Remdesivir and Nitazoxanide for Chronic Norovirus Type 1 Infection in a Child Post-cardiac Transplantation

To the Editors: Norovirus infection is a common cause of self-limiting gastroenteritis. Immunocompromised patients are at risk of developing chronic norovirus infection, leading to unremitting diarrhea, malabsorption and weight loss.1 In solid-organ recipients, the additional risk is graft rejection due to malabsorption of immunosuppressive drugs. There are no licensed vaccines nor antiviral agents available. A variety of (off-label) drugs have been trialed, most widely favipiravir, an RNA-dependent polymerase (RdRp) inhibitor, with nitazoxanide.1 We present the first case of an immunocompromised child with chronic norovirus type 1 infection who successfully cleared the virus following treatment with remdesivir and nitazoxanide. A 7-year-old male, post-cardiac transplantation at 2 years of age for hypoplastic left heart syndrome, presented in September 2024 with fever, diarrhea and vomiting, and was managed supportively. He was on tacrolimus (target trough level 2–3 µg/L) and sirolimus (target trough levels 4–6 µg/L). Three weeks later (day+34 since onset), he re-presented with gastroenteritis and acute kidney injury. He was managed conservatively. A fecal sample was reverse transcription polymerase chain reaction (RT-PCR) positive for norovirus type 1; other enteric viruses and fecal and blood bacterial cultures were negative. Renal function and immunosuppressant levels were carefully monitored, and he was discharged after 3 weeks. He re-presented with similar symptoms and 2.5 kg weight loss (54th–9th centile) on day+90 (Fig. 1). Supportive care was commenced. Norovirus Ct values were falling, indicating high viral load. Tacrolimus and sirolimus doses were increased because of subtherapeutic trough levels (Fig. 1), increasing his risk of graft rejection. However, this increase further impaired his ability to clear the norovirus.FIGURE 1.: Laboratory values over time. A: Weight in kilograms and norovirus stool Ct values; B: immunosuppression trough levels; C: renal function. Vertical dotted line represents commencement of antiviral therapy on day+112.Following multidisciplinary discussion, he was planned to commence oral favipiravir (1000 mg for 1 day, 400 mg twice daily subsequently), intravenous (IV) remdesivir (5 mg/kg loading dose, followed by 2.5 mg/kg once daily subsequently), and IV nitazoxanide (500 mg twice daily). Due to clinical urgency, he commenced on remdesivir and nitazoxanide, awaiting favipiravir approval, on day+112. Renal and liver function, and immunosuppressant trough levels were monitored (Fig. 1). Enteric virus PCRs were monitored (bi)weekly. Stool frequency improved significantly after 2 days, and stool consistency and weight after 2 weeks. In view of clinical improvement, favipiravir was not started. After 2.5 weeks of treatment, norovirus RT-PCR became negative. Following 3 consecutive negative norovirus RT-PCRs, antiviral treatment was stopped (day+143). At the 1-month review post-discharge, he had fully recovered, with a stable cardiac function and without gastrointestinal symptoms. At 12 months post-treatment, he remained well with stable weight gain. Norovirus prevalence in solid-organ recipients is 5% in tertiary care, of whom 20% develop chronic infection.2 Initially, a combination of 2 RdRp inhibitors was chosen, as it had shown synergistic action against other RNA viruses,3 with nitazoxanide, as it boosts the innate immune response, further promoting synergy.4 Remdesivir and nitazoxanide are readily available in the United Kingdom, whereas favipiravir is not. Although favipiravir and nitazoxanide are better studied, remdesivir has shown efficacy and safety against severe acute respiratory syndrome coronavirus 2 another positive-sense single-stranded RNA virus, infection in vivo.5 The combination of readily available remdesivir and nitazoxanide can be a successful and well-tolerated treatment regimen for chronic norovirus infection in immunocompromised children.