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.

Gastrointestinal and extra-intestinal manifestations of childhood shigellosis in a region where all four species of Shigella are endemic.

OBJECTIVE: To determine the clinical manifestations and outcome of shigellosis among children infected with different species of Shigella. METHODS: We identified all patients <15 years infected with Shigella admitted to the icddr, b Dhaka hospital during one year. Study staff reviewed admission records and repeated the physical examinations and history of patients daily. RESULTS: Of 792 children with shigellosis 63% were infected with S. flexneri, 20% with S. dysenteriae type 1, 10% with S. boydii, 4% with S. sonnei, and 3% with S. dysenteriae types 2-10. Children infected with S. dysenteriae type 1, when compared to children infected with other species, were significantly (P<0.05) more likely to have severe gastrointestinal manifestations: grossly bloody stools (78% vs. 33%), more stools in the 24 h before admission (median 25 vs. 11), and rectal prolapse (52% vs. 15%)--and extra-intestinal manifestations--leukemoid reaction (22% vs. 2%), hemolytic-uremic syndrome (8% vs. 1%), severe hyponatremia (58% vs. 26%) and neurologic abnormalities (24% vs. 16%). The overall fatality rate was 10% and did not differ significantly by species. In a multiple regression analysis young age, malnutrition, hyponatremia, lesser stool frequency, documented seizure, and unconsciousness were predictive of death. CONCLUSIONS: Both severe intestinal disease and extra-intestinal manifestations of shigellosis occur with infection by any of the four species of Shigella, but are most common with S. dysenteriae type 1. Among these inpatient children, the risk of death was high with infection of any of the four Shigella species.

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.

HIV infection is associated with decreased dietary diversity in South African children.

Little is known about dietary diversity of children residing in areas of high HIV prevalence. This study examined dietary diversity in 381 children ages 6-24 mo in rural South Africa. Twenty-eight (7.3%) children and 170 mothers (44.6%) were HIV infected. Home visits were conducted weekly and a detailed history of dietary intake obtained. A dietary diversity score was computed based on the weekly consumption of 8 food classes. Low dietary diversity was defined as falling within the lowest quartile of the diversity scale. There were 22,772 child weeks of observation: 1369 for HIV-infected children, 8876 for HIV-uninfected children born to HIV-infected mothers, and 12,527 for HIV-uninfected children born to HIV-uninfected mothers. Low dietary diversity was more common in HIV-infected children [crude odds ratio (OR), 2.59; 95% CI, 1.52 to 4.41) compared with children born to HIV-uninfected mothers. In a multiple logistic regression analysis adjusting for socioeconomic and health status, HIV-infected children had lower dietary diversity (conditional OR, 1.76; 95% CI, 1.06 to 2.94) than HIV-uninfected children. HIV-infected children consumed less in 6 of 8 food classes compared with HIV-uninfected children, with the 2 exceptions being breast milk and formula milk. In rural South Africa, HIV-infected children's diets are significantly less diverse than those of HIV-uninfected children. This may be a factor contributing to increased morbidity and poorer survival in these children.

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.

Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study.

BACKGROUND: Exclusive breastfeeding, though better than other forms of infant feeding and associated with improved child survival, is uncommon. We assessed the HIV-1 transmission risks and survival associated with exclusive breastfeeding and other types of infant feeding. METHODS: 2722 HIV-infected and uninfected pregnant women attending antenatal clinics in KwaZulu Natal, South Africa (seven rural, one semiurban, and one urban), were enrolled into a non-randomised intervention cohort study. Infant feeding data were obtained every week from mothers, and blood samples from infants were taken monthly at clinics to establish HIV infection status. Kaplan-Meier analyses conditional on exclusive breastfeeding were used to estimate transmission risks at 6 weeks and 22 weeks of age, and Cox's proportional hazard was used to quantify associations with maternal and infant factors. FINDINGS: 1132 of 1372 (83%) infants born to HIV-infected mothers initiated exclusive breastfeeding from birth. Of 1276 infants with complete feeding data, median duration of cumulative exclusive breastfeeding was 159 days (first quartile [Q1] to third quartile [Q3], 122-174 days). 14.1% (95% CI 12.0-16.4) of exclusively breastfed infants were infected with HIV-1 by age 6 weeks and 19.5% (17.0-22.4) by 6 months; risk was significantly associated with maternal CD4-cell counts below 200 cells per muL (adjusted hazard ratio [HR] 3.79; 2.35-6.12) and birthweight less than 2500 g (1.81, 1.07-3.06). Kaplan-Meier estimated risk of acquisition of infection at 6 months of age was 4.04% (2.29-5.76). Breastfed infants who also received solids were significantly more likely to acquire infection than were exclusively breastfed children (HR 10.87, 1.51-78.00, p=0.018), as were infants who at 12 weeks received both breastmilk and formula milk (1.82, 0.98-3.36, p=0.057). Cumulative 3-month mortality in exclusively breastfed infants was 6.1% (4.74-7.92) versus 15.1% (7.63-28.73) in infants given replacement feeds (HR 2.06, 1.00-4.27, p=0.051). INTERPRETATION: The association between mixed breastfeeding and increased HIV transmission risk, together with evidence that exclusive breastfeeding can be successfully supported in HIV-infected women, warrant revision of the present UNICEF, WHO, and UNAIDS infant feeding guidelines.

