Nitazoxanide for Severe Cryptosporidial Diarrhea in Human Immunodeficiency Virus Infected Children

Abstract

To the Editors: In human immunodeficiency virus (HIV) infection, Cryptosporidium parvum (CP) causes prolonged refractory diarrhea and signifies advanced disease.1 Treatment has been unsatisfactory, limited mainly to supportive therapy, until the advent of nitazoxanide (NTZ). Food and Drug Administration (FDA) approval for NTZ in November 2002 was based on 2 double-blind controlled clinical trials in immune competent children.2,3 It is registered for twice daily administration for 3 days in children greater than 1 year of age. Although there is no weight based dosage guidance, the recommended dosage approximates 10mg/kg for a 1-year-old male infant on the 50th percentile. (www.CDC.gov/growth charts). Anecdotal experience in HIV-infected children and adults supports a larger dosage for longer periods.4 We report our experience in 3 HIV-infected children with debilitating CP diarrhea treated with NTZ. All had confirmed HIV infection and were receiving trimethoprim-sulfamethaxazole prophylaxis. One had received antiretroviral therapy for the preceding year. NTZ was released on compassionate grounds by the manufacturer, Romark Pharmaceuticals, Tampa, Florida after approval by the South African Medical Control Council. Permission was obtained from the Committee for Human Research at Stellenbosch University and the parents to publish this information. Our dosage was derived from PACTG 369, a dose-finding and dose escalation study for HIV-infected children. We used 22.5 mg/kg of the suspension twice daily. NTZ was given until 3 consecutive stool specimens were CP oocyst free. We defined resolution of diarrhea as a reduction in fluid requirements to baseline in the absence of clinical dehydration.5 Duration of treatment varied between 7 and 40 days. The following blood tests were done weekly to monitor for toxicity: full blood count, urea, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), and gamma gluteryl transferase (GGT). Multiple stool samples from all patients were extensively investigated to exclude rotavirus, adenovirus and cytomegalovirus, Campylobacter jejuni, shigella, salmonella and parasites. All had been empirically treated with metronidazole for possible Clostridium difficile and giardiasis before initiation of NTZ. CP was diagnosed by demonstrating oocysts on stool specimens using auramine staining. Details of diarrhea are shown in the Table 1. Duration of diarrhea preceding NTZ ranged from 2 to 8 weeks. All children had large prior ongoing losses and high daily fluid requirements. Fluid requirements reduced to maintenance volumes within 3 weeks and NTZ was associated with clearance of CP from stool and resolution of diarrhea in all 3 children.TABLE 1: Demographic and Clinical Data of 3 Children With HIV Infection and Cryptosporidial DiarrheaOne child died of Klebsiella septicemia resulting from intravascular catheter sepsis a week after resolution of diarrhea. Another developed elevated GGT (12-fold) and ALT (3-fold increase) attributed to either CMV, sclerosing cholangitis related to CP or NTZ. All liver enzymes returned to normal within 3 months of resolution of the diarrhea. In conclusion, in our experience, NTZ seems to be a useful agent for severe debilitating CP diarrhea in HIV-infected children. More data are needed. Deepthi R. Abraham, FC Paed (SA) Helena Rabie, FC Paed (SA) Mark F. Cotton, FC Paed (SA), PhD Department of Pediatrics and Child Health Tygerberg Children's Hospital Stellenbosch University Cape Town Republic of South Africa