Welcome to the HSV treatment trial

Study Summary

Rationale

Every year 69.000 patients are admitted to ICUs in the Netherlands. Around 10% of these patients have a prolonged duration of mechanical ventilation due to persistent respiratory failure precluding extubation. Around 40% of these patients die within 60 days and they remain ventilated for a mean of 21 days. They are at risk for additional lung injury due to mechanical ventilation and clinicians focus on minimising such ventilator induced lung injury. Injured lungs are also a preferential site for reactivation of Herpes Simplex virus, a virus that lies dormant in approximately 80% of the adult population.

Problem definition and objective(s)

The last decades, the need for treatment of pulmonary HSV reactivations has been a continuous topic of discussion resulting in enormous practice variation. HSV replication can result in progressive pulmonary injury, but treatment with the anti-viral Aciclovir also has side effects. Our objective is to compare the clinical effectiveness of aciclovir treatment vs waiting in patients with pulmonary HSV reactivation.

Plan of approach

Randomised controlled trial with 1:1 randomisation between standard of care + aciclovir and standard of care alone. Eligible patients have >10^4 copies HSV per mL in broncho-alveolar lavage fluid. The primary outcome is ventilator-free days and alive at day 30 post randomisation. Based on simulations of trials based on observational data with a mortality reduction from 40 to 35% and a reduction in mean duration of mechanical ventilation from 21 to 13 days (modelled on a log2 scale), 240 patients are required per arm to provide a power of 80% at an alpha of 0.05 using proportional odds logistic regression (average simulated OR: 1.57 [1.14-2.18]).

Participants of the project 

Patients with persistent respiratory failure in participating ICUs routinely undergo bronchoscopy with broncho-alveolar lavage for HSV diagnostics.
Inclusion criteria are: (1) Intubated and mechanically ventilated patients with (2) >10^4 copies HSV per mL in broncho-alveolar lavage fluid.
Exclusion criteria are: (1) Clear indication for treatment with aciclovir; stem cell or lung transplantation recipient; (2) No chance for recovery as deemed by clinical team; (3) Expected extubation within 24 hours; (4) Known hypersensitivity.

Intervention

Active arm: Standard of care + intravenous aciclovir 5 mg/kg body weight every 8 hours during 7 days.
Control arm: Standard of care without treatment of HSV reactivation

Intended results

Provide the first objective outcome data on the treatment of HSV reactivation in ICU patients with persistent respiratory failure. Specific focus is given to the influence of age, gender and socio-economical status as these drive HSV seropositivity as well as ICU outcomes.

Impact

We expect to reduce mortality and duration of mechanical ventilation.