Micronutrient status during lactation in HIV-infected and HIV-uninfected South African women during the first 6 mo after delivery.

BACKGROUND: Little information on the micronutrient status of HIV-infected (HIV-positive) breastfeeding women is available. OBJECTIVE: The objective was to compare the protein and micronutrient status of South African breastfeeding women by HIV status. DESIGN: Serum albumin, prealbumin, vitamin B-12, folate, retinol, alpha-tocopherol, hemoglobin, ferritin, and zinc concentrations were compared between 92 HIV-positive and 52 HIV-uninfected (HIV-negative) mothers 6, 14, and 24 wk after delivery. C-reactive protein and alpha1-acid glycoprotein were used as proxy indicators of an inflammatory process. RESULTS: Mean albumin and prealbumin were significantly lower in HIV-positive mothers, and a higher proportion of HIV-positive mothers had low albumin concentrations (< 35 g/L). Less than 45% of the mothers were vitamin B-12 or folate sufficient. Significantly more HIV-positive (70.5%) than HIV-negative (46.2%) mothers had marginal vitamin B-12 status (P < 0.05), and mean folate concentrations were lower in HIV-positive mothers (P = 0.05). Mean serum retinol was significantly lower in HIV-positive mothers, even after control for the acute phase response. At 24 wk, 70% of both groups had an alpha-tocopherol deficiency (< 11.6 micromol/L), but no significant difference by HIV status was observed. More HIV-positive (33.3%) than HIV-negative (8.7%) mothers had anemia (P = 0.018), whereas 25% of all mothers had low serum ferritin concentrations. After the acute phase response was controlled for, zinc deficiency was more common in HIV-positive (45.0%) than in HIV-negative (25.0%) mothers (P = 0.05). CONCLUSIONS: Deficiencies in vitamins B-12, folate, alpha-tocopherol, ferritin, and zinc are common in South African breastfeeding mothers. HIV-positive mothers had lower mean serum concentrations of albumin, prealbumin, folate, retinol, and hemoglobin than did HIV-negative mothers.

Pregnancy outcomes in HIV-infected and uninfected women in rural and urban South Africa.

OBJECTIVE: To describe pregnancy outcomes among clade C HIV-infected and uninfected women in South Africa. DESIGN: A longitudinal cohort study. METHODS: Pregnant women attending 9 rural/urban antenatal clinics were prospectively recruited and followed up. Women were seen at the clinic or at home after delivery on 4 occasions after enrollment: 2 times within the first 2 weeks of the newborn's life at home, and every 2 weeks thereafter until their first health clinic visit when the infant was 6 weeks old. RESULTS: A total of 3465 women were enrolled; 615 withdrew after delivery, moved away, or had a missing or indeterminate HIV status, leaving 2850 women (1449 HIV-infected women). Six women died after delivery and there were 17 spontaneous abortions and 104 stillbirths. An adverse pregnancy outcome was independently associated with HIV infection (adjusted odds ratio [AOR] = 1.63; P = 0.015), urban enrollment (AOR = 0.39; P = 0.020), and nonhospital delivery (AOR = 13.63; P < 0.001) as well as with a CD4 count <200 cells/mL among HIV-infected women (AOR = 1.86; P = 0.127). Among 2529 singleton liveborn babies, birth weight was inversely associated with maternal HIV (AOR = 1.45; P = 0.02) and maternal middle upper arm circumference (AOR = 0.93; P < 0.001). Early infant mortality was not significantly associated with maternal HIV (hazard ratio [HR] = 1.18; P = 0.52) but was with urban sites (HR = 0.34; P = 0.045). Low birth weight substantially increased mortality (AOR = 8.3; P < 0.001). HIV status of infants by 8 weeks of age (14.6%, 95% confidence interval: 12.5% to 17.0%) was inversely associated with maternal CD4 cell count and birth weight. CONCLUSIONS: HIV-infected women are at a significantly increased risk of adverse pregnancy outcomes. Low-birth-weight infants of HIV-infected and uninfected women are at substantially increased risk of dying.

