Cost of childhood diarrhoea in rural South Africa: exploring cost-effectiveness of universal zinc supplementation.

OBJECTIVE: To describe the cost of diarrhoeal illness in children aged 6-24 months in a rural South African community and to determine the threshold prevalence of stunting at which universal Zn plus vitamin A supplementation (VAZ) would be more cost-effective than vitamin A alone (VA) in preventing diarrhoea. DESIGN: We conducted a cost analysis using primary and secondary data sources. Using simulations we examined incremental costs of VAZ relative to VA while varying stunting prevalence. SETTING: Data on efficacy and societal costs were largely from a South African trial. Secondary data were from local and international published sources. SUBJECTS: The trial included children aged 6-24 months. The secondary data sources were a South African health economics survey and the WHO-CHOICE (CHOosing Interventions that are Cost Effective) database. RESULTS: In the trial, stunted children supplemented with VAZ had 2·04 episodes (95 % CI 1·37, 3·05) of diarrhoea per child-year compared with 3·92 episodes (95 % CI 3·02, 5·09) in the VA arm. Average cost of illness was $Int 7·80 per episode (10th, 90th centile: $Int 0·28, $Int 15·63), assuming a minimum standard of care (oral rehydration and 14 d of therapeutic Zn). In simulation scenarios universal VAZ had low incremental costs or became cost-saving relative to VA when the prevalence of stunting was close to 20 %. Incremental cost-effectiveness ratios were sensitive to the cost of intervention and coverage levels. CONCLUSIONS: This simulation suggests that universal VAZ would be cost-effective at current levels of stunting in parts of South Africa. This requires further validation under actual programmatic conditions.

Effect on longitudinal growth and anemia of zinc or multiple micronutrients added to vitamin A: a randomized controlled trial in children aged 6-24 months.

BACKGROUND: The benefits of zinc or multiple micronutrient supplementations in African children are uncertain. African children may differ from other populations of children in developing countries because of differences in the prevalence of zinc deficiency, low birth weight and preterm delivery, recurrent or chronic infections such as HIV, or the quality of complementary diets and genetic polymorphisms affecting iron metabolism.The aim of this study was to ascertain whether adding zinc or multiple micronutrients to vitamin A supplementation improves longitudinal growth or reduces prevalence of anemia in children aged 6-24 months. METHODS: Randomized, controlled double-blinded trial of prophylactic micronutrient supplementation to children aged 6-24 months. Children in three cohorts - 32 HIV-infected children, 154 HIV-uninfected children born to HIV-infected mothers, and 187 uninfected children born to HIV-uninfected mothers - were separately randomly assigned to receive daily vitamin A (VA) [n = 124], vitamin A plus zinc (VAZ) [n = 123], or multiple micronutrients that included vitamin A and zinc (MM) [n = 126]. RESULTS: Among all children there were no significant differences between intervention arms in length-for-age Z scores (LAZ) changes over 18 months. Among stunted children (LAZ below -2) [n = 62], those receiving MM had a 0.7 Z-score improvement in LAZ versus declines of 0.3 in VAZ and 0.2 in VA (P = 0.029 when comparing effects of treatment over time). In the 154 HIV-uninfected children, MM ameliorated the effect of repeated diarrhea on growth. Among those experiencing more than six episodes, those receiving MM had no decline in LAZ compared to 0.5 and 0.6 Z-score declines in children receiving VAZ and VA respectively (P = 0.06 for treatment by time interaction). After 12 months, there was 24% reduction in proportion of children with anemia (hemoglobin below 11 g/dL) in MM arm (P = 0.001), 11% in VAZ (P = 0.131) and 18% in VA (P = 0.019). Although the within arm changes were significant; the between-group differences were not significant. CONCLUSIONS: Daily multiple micronutrient supplementation combined with vitamin A was beneficial in improving growth among children with stunting, compared to vitamin A alone or to vitamin A plus zinc. Effects on anemia require further study. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number. NCT00156832.

Maintaining data integrity in a rural clinical trial.

BACKGROUND: Clinical trials conducted in rural resource-poor settings face special challenges in ensuring quality of data collection and handling. The variable nature of these challenges, ways to overcome them, and the resulting data quality are rarely reported in the literature. PURPOSE: To provide a detailed example of establishing local data handling capacity for a clinical trial conducted in a rural area, highlight challenges and solutions in establishing such capacity, and to report the data quality obtained by the trial. METHODS: We provide a descriptive case study of a data system for biological samples and questionnaire data, and the problems encountered during its implementation. To determine the quality of data we analyzed test-retest studies using Kappa statistics of inter- and intra-observer agreement on categorical data. We calculated Technical Errors of Measurement of anthropometric measurements, audit trail analysis was done to assess error correction rates, and residual error rates were calculated by database-to-source document comparison. RESULTS: Initial difficulties included the unavailability of experienced research nurses, programmers and data managers in this rural area and the difficulty of designing new software tools and a complex database while making them error-free. National and international collaboration and external monitoring helped ensure good data handling and implementation of good clinical practice. Data collection, fieldwork supervision and query handling depended on streamlined transport over large distances. The involvement of a community advisory board was helpful in addressing cultural issues and establishing community acceptability of data collection methods. Data accessibility for safety monitoring required special attention. Kappa values and Technical Errors of Measurement showed acceptable values. Residual error rates in key variables were low. LIMITATIONS: The article describes the experience of a single-site trial and does not address challenges particular to multi-site trials. CONCLUSIONS: Obtaining and maintaining data integrity in rural clinical trials is feasible, can result in acceptable data quality and can be used to develop capacity in developing country sites. It does, however, involve special challenges and requirements.

