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Antiviral Res. 2017 Oct;146:205-212. doi: 10.1016/j.antiviral.2017.09.013. Epub 2017 Sep 20.

Recurrent herpetic keratitis despite antiviral prophylaxis: A virological and pharmacological study.

Author information

1
Service d'Ophtalmologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud, DHU Vision et Handicaps, 78, rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France; Service d'Immunologie des Infections Virales et des Maladies Auto-immunes (IMVA), 18, Route du Panorama, 92260 Fontenay-aux-Roses, France. Electronic address: antoine.rousseau@aphp.fr.
2
Service de Virologie, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, 47-83 Boulevard de l'Hôpital, 75013 Paris, France; Sorbonne Universités, UPMC Université Paris 6, CR7, CIMI, INSERM U1135, 91, Boulevard de l'Hôpital, 75013, Paris, France. Electronic address: david.boutolleau@aphp.fr.
3
Service de Pharmacologie Clinique et Toxicologie, CHU de Bordeaux, Hôpital Pellegrin, Place Amélie Raba Léon, 33076 Bordeaux, France. Electronic address: karine.titier@chu-bordeaux.fr.
4
Service d'Ophtalmologie, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital, 67000 Strasbourg, France. Electronic address: tristan.bourcier@chru-strasbourg.fr.
5
Service d'Ophtalmologie, CHU de Grenoble, Université Joseph Fourier-Grenoble 1, Avenue Maquis du Grésivaudan, 38700 La Tronche, France. Electronic address: christophe.chiquet@inserm.fr.
6
Service d'Ophtalmologie, CHU de Nantes, 1 Place Alexis-Ricordeau, 44093 Nantes, France. Electronic address: michel.weber@chu-nantes.fr.
7
Service d'Ophtalmologie, CHU de Bordeaux, Hôpital Pellegrin, Place Amélie Raba Léon, 33076 Bordeaux, France. Electronic address: marc.labetoulle@aphp.fr.
8
Service d'Ophtalmologie, CHU de Rouen, Hôpital Charles Nicolle, 1 rue de Germont, 76031 Rouen Cedex, France. Electronic address: julie.gueudry@chu-rouen.fr.
9
Service d'Ophtalmologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud, DHU Vision et Handicaps, 78, rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France. Electronic address: mgarrech@yahoo.fr.
10
Service d'Ophtalmologie, Hôpital Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, DHU Vision et Handicaps, 47-83 Boulevard de l'Hôpital, 75013 Paris, France. Electronic address: bahram.bodaghi@aphp.fr.
11
Service de Virologie, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, 47-83 Boulevard de l'Hôpital, 75013 Paris, France; Sorbonne Universités, UPMC Université Paris 6, CR7, CIMI, INSERM U1135, 91, Boulevard de l'Hôpital, 75013, Paris, France. Electronic address: sonia.burrel@aphp.fr.
12
Service de Virologie, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, 47-83 Boulevard de l'Hôpital, 75013 Paris, France; Sorbonne Universités, UPMC Université Paris 6, CR7, CIMI, INSERM U1135, 91, Boulevard de l'Hôpital, 75013, Paris, France. Electronic address: henri.agut@aphp.fr.
13
Service de Virologie, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, 12, Avenue Paul Vaillant Couturier, 94800 Villejuif, France. Electronic address: claire.deback@aphp.fr.
14
Service d'Ophtalmologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud, DHU Vision et Handicaps, 78, rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France; Service d'Immunologie des Infections Virales et des Maladies Auto-immunes (IMVA), 18, Route du Panorama, 92260 Fontenay-aux-Roses, France. Electronic address: marc.labetoulle@aphp.fr.
15
Service d'Ophtalmologie, CHU de Nancy, France.
16
Service d'Ophtalmologie, CHU Pitié-Salpétrière, Paris, France.
17
Service d'Ophtalmologie, CHU de Strasbourg, France.
18
Département de Virologie, CHU Pitié-Salpétrière, Paris, France.
19
Service d'Ophtalmologie, CHU de Grenoble, France.
20
Service d'Ophtalmologie, CHU de Bordeaux, Bordeaux, France.
21
Service de Virologie, CHU Paul Brousse, Villejuif, France.
22
Service d'Ophtalmologie, CHU de Rouen, France.
23
Service d'Ophtalmologie, CHU Bichat, Paris, France.
24
Service d'Ophtalmologie, CHU de Marseille, France.
25
Service d'Ophtalmologie, CHU de Bicêtre, Le Kremlin Bicêtre, France.
26
Service d'Ophtalmologie, CHU de Nantes, France.

Abstract

Recurrent herpes simplex keratitis (HSK) is a leading infectious cause of blindness in industrialized countries. Antiviral prophylaxis (AVP) may fail to prevent recurrence of HSK due to viral resistance, inadequate dosing, or poor patient compliance. In this prospective multicenter study, we enrolled immunocompetent patients with recurrent HSK despite AVP. Ocular samples were tested by PCR for herpes simplex virus 1 (HSV-1). HSV-1 drug resistance was assessed with a genotypic assay based on UL23 and UL30 gene sequencing. After curative full dose valacyclovir (VACV) treatment was started, peak and trough acyclovir (ACV) plasma concentrations were measured, and patient compliance to AVP was assessed with a questionnaire. The study sample was comprised of 43 patients. Six (14%) patients were positive for HSV-1 using PCR, of whom 5 (83%) harbored genotypically ACV-resistant (ACVR) virus, due to mutations in UL23 (n = 4) or UL30 (n = 1). Disease duration was statistically significantly longer in patients with viral resistance compared to other HSK patients [35.5 ± 23.4 years (range, 6.8-68.4 years) versus 11.1 ± 12.3 years (range, 0.8-56.3 year) respectively; Mann-Whitney p = 0.01)]. While patients were treated with full dose VACV, trough ACV plasma concentrations were below the threshold for ACV sensitivity in 9.5% of cases, and compliance was poor in 5.3% of cases. To summarize, HSV-1 resistance to ACV seems to be a significant cause of failure of prophylaxis in patients with HSK and is associated with longer disease duration. Most PCR-positive samples contained genotypically ACVR virus and identification may aid in adapting treatment. Incomplete 24-h drug coverage may also explain some cases of failure of prophylaxis.

KEYWORDS:

Acyclovir; Herpes simplex keratitis; Pharmacokinetics; Valacyclovir; Viral resistance

PMID:
28939476
DOI:
10.1016/j.antiviral.2017.09.013
[Indexed for MEDLINE]

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