Rates and causes of child mortality in an area of high HIV prevalence in rural South Africa.

OBJECTIVE: To determine child mortality rates in a rural area of South Africa with high HIV prevalence. METHODS: A community-based survey was conducted between 1 January 2000 and 31 December 2002 on deaths in children under the age of 15 years. Children were followed up through four monthly home visits. Cause of death was ascertained by verbal autopsy. Rates were calculated using Poisson regression. RESULTS: Mortality ratios were 59.6 deaths per 1000 live births for infants and 97.1 for children under 5 years of age. Infant and under-5 mortality rates were, respectively, 67.5 and 21.1 deaths per 1000 person-years. HIV/AIDS was attributed to 41% of deaths in the under-5 age group, with a mortality rate of 8.6 per 1000 person-years. Lower respiratory infections caused an estimated 24.9 deaths per 1000 person-years in children under 1 year of age. CONCLUSIONS: In rural South Africa, infant and child mortality levels are high, with HIV/AIDS estimated as the single largest cause of death. Interventions to reduce child mortality are required urgently.

Body composition changes during lactation in HIV-infected and HIV-uninfected South African women.

BACKGROUND: The nutritional consequences of HIV infection in lactating women are unknown. OBJECTIVE: To measure the body composition of South African lactating women in relation to HIV status. METHODS: Fat-free mass (FFM) and fat mass (FM) using bioimpedance spectrometry (BIS) and anthropometric measurements were obtained at 8 and 24 weeks postpartum in 92 HIV-infected (HIVpos) and 50 HIV-uninfected (HIVneg) lactating mothers. RESULTS: At 8 weeks, HIVpos and HIVneg mothers were not significantly different in height (159.7 vs. 158.9 cm), weight (62.7 vs. 63.9 kg), body mass index (BMI; 24.6 vs. 25.3 kg/m), FFM (40.7 vs. 42.8 kg), or FM (21.6 vs. 22.0 kg), respectively. In HIVpos women, the median CD4 count was 621 (range: 101-1585) cells/muL; 95% had CD4 counts >200 cells/muL. Between 8 and 24 weeks, HIVpos mothers had a mean weight loss of 1.4 kg in contrast to a 0.4-kg weight gain in HIVneg mothers (P < 0.01). There were no significant group differences with regard to change in FFM (0.3 vs. 0.1 kg; P = 0.9) and FM (-1.5 vs. -0.3 kg; P = 0.2). CONCLUSION: HIVpos South African breast-feeding mothers without severe immune suppression lost weight and subcutaneous fat between 8 and 24 weeks postpartum, whereas HIVneg mothers gained weight. FFM was maintained postpartum in HIVpos and HIVneg mothers.

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.).

Low risk of hemolytic uremic syndrome after early effective antimicrobial therapy for Shigella dysenteriae type 1 infection in Bangladesh.

