# Efficacy of Acyclovir to Suppress Herpes Simplex Virus Oropharyngeal Reactivation in Patients Who Are Mechanically Ventilated

Charles-Edouard Luyt, David Hajage, Sonia Burrel, Sami Hraiech, Mamadou Hassimiou Diallo, Laurent Papazian, David Boutolleau

<figure><img src="image_1.png" /></figure>

## To cite this version:

Charles-Edouard Luyt, David Hajage, Sonia Burrel, Sami Hraiech, Mamadou Hassimiou Diallo, et al. Efficacy of Acyclovir to Suppress Herpes Simplex Virus Oropharyngeal Reactivation in Patients Who Are Mechanically Ventilated. JAMA Network Open, 2021, 4 (12), pp.e2139825. 10.1001/jamanet-workopen.2021.39825. hal-03500885

HAL Id: hal-03500885

https://hal.sorbonne-universite.fr/hal-03500885

Submitted on 22 Dec 2021

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_3.png" /></figure>

**Research Letter** | Critical Care Medicine

# Efficacy of Acyclovir to Suppress Herpes Simplex Virus Oropharyngeal Reactivation in Patients Who Are Mechanically Ventilated
An Ancillary Study of the Preemptive Treatment for Herpesviridae (PTH) Trial

Charles-Edouard Luyt, MD, PhD; David Hajage, MD, PhD; Sonia Burrel, MD, PhD; Sami Hraiech, MD, PhD; Mamadou Hassimiou Diallo, MSc; Laurent Papazian, MD, PhD; David Boutolleau, MD, PhD

## Introduction

In the recently published Preemptive Treatment for Herpesviridae (PTH) randomized clinical trial (NCT02152358),¹ preemptive use of acyclovir for patients who were mechanically ventilated with oropharyngeal herpes simplex virus (HSV) reactivation failed to demonstrate a positive impact on day-60 ventilator-free days; however, a trend toward a decreased day-60 mortality rate was found in favor of acyclovir. However, the impact of acyclovir on oropharyngeal HSV reactivation was not assessed. We performed this retrospective study to evaluate the efficacy of acyclovir to suppress HSV oropharyngeal reactivation within the PTH trial.

## + Supplemental content

Author affiliations and article information are listed at the end of this article.

## Methods

This analysis of a randomized clinical trial was planned in the original protocol (available with the original publication and in Supplement 1),¹ which was approved by an independent ethics committee (Comité de Protection des Personnes Sud Méditéranée 5). Written informed consent was obtained from patients or their legally authorized representatives. For the latter, the patient's follow-up informed consent was obtained when possible. Conduct of the study and reports of results follow the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.

The PTH trial was performed in 16 French intensive care units among 238 adults aged older than 18 years. Participants were mechanically ventilated for at least 96 hours, were expected to remain on mechanical ventilation for 48 hours or more, and had HSV oropharyngeal reactivation. Patients were randomized to receive acyclovir 5 mg/kg or a matching placebo 3 times daily for 14 days.¹

HSV shedding was assessed on prospectively collected oropharyngeal swabs from patients included in 2 centers (Hôpital Pitié-Salpêtrière, Paris, and Hôpital Nord, Marseille) at randomization and at days 7, 14, and 21 postrandomization. All patients with at least 1 follow-up swab were included in this study (eFigure in Supplement 2). Details regarding patient sampling and sample processing are available in eMethods in Supplement 2.

Data are expressed as median (IQR), mean (SD), or mean with 95% CI, as appropriate. Between-group comparisons used Student t test or Mann-Whitney U test for continuous variables according to variable distribution (ie, normal or not normal). For categorical variables, between-group comparisons used χ² or Fischer exact tests. All analyses were computed with R software version 3.5.1 (R Project for Statistical Computing) at a 2-sided 5% level of significance. Data were analyzed from February through April 2021. Further details regarding statistical analysis are given in eMethods in Supplement 2.

