Acyclovir in Ventilated Patients With Pneumonia and HSV-1 in BAL

Herpes-simplex virus (HSV) can be detected in the bronchoalveolar lavage (BAL) in up to 60% of mechanically ventilated (MV) ICU patients with a lower respiratory tract infection (LRTI), depending on the study population and the severity of disease. However, it remains unclear whether the detection represents a harmless viral shedding as a consequence of reactivation, reflecting the severity of the underlying disease and immunoparalysis, or a true clinical infection requiring antiviral therapy. To date, only retrospective studies have investigated the benefit of an antiviral therapy in HSV-positive ICU patients on mechanical ventilation (MV) with LRTI. In a retrospective study and additional meta-analysis on this topic a antiviral treatment was associated with an improved patient outcome, i.e.; lower all-cause hospital mortality (RR 0.74, 95% CI 0.64-0.85) and lower 30-day all-cause mortality (RR 0.75, 95% CI 0.59-0.94; 3 studies). Aim of this study is to determine prospectively in a multicenter, randomized controlled trial whether acyclovir therapy improves outcome in ventilated ICU patients with a LRTI and HSV detection in BAL. Overall, 616 ICU patients with MV and LRTI and HSV1-PCR-detection in BAL (>= 10E3 copies/ml) will be either randomized to receive acyclovir (10mg/kg body weight tid) for 10 days (or discharge from ICU if this is earlier) or no antiviral therapy (control group). Primary efficacy endpoint will be overall survival within 30 days comparing the acyclovir therapy and the control group. Secondary endpoints include ventilation-free days up to day 30, vasopressor-free days until day 30 and safety.

• Acyclovir (Drug), also known as Aciclovir: Dosage: 10mg/kg (current) body weight every 8 hours, dose adjustment to renal function according to technical information. Mode of administration: intravenous (i.v.)

Primary outcomes

• mortality (survival status) [day 30]: survival status

Secondary outcomes

• Ventilation-free days [day 30]: days without mechanically ventilation via endotracheal tube, incl. tracheostoma
• Vasopressor-free days [day 30]: days without continuous vasopressor administration > 1h/day
• Delta SOFA score (Sepsis-related Organ Failure Assessment Score) [Baseline - Day 10 or EOT if this event occurs earlier]: Each of six organ systems receive a score ranging from 0 (normal) to 4 (most abnormal), with a minimum SOFA score of 0 and a maximum SOFA score of 24
• Delta SOFA sub-score kidney (Sepsis-related Organ Failure Assessment Score) [Baseline - Day 10 or EOT if this event occurs earlier]: Sub-score for kidney function, the score ranges from 0 (normal) to 4 (most abnormal)
• Delta GFR value [Baseline - Day 10 or EOT if this event occurs earlier]: GFR value
• Length of stay in ICU [day 30]: days LOS in ICU
• Length of stay in Hospital [day 30]: days LOS in hospital
• Cost of intervention [up to day 90]: ICU and hospitalization days + acyclovir
• Days without delirium/coma [Until day 10 or until EOT if this event occurs earlier]: based on CAM-ICU / RASS
• Microbiological cure (EOT) [At day 10 or day of EOT if this event occurs earlier]: Percent of participants with HSV eradication (PCR testing negative) in blood and respiratory tract
• mortality (survival status) [90 days]: survival status
• mortality (survival status) [180 days]: survival status
• Quality of life (EQ-5D-5L) [Measurement at day 10 or EOT if this event occurs earlier, day 30, day 90, and day 180]: EuroQuality of Life Five Dimensions (EQ-5D-5L), the descriptive system comprises five dimensions (MOBILITY, SELF-CARE, USUAL ACTIVITIES, PAIN / DISCOMFORT and ANXIETY / DEPRESSION), with five response levels: no problems, slight problems, moderate problems, severe problems, unable to/extreme problems.
• Incidence SAEs [From time of randomization until day 10 or EOT if this event occurs earlier]: Incidence of serious adverse events

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. ≥ 18 years
2. need for invasive or non-invasive respiratory support
3. PCR HSV-1 detection in BAL (≥ 10\^3 copies/ml)
4. Pneumonia (community or healthcare acquired, incl. ventilator-associated pneumonia)
5. declaration of consent by the patient or legal representative

Exclusion Criteria:

1. History of hypersensitivity to acyclovir or valacyclovir or other components of the investigational product.
2. Pregnancy/Lactation 3.3. Simultaneous participation in another clinical interventional trial under EU Regulation 536/2014, the German Medicines Act (AMG), Medical Devices Regulation (MDR), or Medical Devices Act (MPDG) without prior consultation and approval by the respective sponsors prior to randomization

4.Decision to withhold life-sustaining therapies 5.Use of a virostatic agent (i.v. or p. os) with activity against herpes simplex (acyclovir, valacyclovir, famciclovir/penciclovir, brivudine, cidofovir, foscarnet) for therapeutic or prophylactic reasons at the time of randomization.

6.Solid organ transplantation, stem cell transplantation 7.Neutropenia (absolute neutrophil count <1500/μl (<1.5 × 109 /l) 8.Previous study participation in HerpMV

• Results publication: Hagel S, Brillinger N, Decker S, Deja M, Ertmer C, Fiedler S, Franken P, Heim M, Weigand MA, Zarbock A, Pletz MW; SepNet Critical Care Trials Group. Effect of acyclovir therapy on the outcome of mechanically ventilated patients with lower respiratory tract infection and detection of herpes simplex virus in bronchoalveolar lavage: protocol for a multicentre, randomised controlled trial (HerpMV). BMJ Open. 2024 Apr 25;14(4):e082512. doi: 10.1136/bmjopen-2023-082512. PMID 38670599