BACKGROUND: Hemolytic uremic syndrome (HUS) may complicate up to 15% of cases of Shiga toxin (Stx)-expressing enterohemorrhagic Escherichia coli (STEC) O157:H7 infections in children. Administration of antimicrobials has been reported to increase the risk of STEC-associated HUS by >10-fold, presumably by increasing the expression and release of Stx by dying STEC bacteria. Shigella dysenteriae type 1 also expresses Stx. However, the effect of antimicrobial therapy on Stx release and the risk of HUS in humans is unknown. METHODS: We measured serial stool Stx concentrations before and after administration of antimicrobials in 20 children infected with S. dysenteriae type 1 who had frank dysentery of <72 h duration. We also reviewed the results of 7 shigellosis drug trials performed in Bangladesh during 1988-2000 to estimate the risk of HUS. In these studies, antimicrobials were administered within 96 h after the onset of dysentery. RESULTS: Stx levels decreased in stool samples obtained from 17 of 20 children after administration of antimicrobial agents; none of the 20 children developed HUS. Of 378 individuals infected with S. dysenteriae type 1 who were enrolled in drug trials (128 adult men [age, 18-60 years] and 250 children [age, 6 months to 15 years]), 351 (93%) received an antimicrobial agent to which the S. dysenteriae organism was susceptible

Comparison of isotope dilution with bioimpedance spectroscopy and anthropometry for assessment of body composition in asymptomatic HIV-infected and HIV-uninfected breastfeeding mothers.

BACKGROUND: The effect of breastfeeding on the nutrition of HIV-infected (HIV+) mothers is unknown. Simple, valid methods are needed for body-composition assessment of HIV+ women. OBJECTIVE: We compared the ability of bioimpedance spectroscopy (BIS) and anthropometry with that of isotope dilution (2H2O) to measure fat-free mass (FFM) and fat mass (FM) in HIV+ and HIV-uninfected (HIV-) breastfeeding South African mothers. DESIGN: Total body water (TBW) content of 68 lactating mothers (20 HIV+, 48 HIV-) was measured 10 wk after delivery by using BIS and 2H2O to measure FFM and FM. Anthropometric measurements included body mass index (BMI; in kg/m2), midupper arm circumference (MUAC), and 4 skinfold thicknesses. RESULTS: TBW, FFM, and FM measurements determined by BIS were correlated with 2H2O measurements in HIV+ (r = 0.664, 0.621, and 0.872, respectively; P < 0.01) and HIV- (r = 0.876, 0.868, and 0.932, respectively; P < 0.001) mothers. TBW measured by BIS was greater than that measured by the 2H2O method in both HIV+ (1.8 L) and HIV- (1.5 L) women; FM or FFM did not differ significantly by method. BMI, MUAC, and all skinfold-thickness measurements correlated strongly (r > 0.62, P < 0.001) with FM measured by 2H2O in both groups. BMI and MUAC correlated (r > 0.64, P < 0.001) with FFM in HIV- mothers but not in HIV+ mothers. CONCLUSIONS: In HIV+ and HIV- breastfeeding mothers, BIS provides an estimate of body composition comparable to that obtained with the 2H2O method. BMI and MUAC are useful in predicting FM in both groups but are not valid measures of FFM in HIV+ mothers.

Single-dose ciprofloxacin versus 12-dose erythromycin for childhood cholera: a randomised controlled trial.

BACKGROUND: Single-dose ciprofloxacin is effective for the treatment of severe cholera in adults. We assessed whether single-dose ciprofloxacin would be as effective as 3-day, 12-dose erythromycin in achieving clinical cure in children with severe cholera. METHODS: We did a randomised, open label, controlled trial in children age 2-15 years with V cholerae O1 or O139 present in stool on dark-field microscopy. Children received either a single 20 mg/kg dose of ciprofloxacin (n=90) or 12.5 mg/kg of erythromycin (n=90) every 6 h for 3 days, and remained in hospital for 5 days. The primary outcome was clinical success of treatment, defined as cessation of watery stools within 48 h of start of drug treatment. Analysis was per protocol. This study is registered with the ClinicalTrials.gov Protocol Registration System at http://www.clinicaltrials.gov (registration number NCT 00142272) [corrected] FINDINGS: Of 180 children randomised 162 completed the study. Treatment was clinically successful in 60% (47/78) of children treated with ciprofloxacin and in 55% (46/84) of those treated with erythromycin (difference 5% [95% CI -10 to 21]). Children receiving ciprofloxacin vomited less often (58%vs 74%; difference 16% [2 to 30]), had fewer stools (15 vs 21; 6 [0 to 9]), and less stool volume (152 vs 196 mL/kg; 43 mL/kg [13 to 87]) than those receiving erythromycin. Bacteriological failure was more common in ciprofloxacin-treated patients (58%vs 30%; 28% [13 to 43]) than erythromycin-treated patients. INTERPRETATION: Single-dose ciprofloxacin achieves clinical outcomes similar to, or better than, those achieved with 12-dose erythromycin treatment in childhood cholera, but is less effective in eradicating V cholerae from stool.

