{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:04:43Z","timestamp":1790186683276,"version":"4.1.0"},"reference-count":65,"publisher":"BMJ","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["Br J Ophthalmol"],"accepted":{"date-parts":[[2026,9,10]]},"abstract":"<jats:p>Herpes simplex keratitis (HSK) caused by herpes simplex virus type 1 (HSV-1) is a major cause of infectious corneal blindness in developed countries. The disease reflects a variable combination of viral replication, immune-mediated inflammation and neurotrophic dysfunction, whose respective contributions determine both the clinical presentation and therapeutic strategy. Standard management relies on antiviral agents to suppress viral replication, corticosteroids to control immune stromal involvement and ocular surface optimisation to address chronic inflammation and neurotrophic impairment. Refractory forms, defined by a lack of clinical improvement despite appropriate treatment, require reassessment of adherence, pharmacokinetic exposure<\/jats:p>\n                  <jats:p>and underlying pathophysiology. In such cases, antiviral dose adjustment, the use of steroid-sparing immunomodulators and rigorous control of ocular surface inflammation are essential. Neurotrophic keratopathy may benefit from growth factor-based therapies, autologous serum, recombinant nerve growth factor or scleral lenses. The emergence of acyclovir-resistant HSV-1 strains, particularly in immunocompromised or long-term treated patients, represents an increasing concern. In these situations, alternative agents such as trifluridine, foscarnet or more recently, helicase\u2013primase inhibitors, including amenamevir, have demonstrated clinical efficacy. The new strategies outlined here will all provide benefit in treating the drivers of refractory HSK, to quickly resolve and reduce risk of recurrence, providing new opportunities to prevent vision loss in refractory and antiviral-resistant cases.<\/jats:p>","DOI":"10.1136\/bjo-2025-329213","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T17:20:25Z","timestamp":1790184025000},"page":"bjo-2025-329213","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Managing refractory herpes simplex keratitis"],"prefix":"10.1136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2355-2804","authenticated-orcid":false,"given":"Antoine","family":"Rousseau","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, APHP, Universit\u00e9 Paris Saclay, OPHTARA, Le Kremlin Bic\u00eatre, France"},{"name":"Universit\u00e9 Paris-Saclay, Institut national de la sant\u00e9 et de la recherche m\u00e9dicale (Inserm), U1184, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB). Commissariat \u00e0 l'\u00c9nergie Atomique et aux \u00c9nergies renouvelables (CEA), Fontenay-Aux-Roses, France"},{"name":"Department of Ophthalmology, H\u00f4pital National des 15-20, IHU ForeSight, Paris, \u00cele-de-France, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Boucher","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, APHP, Universit\u00e9 Paris Saclay, OPHTARA, Le Kremlin Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Haigh","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Institut national de la sant\u00e9 et de la recherche m\u00e9dicale (Inserm), U1184, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB). Commissariat \u00e0 l'\u00c9nergie Atomique et aux \u00c9nergies renouvelables (CEA), Fontenay-Aux-Roses, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Labetoulle","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, APHP, Universit\u00e9 Paris Saclay, OPHTARA, Le Kremlin Bic\u00eatre, France"},{"name":"Universit\u00e9 Paris-Saclay, Institut national de la sant\u00e9 et de la recherche m\u00e9dicale (Inserm), U1184, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases (IMVA-HB). Commissariat \u00e0 l'\u00c9nergie Atomique et aux \u00c9nergies renouvelables (CEA), Fontenay-Aux-Roses, France"},{"name":"Department of Ophthalmology, H\u00f4pital National des 15-20, IHU ForeSight, Paris, \u00cele-de-France, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"2026092310201069000_bjo-2025-329213v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.survophthal.2012.01.005"},{"key":"2026092310201069000_bjo-2025-329213v1.2","doi-asserted-by":"crossref","first-page":"104433","DOI":"10.1016\/j.jfo.2025.104433","article-title":"Pathophysiology and treatment of acyclovir-resistant herpes simplex virus keratitis","volume":"48","author":"Boucher","year":"2025","journal-title":"J Fr Ophtalmol"},{"key":"2026092310201069000_bjo-2025-329213v1.3","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.jtos.2021.07.002","article-title":"Herpes simplex virus, varicella-zoster virus and cytomegalovirus keratitis: Facts for the clinician","volume":"28","author":"Labetoulle","year":"2023","journal-title":"Ocul Surf"},{"key":"2026092310201069000_bjo-2025-329213v1.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2011.00320.x"},{"key":"2026092310201069000_bjo-2025-329213v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2020.01.004"},{"key":"2026092310201069000_bjo-2025-329213v1.6","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41586-024-08119-z","article-title":"Genetic defects of brain immunity in childhood herpes simplex encephalitis","volume":"635","author":"Zhang","year":"2024","journal-title":"Nature"},{"key":"2026092310201069000_bjo-2025-329213v1.7","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.ophtha.2016.10.001","article-title":"Persistent Impairment of Quality of Life in Patients with Herpes Simplex Keratitis","volume":"124","author":"Reynaud","year":"2017","journal-title":"Ophthalmology"},{"key":"2026092310201069000_bjo-2025-329213v1.8","doi-asserted-by":"crossref","DOI":"10.3390\/tropicalmed7060092","article-title":"Incidence and Risk Factors of Bilateral Herpetic Keratitis: 2022 Update","volume":"7","author":"Chaloulis","year":"2022","journal-title":"Trop Med Infect Dis"},{"key":"2026092310201069000_bjo-2025-329213v1.9","unstructured":"Lee White M , Chodosh J . 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