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

Official title

Effect of Acyclovir Therapy on the Outcome of Ventilated Patients With Lower Respiratory Tract Infection and Detection of Herpes Simplex Virus in Bronchoalveolar Lavage

Overview

Almost 90 out of 100 people carry herpes simplex viruses (HSV). Once a person has been infected with the herpes viruses, he or she can't get rid of them for the rest of her/his life. For the most part, the viruses are in a dormant state. Only when the immune system is weakened, for example in the case of a serious illness or stress, are the viruses reactivated. They then mainly cause cold sores, which are harmless for healthy people and usually heal without therapy. However, especially in people with a weakened immune system, HSV can also cause serious infections, such as meningitis. In almost every second mechanically ventilated patient in intensive care who has pneumonia, HSV can be detected in the respiratory tract. This is caused by reactivation of the viruses as a result of the severe underlying disease and stress during intensive care therapy. Whether treatment of the herpes viruses (e.g. with acyclovir) is necessary in this situation and helps the patients to cure has not been clarified, especially as acyclovir can also cause side effects such as a deterioration in kidney function. Currently, the physicians decide to treat the herpes viruses in about half of the patients. Several studies have shown that patients for whom the physician decided to treat the viruses survived more often. However, all of these studies looked at the course of the disease only retrospectively and thus are subject to many biases (including physician selection of who receives treatment, missing data). A definitive conclusion as to whether herpesvirus therapy can be recommended cannot be drawn without doubt from these studies. Therefore, the investigators would like to investigate in a randomized controlled trial, i.e. patients are randomly assigned to the experimental (therapy of herpesviruses) or control group (no therapy of herpesviruses), the effect of therapy with acyclovir on survival in ventilated intensive care patients with lower respiratory tract infection (pneumonia) in whom a large amount of HSV was found in the respiratory tract. The goal of the study is to provide clarity on whether therapy will help patients recover.

Detailed description

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.

Interventions

• Drug Acyclovir
  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 outcome measures

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

Secondary outcome measures (12)

• Ventilation-free days [Time frame: day 30]
• Vasopressor-free days [Time frame: day 30]
• Delta SOFA score (Sepsis-related Organ Failure Assessment Score) [Time frame: Baseline - Day 10 or EOT if this event occurs earlier]
• Delta SOFA sub-score kidney (Sepsis-related Organ Failure Assessment Score) [Time frame: Baseline - Day 10 or EOT if this event occurs earlier]
• Delta GFR value [Time frame: Baseline - Day 10 or EOT if this event occurs earlier]
• Length of stay in ICU [Time frame: day 30]
• Length of stay in Hospital [Time frame: day 30]
• Cost of intervention [Time frame: up to day 90]
• Days without delirium/coma [Time frame: Until day 10 or until EOT if this event occurs earlier]
• Microbiological cure (EOT) [Time frame: At day 10 or day of EOT if this event occurs earlier]
• mortality (survival status) [Time frame: 90 days]
• mortality (survival status) [Time frame: 180 days]

Eligibility criteria

Inclusion criteria

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

Exclusion criteria

• History of hypersensitivity to acyclovir or valacyclovir or other components of the investigational product.
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 28 centers

• Universitätsklinikum Freiburg — Freiburg im Breisgau
• Universitätsklinikum Heidelberg — Heidelberg
• Universitätsklinikum Heidelberg — Heidelberg
• Universitätsklinikum Tübingen — Tübingen
• Universitätsklinikum Augsburg — Augsburg
• Klinikum der Ludwig-Maximilian-Universität München — München
• Klinikum rechts der Isar — München
• Klinikum rechts der Isar — München
• … and 20 more centers

Publications

• 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). BM PMID 38670599

Identifiers

NCT: NCT06134492 · ZKSJ0153 · BMBF 01KG2301

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