## Results

Among 239 patients included in the PTH trial, 133 patients were included in the 2 centers participating in this ancillary study; among these patients, 130 individuals (87 patients in Paris and 43

<figure><img src="image_4.png" /></figure>

Open Access. This is an open access article distributed under the terms of the CC-BY License.
patients in Marseille) had at least 1 follow-up swab and were included in the study. Patient baseline characteristics were comparable between groups; among 66 patients in the acyclovir group and 64 patients in the placebo group, there were 43 (65.2%) men and 46 (71.9%) men, respectively. The groups had a median (IQR) age of 59 (50-66) years and 59 (43-66) years, admission simplified acute physiology score II of 42 (35-54) and 43 (36-50), and admission sequential organ failure assessment score of 10 (7-13) and 9 (7-12), respectively. Median (IQR) body mass index (calculated as weight in

<table><caption>Table. Cumulative Incidence of HSV Shedding, Extubation, and Death</caption><thead><tr><th rowspan="2">Outcome and<br>treatment group</th><th colspan="4">Cumulative incidence, % (95% CI)</th><th rowspan="2">P value</th></tr><tr><th>Day 1<sup>a</sup></th><th>Day 7</th><th>Day 14</th><th>Day 21</th></tr></thead><tbody><tr><td><strong>HSV-negative swab</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Acyclovir</td><td>0</td><td>0.21 (0.12-0.32)</td><td>0.46 (0.33-0.58)</td><td>0.67 (0.49-0.81)</td><td>.008</td></tr><tr><td>Placebo</td><td>0</td><td>0.17 (0.09-0.27)</td><td>0.24 (0.14-0.36)</td><td>0.37 (0.23-0.51)</td><td></td></tr><tr><td><strong>Extubation</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Acyclovir</td><td>0.02 (0.00-0.08)<sup>b</sup></td><td>0.06 (0.02-0.14)</td><td>0.10 (0.04-0.013)</td><td>0.14 (0.07-0.25)</td><td>.11</td></tr><tr><td>Placebo</td><td>0</td><td>0.05 (0.01-0.13)</td><td>0.14 (0.06-0.24)</td><td>0.29 (0.17-0.43)</td><td></td></tr><tr><td><strong>Death</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Acyclovir</td><td>0</td><td>0.03 (0.01-0.10)</td><td>0.09 (0.03-0.17)</td><td>0.13 (0.06-0.24)</td><td></td></tr><tr><td>Placebo</td><td>0</td><td>0.05 (0.01-0.13)</td><td>0.11 (0.04-0.02)</td><td>0.22 (0.11-0.35)</td><td>.29</td></tr></tbody></table>

Abbreviation: HSV, herpes simplex virus.

<figure><img src="image_5.png" /><figcaption>Figure. Kinetics of Herpes Simplex Virus (HSV) Shedding During First 21 Days After Randomization</figcaption></figure>

<figure><img src="image_6.png" /></figure>

<footnote>a Day 1 is the day of randomization.</footnote>

<footnote>b One patient was extubated on the day of randomization.</footnote>
kilograms divided by height in meters squared) differed significantly between groups: 29.5 (26.2-34.4) for the acyclovir group vs 26.8 (23.4-31.4) for the placebo group.

Proportions of patients who were deceased or extubated were not significantly different from day 1 to day 21 in the acyclovir or placebo groups. However, the cumulative incidence of patients with HSV-negative oropharyngeal swabs was significantly increased in the acyclovir group from randomization to day 21 compared with the placebo group (from 0% at randomization to 67.3% at day 21 [95% CI, 49.0%-81.0%] in the acyclovir group vs 0% at randomization to 36.8% [95% CI, 23.0%-51.0%] at day 21 in the placebo group; *P* = .008) (Table and Figure). Subdistribution hazard ratios for acyclovir vs placebo obtained from the Fine-Gray model for HSV negative swab, extubation, and death were 2.50 (95% CI, 1.42-4.39), 0.41 (95% CI, 0.17-0.96), and 0.52 (95% CI, 0.20-1.35), respectively.

Discussion

This analysis of a randomized clinical trial found that intravenous acyclovir at a dosing of 15 mg/kg/d for 14 days was effective in decreasing the duration of HSV oropharyngeal shedding compared with placebo among patients mechanically ventilated for 96 hours or more. However, throat HSV shedding was still detected among one-third of patients after 14 days of antiviral treatment. In the parent trial,¹ patients in the acyclovir group had a decreased mortality rate but increased duration of mechanical ventilation.

