Preemptive Treatment With Acyclovir in Intubated and Mechanically Ventilated Patients With Herpes (PTH2)

This research aims to assess the interest of preemptive treatment with Acyclovir in mechanically ventilated patients with reactivation of Herpes simplex (HSV) in the throat and failure of one organ or less. HSV reactivation is common in patients hospitalized in an intensive care unit (ICU) on invasive mechanical ventilation. It begins at the oropharyngeal level (incidence up to 20-50%), then progresses downward with contamination of the distal airways (reported incidence of 20-65%). HSV reactivation is associated with high mortality. The investigators aim to disable that, in mechanically ventilated patients with HSV reactivation in the throat and failure of one organ or less, preemptive treatment with Acyclovir may reduce mortality.

To answer the question posed in the research, it is planned to include 246 people hospitalized in intensive care on invasive mechanical ventilation, presenting with HSV reactivation of the throat and one organ failure or less.

Herpes simplex virus (HSV) reactivations are frequent in intensive care unit (ICU) patients receiving invasive mechanical ventilation. HSV reactivation first occurs in the throat (incidence up to 20-50%), then progress through a descending way with HSV reactivation in the lung (incidence reported from 20-65%). In some patients, a true HSV bronchopneumonitis can occur: in a prospective study, Luyt et al. found that 24% of patients ventilated for more than 4 days and having ventilator-associated pneumonia suspicion had HSV bronchopneumonitis. These reactivations have been associated with increased mortality, which could be explained by the virus-induced injury on the lung parenchyma, by the increased rate of bacterial pneumonia associated with viral infection, or by the prolongation of mechanical ventilation induced by the previous factors. However, to date it is still unknown if HSV is really a pathogen with its own morbidity/mortality, or only a bystander (with reactivation occurring preferentially in the most severe patients). The only way to know whether or not HSV reactivation has an attributable mortality is to show that a specific treatment, namely acyclovir, has an impact on mortality. One recent randomized controlled study, the PTH study, found that preemptive acyclovir treatment was not associated with shorter duration of mechanical ventilation, as compared to placebo. However, the 60-day mortality rate of patients having received acyclovir was 22% vs. 33% for patients having received a placebo (delta = 11%, p=0.06). Moreover, in the subgroup of patients with 1 organ failure or less (organ failure being defined as a corresponding organ-SOFA (Sepsis-related Organ Failure Assessment) score of 3 or 4), 60-day mortality was significantly lower in patients receiving acyclovir (9%) than mortality of patients receiving placebo (30%, p =0.004). As mortality was not the primary endpoint of PTH study, these exploratory but promising results have yet to be formally confirmed. Therefore, the investigators aim to demonstrate that, in patients mechanically ventilated with HSV reactivation in the throat and 1 organ failure or less, pre-emptive treatment with acyclovir may decrease mortality.

This study is a multicenter, randomized, double-blind, placebo-controlled, concealed allocation superiority trial of intravenous acyclovir vs. placebo for mechanically ventilated patients with 1 organ failure or less and HSV reactivation in the throat. Patients ventilated \>96 hours and without exclusion criteria will be screened twice weekly for HSV reactivation using quantitative PCR on swab collected in the throat.

Patients with HSV reactivation will be included and randomized into 2 groups (1:1): acyclovir or placebo. Patients will receive intravenous acyclovir or placebo during 14 days. To keep the blind design of the study, acyclovir and placebo will be reconstituted and/ diluted before the administration in saline bag by the pharmacy or a research's dedicated person (according to sites' possibilities) and dispensed to clinicians. Study drug will be stopped in patients discharged from ICU before end of treatment, i.e. if the patient is discharged before 14 days post randomization.

Allocation concealment will be centralized using a secure web-based randomization system. Patients will be reviewed daily in ICU, at hospital discharge and/or at day 60 post-randomization. Vital status, nosocomial bacterial and viral infection will be collected from day 1 to ICU discharge or day 60. Vital status will be collected at day 90. If discharged from hospital prior to 90 days, the patient (or substitute decision-maker if unable to communicate) will be contacted by telephone to determine the disposition and vital status.

Eligibility Criteria:
Inclusion Criteria:

* aged ≥ 18 year-old
* invasive mechanical ventilation(MV) for 96 hours and planned to last for at least 48 hours longer
* HSV reactivation in the throat (qualitative PCR positive for HSV on a throat swab)
* Presence of 1 or less organ failure; organ failure being defined as a corresponding-organ SOFA score of 3 or 4 (for example, renal failure will be defined as a renal SOFA score of 3 or 4)
* Effective contraception for patients of childbearing age, throughout the treatment period
* Written consent from the patient, from a close relative or from the person of trust previously appointed (or inclusion procedure in emergency situations)
* Under social security cover

Exclusion Criteria:

* Hypersensitivity to acyclovir and excipient
* Pregnant or breastfeeding (controlled by a blood pregnancy test)
* Patient who received an antiviral drug active against HSV (acyclovir, valacyclovir, gancyclovir, valgancyclovir, foscavir, cidofovir) in the previous 30 days
* Duration of ventilation before randomization \>15 days
* Neutropenia, defined by an absolute neutrophils count \< 1,000/mm3
* Solid organ or bone-marrow transplant
* Immunosuppressive treatment (including steroids at a dose \>0.5 mg/kg/day of prednisone or equivalent for \>1 month)
* HIV infection
* Moribund, defined by a Simplified Acute Physiology Score (SAPS) II score at inclusion \>75 points
* Decision of withholding/withdrawing care