mucocutaneous Infections in Immunocompromised Patients: Literature Review and Proposed Definitions for Use in Clinical Trials

Roy F Chemaly¹, Tali Shafat¹, Anna Wald², Camille N Kotton³, Genovefa Papanicolaou^{4

5}, Michelle K Yong^{6

7

8}, Veronica Miller⁹, Takashi E Komatsu¹⁰, Charu Mullick¹⁰, Aimee C Hodowanec¹⁰, Gabriel Westman^{11

12}, Fareed Khawaja¹, Alexander Birkmann¹³, Per Ljungman^{14

15}

Affiliations

¹ Department of Infectious Diseases, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
² Departments of Medicine, Laboratory Medicine and Pathology, and Epidemiology, University of Washington School of Medicine and Vaccine and Infectious Diseases Division, Fred Cancer Research Center, Seattle, Washington, USA.
³ Transplant Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁴ Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁵ Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
⁶ Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia.
⁷ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
⁸ Department of Infectious Diseases, Royal Melbourne Hospital, Melbourne, Australia.
⁹ Forum for Collaborative HIV Research, University of California, Berkeley, California, USA.
¹⁰ Division of Antiviral Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
¹¹ Swedish Medical Products Agency, Uppsala, Sweden.
¹² Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.
¹³ AiCuris Anti-Infective Cures AG, Wuppertal, Germany.
¹⁴ Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Karolinska Comprehensive Cancer Center, Stockholm, Sweden.
¹⁵ Department of Medicine Huddinge, Division of Hematology, Karolinska Institute, Stockholm, Sweden.

PMID: 39878032
DOI: 10.1093/cid/ciae638

Refractory and Resistant Herpes Simplex Virus Mucocutaneous Infections in Immunocompromised Patients: Literature Review and Proposed Definitions for Use in Clinical Trials

Roy F Chemaly et al. Clin Infect Dis. 2025.

. 2025 Jan 29:ciae638.

doi: 10.1093/cid/ciae638. Online ahead of print.

Authors

Affiliations

¹ Department of Infectious Diseases, Infection Control, and Employee Health, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
² Departments of Medicine, Laboratory Medicine and Pathology, and Epidemiology, University of Washington School of Medicine and Vaccine and Infectious Diseases Division, Fred Cancer Research Center, Seattle, Washington, USA.
³ Transplant Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁴ Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
⁵ Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
⁶ Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia.
⁷ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
⁸ Department of Infectious Diseases, Royal Melbourne Hospital, Melbourne, Australia.
⁹ Forum for Collaborative HIV Research, University of California, Berkeley, California, USA.
¹⁰ Division of Antiviral Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.
¹¹ Swedish Medical Products Agency, Uppsala, Sweden.
¹² Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.
¹³ AiCuris Anti-Infective Cures AG, Wuppertal, Germany.
¹⁴ Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Karolinska Comprehensive Cancer Center, Stockholm, Sweden.
¹⁵ Department of Medicine Huddinge, Division of Hematology, Karolinska Institute, Stockholm, Sweden.

PMID: 39878032
DOI: 10.1093/cid/ciae638

Abstract

Herpes simplex virus (HSV) infection is one of the most prevalent viral infections worldwide. In general, host immunity is sufficient to clear viral shedding and recurrences, although it is insufficient to prevent subsequent virologic reactivations. In immunocompromised patients, prolonged and difficult-to-treat HSV infections may develop. The diagnosis of refractory HSV infection is based on the lack of clinical response to nucleoside analogs. Antiviral resistance is confirmed via genotypic and/or phenotypic testing. To provide consensus definitions of refractory and/or resistant (R/R) HSV mucocutaneous infections for clinical trial use, the HSV Resistance Working Group of the Transplant Associated Viral Infections Forum, which includes international clinicians, scientists, industry representatives, and regulatory officials, conducted a literature review of previously published data related to R/R HSV infections in immunocompromised patients. We propose definitions of R/R HSV mucocutaneous infections, which will be subject to re-evaluation and revision based on forthcoming data and future studies.

Keywords: definitions; herpes simplex virus; immunosuppression; refractory; resistance.

© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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Conflict of interest statement

Potential conflicts of interest . R. F. C.: Consultant/speaker/advisor for ADMA Biologics, Janssen, Merck/MSD, Takeda, Shinogi, AiCuris, Roche/Genentech, Astellas, Tether, Oxford Immunotec, Karius, Moderna, InflaRX, and Ansun Pharmaceuticals. He received research grants paid to his institution from Merck/MSD, Karius, AiCuris, Ansun Pharmaceuticals, Takeda, Genentech, Oxford Immunotec, and Eurofins-Viracor. He also serves as a Data and Safety Monitoring Committee (DSMC) member for AstraZeneca. A. W.: Consulting for Aicuris, GSK, Heidelberg Therapeutics, Innovative Molecules, and Bayer, and research grants support from GSK and Moderna. C. N. K.: Consulting for Biotest, ExeVir, Evrys Bio, Hookipa, Takeda, Merck, Qiagen, Roche Diagnostics, and Abbot Laboratories; has received honoraria from Takeda, Roche Diagnostics, Qiagen, and Biotest; participates on Takeda, Roche Diagnostics, Abbott Laboratories, Biotest, ExeVir, and Evrys Bio data and safety monitoring/advisory boards; and participates in a leadership role for the Transplantation Society. G. P.: Consultant/advisor for Merck/MSD, Takeda, Astellas, Symbio, and Genentech. She has received research grants paid to her institution from Merck/MSD and AiCuris. She has received speaking fees from Merck/MSD. She serves as a DSMC member for Allovir, Armata, Vera, and Trellis Bioscience. M. K. Y.: Consultant/speaker for MSD, Takeda, and Gilead. She has received research grants paid to her institution from MSD and Moderna. V. M.: Received research grants from AiCuris, AlloVir, Evrys Bio, Merck, Takeda, Symbio Pharma, Qiagen, Vera Therapeutics, and Eurofins-Viracor. T. E. K.: An employee of the Division of Antiviral Products, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA). C. M.: An employee of the Division of Antiviral Products, Center for Drug Evaluation and Research, US FDA. A. C. H.: An employee of the Division of Antiviral Products, Center for Drug Evaluation and Research, US FDA. F. K.: Received research grants from Eurofins Viracor and has received honoraria from Medscape. A. B.: Employee of AiCuris, the company developing pritelivir. P. L.: Scientific expert/speaker for Merck/MSD, Takeda, Moderna, Pfizer, AstraZeneca, and Octa Pharma. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Refractory and Resistant Herpes Simplex Virus Mucocutaneous Infections in Immunocompromised Patients: Literature Review and Proposed Definitions for Use in Clinical Trials

Affiliations

Refractory and Resistant Herpes Simplex Virus Mucocutaneous Infections in Immunocompromised Patients: Literature Review and Proposed Definitions for Use in Clinical Trials

Authors

Affiliations

Abstract

Conflict of interest statement

Grants and funding

LinkOut - more resources

Full Text Sources