One hypothesis for the negative result of the PTH trial was the inefficacy of acyclovir to cure HSV oropharyngeal reactivation,¹ although this drug has been shown to prevent HSV reactivation.² Although we found here that acyclovir allowed the shortening of HSV shedding duration, this dosing and duration of antiviral treatment do not appear to be sufficient to totally suppress oropharyngeal HSV reactivation and shedding among patients who are mechanically ventilated. Whether increased doses and prolonged duration of treatment may lead to complete suppression of HSV shedding and may improve outcomes remains to be determined. Limitations of our study include the limited number of patients included and missing samples.

ARTICLE INFORMATION

Accepted for Publication: October 26, 2021.

Published: December 20, 2021. doi:10.1001/jamanetworkopen.2021.39825

**Open Access:** This is an open access article distributed under the terms of the [CC-BY License](https://creativecommons.org/licenses/by/4.0/). © 2021 Luyt CE et al. *JAMA Network Open*.

**Corresponding Author:** Charles-Edouard Luyt, MD, PhD, Service de Médecine Intensive Réanimation, Sorbonne Université, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de Paris, 47-83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France (charles-edouard.luyt@aphp.fr).

**Author Affiliations:** Service de Médecine Intensive Réanimation, Sorbonne Université, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de Paris, Paris, France (Luyt); Institut national de la Santé et de la Recherche Médicale Mixte de Recherche S 1166-Institute of Cardiometabolism and Nutrition, Paris, France (Luyt); Sorbonne Université, Institut national de la Santé et de la Recherche Médicale, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Département de Santé Publique, Centre de Pharmacoépidémiologie, Centre d'Investigation Clinique-1421, Paris, France (Hajage, Diallo); Centre National de Référence Herpèsvirus, Département de Virologie, Sorbonne Université, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de Paris (Burrel, Boutolleau); Institut National de la Santé et de la Recherche Médicale U1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France (Burrel, Boutolleau); Médecine Intensive Réanimation, Aix-Marseille Université, Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, Marseille, France (Hraiech, Papazian).

**Author Contributions:** Dr Luyt had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

<figure><img src="image_7.png" /></figure>
**Concept and design:** Luyt.

**Acquisition, analysis, or interpretation of data:** All authors.

**Drafting of the manuscript:** Luyt.

**Critical revision of the manuscript for important intellectual content:** All authors.

**Statistical analysis:** Hajage, Diallo.

**Obtained funding:** Papazian.

**Administrative, technical, or material support:** Luyt, Burrel, Papazian, David.

**Supervision:** Luyt, Hajage, Hraiech.

**Conflict of Interest Disclosures:** Dr Luyt reported receiving personal fees from Bayer Healthcare, Merck, Thermo Fisher Brahms, Carmat, Biomérieux, and Aerogen outside the submitted work. Drs Hajage and Papazian reported receiving grants from the French Ministry of Health during the conduct of the study. No other disclosures were reported.

**Funding/Support:** This study was supported by a grant Bourse Biobanque 2020 from the Société de Réanimation de Langue Française.

**Role of the Funder/Sponsor:** The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

**Trial Registration:** ClinicalTrials.gov Identifier: NCT02152358

**Data Sharing Statement:** See Supplement 3.

REFERENCES

1. Luyt CE, Forel JM, Hajage D, et al; Preemptive Treatment for Herpesviridae Study Group, Réseau Européen de recherche en Ventilation Artificielle Network. Acyclovir for mechanically ventilated patients with herpes simplex virus oropharyngeal reactivation: a randomized clinical trial. JAMA Intern Med. 2020;180(2):263-272. doi:10.1001/jamainternmed.2019.5713

2. Tuxen DV, Wilson JW, Cade JF. Prevention of lower respiratory herpes simplex virus infection with acyclovir in patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1987;136(2):402-405. doi:10.1164/ajrccm/136.2.402

SUPPLEMENT 1.

Trial Protocol

SUPPLEMENT 2.

eMethods.

eFigure. Study Flowchart

SUPPLEMENT 3.

Data Sharing Statement

<figure><img src="image_8.png" /></figure>