Nitazoxanide Treatment of Cryptosporidium parvum in Human Immunodeficiency Virus-Infected Children

Abstract

To the Editors: Cryptosporidium parvum is a significant cause of diarrhea and wasting in human immunodeficiency virus (HIV)-infected individuals.1 Chronic cryptosporidiosis represents a common, serious problem in less developed countries, particularly among HIV-infected children. Several studies showed the prevalence of cryptosporidiosis in African countries and Thailand to range from 6% to 25.6%.2–3 Whereas nitazoxanide (NTZ) is the drug of choice for immunocompetent individuals with diarrhea caused by C. parvum, it is not approved for HIV-infected patients. NTZ and its metabolites have a wide range of activity against protozoal infections, including C. parvum.4 A randomized double-blind placebo-controlled trial of NTZ was conducted in Zambian children, 12 to 36 months of age, with C. parvum diarrhea. Children were randomized to receive NTZ (100 mg twice daily orally for 3 days) or placebo. Three days of NTZ treatment significantly improved resolution of diarrhea, parasitologic response, and mortality in non–HIV-infected children. HIV-infected children did not benefit from 3 days of treatment, but after 3 more days of open-label treatment, 77% showed clinical responses. The trial suggested that HIV-infected children may benefit from longer courses of therapy.5 The Pediatric AIDS Clinical Trials Group 369 protocol, a collaborative study to determine the pharmacokinetic profile of oral NTZ in HIV-infected children with C. parvum diarrhea, terminated early because of slow accrual. Six subjects enrolled, but pharmacokinetic results were available for 3 subjects. The 3 subjects (6 months to 3 years of age) received NTZ 22.5 mg/kg every 12 hours for 56 days. Pharmacokinetic samples were collected on day 7 and predose pharmacokinetic samples were collected on days 14, 28, and 56 to assess drug accumulation. Samples were analyzed for nitazoxanide metabolites, tizoxanide (TZ) and tizoxanide-glucuronide (TZG). Our study demonstrated significant variability in TZ exposure with the range of area under the curves (AUCs) from 2.29 to 31.53 mcg*h/mL. These values were significantly lower than the AUC of 144 mcg*h/mL reported in adults following 1000 mg, but consistent with reduced concentrations reported in HIV patients. The observed TZ maximum concentrations (Cmax: 1.04–5.86 mcg/mL), were less variable than AUCs. These values were also lower than the Cmax of 14 mcg/mL seen in adults and below the reported inhibition concentration for intracellular replicating cryptosporidia in vitro.4 The TZG AUC ranged from 30.20 to 68.52 mcg*h/mL. Although the study terminated early, pharmacokinetic analysis of 3 subjects suggests the dosage of NTZ used may not be as sufficient as the doses used in adults. The approved dose for NTZ for the treatment of diarrhea caused by C. parvum in immunocompetent children from 1 to 3 years of age is 100 mg every 12 hours. Because the dosages used in our study were weight based and were higher at 22.5 mg/kg every 12 hours, the effective dosage would probably be much higher than that approved for non–HIV-infected children. While NTZ treatment may be considered in HIV-infected children with C. parvum diarrhea, the dosage required for children should be further investigated as a larger dosage will likely be needed to achieve the adult AUC values.