Nitazoxanide Is Effective Therapy For Norovirus Gastroenteritis After Chemotherapy and Hematopoietic Stem Cell Transplantation (HSCT)

Abstract

Norovirus infection is a major cause of nonbacterial gastroenteritis and is a self-limited infection in immunocompetent patients. However, in immune compromised patients, norovirus has been reported to cause prolonged infection resulting in complications such as graft versus host disease and sepsis due to mucosal breakdown. Supportive care is the only current therapy for norovirus as attempts to treat norovirus with ribavirin or oral immunoglobulin have been unsuccessful. Nitazoxanide is a thiazolide antimicrobial with broad activity against anaerobic bacteria, protozoa, and a range of viruses in cell culture models. The antiviral activity of nitazoxanide may relate to activation of natural host antiviral defenses, but there is also evidence for a direct-acting antiviral effect on cellular processes possibly through inhibition of virus protein production/maturation and/or assembly. We report our experience treating norovirus gastroenteritis occurring in 12 patients after (9) or prior to (3) HSCT with Nitazoxanide. From November 2012 to July 2013, 12 patients (2 receiving chemotherapy, 1 autologous HSCT and 9 allogeneic HSCT) developed norovirus gastroenteritis. Ages ranged from 1 to 21 years (median 10) diagnoses included ALL/AML (6), aplastic anemia (2), and 1 each for osteopetrosis, Wiskott Aldrich, neuroblastoma, and brain tumor. Norovirus was detected by RNA RT-PCR test of stool performed by Focus Diagnostics, Cypress, Ca. The dose of Nitazoxanide was 100 mg po BID for ages 1 to 4 years, 200 mg po BID for age 4 to 11 years, and 500 mg po BID for greater than 11 years. One patient, 33 months post HSCT with normal immune studies was not treated as his symptoms resolved prior to availability of test results. All other patients clinically responded with improvements in diarrhea, nausea, and abdominal pain within 2-4 days (median 2 days). Three patients were pre-HSCT on chemo/immunotherapy and 8 patients were 1 day to 34 months after HSCT. All of the treated patients were on immune suppression or chemotherapy. Eight allogeneic HSCT patients were on immunosuppression and four of these patients had GVHD at onset of symptoms. Immune suppression included tacrolimus/solumedrol (3), cellcept/solumedrol (2) plus infliximab (1), tacrolimus (1), cyclosporine (1). Three patients were receiving immunotherapy (1), or chemotherapy for solid tumors (2) prior to planned HSCT. Clearance of stool virus was variable. Two of 3 patients treated prior to HSCT became negative on stool study within 3-14 days of treatment (1 unknown duration). Among patients treated after HSCT 5 of 8 had persistent viral shedding, 2 received drug until death (1 adenovirus, 1 congestive heart failure) both were treated greater than 2 months, 3 with GVHD continue to shed virus after 6 months of treatment, and 3 have come off therapy and remain negative for norovirus RNA. One HSCT patient with clinical resolution but persistent viral shedding stopped treatment resulting in re-occurrence of clinical symptoms. This patient responded clinically to reinstitution of therapy within 2 days but continues to shed virus. UGI endoscopy and colonoscopy were performed in 5 patients at the time of clinical infection, all showed inflammation and edema but no GVHD was seen on histology. Peripheral blood CD4 counts among those with persistent viral shedding ranged from<50-445/ul and for those that cleared virus 143-1222/ul. Nitazoxinide is effective therapy for norovirus gastroenteritis in immune compromised patients. Therapy needs to be continued until stool RNA studies become negative. Disclosures: Off Label Use: Nitazoxide is a thiazolide antimicrobial that is FDA approved for treatment of cryptosporidium and is known to have broad spectrum activity to bacteria and viral infections. We used it to treat norovirus infections in immune compromised SCT patients.