High dose prolonged treatment with nitazoxanide is not effective for cryptosporidiosis in HIV positive Zambian children: a randomised controlled trial
BMC Infectious Diseases
High dose prolonged treatment with nitazoxanide is not effective for cryptosporidiosis in HIV positive Zambian children: a randomised controlled trial
Beatrice Amadi 1
Mwiya Mwiya 1
Sandie Sianongo 1
Lara Payne 1
Angela Watuka 1
Max Katubulushi 1
Paul Kelly 0 1
0 Institute of Cell and Molecular Science, Barts & The London School of Medicine, Queen Mary University of London , London , UK
1 Tropical Gastroenterology and Nutrition Group, University of Zambia School of Medicine , Lusaka , Zambia
Background: Treatment of cryptosporidiosis in HIV infected children has proved difficult and unsatisfactory with no drugs having demonstrable efficacy in controlled trials except nitazoxanide. We hypothesised that a prolonged course of treatment with high dose nitazoxanide would be effective in treating cryptosporidiosis in HIV positive Zambian children. Methods: We performed a double-blind, randomised, placebo controlled trial in paediatric patients in the UTH in Lusaka. The study included HIV positive children between one and eleven years of age if 2 out of 3 stool samples were positive for oocysts of Cryptosporidium spp. Children were given nitazoxanide suspension in a dose of 200 mg twice daily (bid) for 28 days (if 1-3 years old) or 400 mg bid for 28 days (if 4-11 years old), or matching placebo. Results: Sixty children were randomised and 52 were fully evaluated. Only five children were 4 years of age or over and received the higher dose. In the primary efficacy analysis, 11 out of 26 (42%) in the active treatment group achieved a 'Well' clinical response compared to 8 out of 26 (35%) in the placebo group. Parasitological response was declared as 'Eradicated' in 27% in the active group and 35% in the placebo group. Mortality (16/52, 31%) did not differ by treatment allocation. Conclusion: We found no significant benefit in children with cryptosporidiosis despite high dose and longer treatment duration. This is the second randomised controlled trial to suggest that in Zambian children with HIV-related immunosuppression nitazoxanide does not eradicate this infection nor provide clinical symptom reduction. Trial Registration: The trial was registered as ISRCTN41089957.
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Background
Cryptosporidiosis is an important cause of morbidity and
mortality in malnourished children [1,2] and in children
with AIDS [2]. In immunocompetent children
cryptosporidiosis is a frequent cause of diarrhoea [3], and even
these episodes which are usually of limited duration can
have long-term consequences [4]. However, treatment
remains difficult and unsatisfactory, with no drugs having
any proven efficacy except nitazoxanide [5-7]. We have
previously reported that three day treatment with the
antiparasitic drug nitazoxanide was effective in treatment of
HIV-seronegative children but demonstrated insignificant
activity in HIV-seropositive children [8]. There is an
urgent need for effective treatment for cryptosporidiosis in
HIV-infected children [9]. We postulated that the
performance of this drug in such patients could be improved
by a higher dosage and by giving a longer course of
treatment. We report here the results of a randomised
controlled trial to evaluate this hypothesis in the same setting as
our earlier study. The doses of nitazoxanide chosen were
double those used in the previous study, and the duration
was increased from 3 to 14 days. Ethics approval was
obtained from the University of Zambia Research Ethics
Committee. The trial was registered as ISRCTN41089957.
Methods
We carried out a double-blind, randomised, placebo
controlled trial in paediatric patients shown to be positive for
both HIV and cryptosporidiosis, in the children's
diarrhoea/malnutrition ward of the University Teaching
Hospital, Lusaka. Children were included if between 1 and 11
years of age, if positive in at least 2 of 3 stool samples for
Cryptosporidium spp. (oocysts identified using auramine
phenol staining), if they had had diarrhoea with 3 or
more unformed stools daily, and if HIV seropositive as
confirmed by the Capillus Rapid Test (Trinity Biotech,
Ireland). If Cryptosporidium spp. oocysts were present in the
initial screening but not in the baseline samples, the
patient was excluded unless they tested positive for
oocysts within one week from this first sample. Children
were excluded if they had a bacterial cause for diarrhoea
or if positive for Entamoeba histolytica or Giardia lamblia by
the TriageĀ® Parasitic Panel (Biosite Diagnostics, San Diego,
CA). Other exclusion criteria were a history of
investigational drug therapy within one month prior to enrolment,
or other recognised anti-protozoal therapy within two
weeks prior to enrolment. Children who were moribund
were not randomised and gravely ill were observed for a
period of 1-2 weeks prior to randomisation.
Study procedures
At the initial visit a complete medical history was
reviewed to evaluate conformity with inclusion and
exclusion criteria. A physical exam (...truncated)