Zinc or multiple micronutrient supplementation to reduce diarrhea and respiratory disease in South African children: a randomized controlled trial.

BACKGROUND: Prophylactic zinc supplementation has been shown to reduce diarrhea and respiratory illness in children in many developing countries, but its efficacy in children in Africa is uncertain. OBJECTIVE: To determine if zinc, or zinc plus multiple micronutrients, reduces diarrhea and respiratory disease prevalence. DESIGN: Randomized, double-blind, controlled trial. SETTING: Rural community in South Africa. PARTICIPANTS: THREE COHORTS: 32 HIV-infected children; 154 HIV-uninfected children born to HIV-infected mothers; and 187 HIV-uninfected children born to HIV-uninfected mothers. INTERVENTIONS: Children received either 1250 IU of vitamin A; vitamin A and 10 mg of zinc; or vitamin A, zinc, vitamins B1, B2, B6, B12, C, D, E, and K and copper, iodine, iron, and niacin starting at 6 months and continuing to 24 months of age. Homes were visited weekly. OUTCOME MEASURES: Primary outcome was percentage of days of diarrhea per child by study arm within each of the three cohorts. Secondary outcomes were prevalence of upper respiratory symptoms and percentage of children who ever had pneumonia by maternal report, or confirmed by the field worker. RESULTS: Among HIV-uninfected children born to HIV-infected mothers, median percentage of days with diarrhea was 2.3% for 49 children allocated to vitamin A; 2.5% in 47 children allocated to receive vitamin A and zinc; and 2.2% for 46 children allocated to multiple micronutrients (P = 0.852). Among HIV-uninfected children born to HIV-uninfected mothers, median percentage of days of diarrhea was 2.4% in 56 children in the vitamin A group; 1.8% in 57 children in the vitamin A and zinc group; and 2.7% in 52 children in the multiple micronutrient group (P = 0.857). Only 32 HIV-infected children were enrolled, and there were no differences between treatment arms in the prevalence of diarrhea. The prevalence of upper respiratory symptoms or incidence of pneumonia did not differ by treatment arms in any of the cohorts. CONCLUSION: When compared with vitamin A alone, supplementation with zinc, or with zinc and multiple micronutrients, did not reduce diarrhea and respiratory morbidity in rural South African children. TRIAL REGISTRATION: ClinicalTrials.gov NCT00156832.

Single-dose azithromycin for the treatment of cholera in adults.

BACKGROUND: Single-dose azithromycin is effective in the treatment of severe cholera in children, but its effectiveness in adults has not been evaluated. METHODS: We conducted a double-blind, randomized trial comparing the equivalence of azithromycin and ciprofloxacin (each given in a single 1-g dose of two 500-mg tablets) among 195 men with severe cholera caused by Vibrio cholerae O1 or O139. Patients were hospitalized for five days. A stool culture was performed daily. Primary outcome measures were clinical success (the cessation of watery stools within 48 hours after drug administration) and bacteriologic success (the inability to isolate V. cholerae after 48 hours). RESULTS: Therapy was clinically successful in 71 of 97 patients receiving azithromycin (73 percent) and in 26 of 98 patients receiving ciprofloxacin (27 percent) (P<0.001) and bacteriologically successful in 76 of 97 patients receiving azithromycin (78 percent) and in 10 of 98 patients receiving ciprofloxacin (10 percent) (P<0.001). Patients who were treated with azithromycin had a shorter duration of diarrhea than did patients treated with ciprofloxacin (median, 30 vs. 78 hours); a lower frequency of vomiting (43 percent vs. 67 percent); fewer stools (median, 36 vs. 52); and a lower stool volume (median, 114 vs. 322 ml per kilogram of body weight). The median minimal inhibitory concentration of ciprofloxacin for the 177 isolates of V. cholerae O1 was 0.25 mug per milliliter, which was 11 to 83 times as high as that in previous studies at this site. CONCLUSIONS: Single-dose azithromycin was effective in the treatment of severe cholera in adults. The lack of efficacy of ciprofloxacin may result from its diminished activity against V. cholerae O1 strains currently circulating in Bangladesh. (ClinicalTrials.gov number, NCT00229944.).