Antiretroviral treatment in resource-poor settings: public health research priorities.

Many countries in Africa are planning to provide highly active antiretroviral therapy (HAART) to millions of people with acquired immune deficiency syndrome. This will be a highly complex therapy programme. Physician-based models of care adapted from industrialized countries will not succeed in providing treatment to the majority of those who need it in resource-constrained settings. A high priority is to identify care models for Africa that will increase coverage of HAART safely and effectively: key issues are (i) whether nursing staff or non-clinically qualified staff can take the major role in the treatment programme and reduce the workload of physicians, (ii) whether treatment and monitoring can be delivered through peripheral health centres or through home visits and achieve better adherence and be more cost-effective than delivery at hospitals and (iii) which clinical algorithms used by nursing or non-clinically qualified staff will be effective for screening, diagnosing and managing treatment-related side-effects and medical problems being incurred. Many current ART support programmes are making little or no investment in research, but answering important questions on delivery of HAART will be essential if HAART programmes are to be successful in African nations with a high burden of human immunodeficiency virus infection.

Clinical trials in sub-Saharan Africa and established standards of care: a systematic review of HIV, tuberculosis, and malaria trials.

CONTEXT: The minimum standard of care required for participants in clinical trials conducted in resource-poor settings is a matter of controversy; international documents offer contradictory guidance. OBJECTIVE: To determine whether recently published trials conducted in sub-Saharan Africa met standards of care consistent with best current clinical standards for human immunodeficiency virus (HIV) treatment, tuberculosis treatment, and malaria prevention. DATA SOURCES: Trials published during or after January 1998 that were indexed at the time of the MEDLINE and Cochrane Controlled Trials Register Search (November 20, 2003). STUDY SELECTION: All randomized clinical trials that were conducted in sub-Saharan Africa in 3 clinical domains: HIV disease, tuberculosis treatment, and malaria prophylaxis. DATA EXTRACTION: To establish criteria for best current standards of care, evidence from the literature and published guidelines accepted for well-resourced settings were analyzed; the actual care offered in the trial was then compared with these standards. DATA SYNTHESIS: A total of 128 eligible articles described data from 73 different randomized clinical trials. Only 12 trials (16%) provided care that met guidelines to both intervention and control patients. Only 1 of the 34 trials that enrolled patients with HIV disease provided antiretroviral treatment that conformed to guidelines. Conversely, all tuberculosis treatment trials (n = 13, including 3 for HIV-infected patients) provided tuberculosis therapy that conformed to guidelines. Twenty-one (72%) of 29 malaria prophylaxis trials tested interventions that met guidelines, but only 3 (10%) used any active prophylactic intervention in the control group. Of the 59 trials (81%) that reported on the process of ethical review, all were reviewed by a host African institution and 64% were additionally reviewed by an institution in a developed country. CONCLUSIONS: Rates of adherence to established clinical guidelines of care in randomized clinical trials of HIV treatment, tuberculosis treatment, and malaria prophylaxis varied considerably between disease categories. In determining clinical standards for trials in sub-Saharan Africa, researchers and ethics committees appear to take the local level of care into account.

Testing therapies less effective than the best current standard: ethical beliefs in an international sample of researchers.

To test the range of beliefs regarding the ethics of testing, in resource poor settings, new therapies that are less efficacious but more affordable and feasible than the best current therapeutic standard.

Suitable monitoring approaches to antiretroviral therapy in resource-poor settings: setting the research agenda.

The delivery of antiretroviral therapy in the developing world requires guidelines for the appropriate monitoring of therapy, including monitoring for treatment effectiveness and treatment failure, drug toxicities, adherence to therapy, and the emergence of resistant organisms. Guidelines developed in wealthy industrialized countries, which rely heavily on laboratory tests often unavailable in the developing world, may not be feasible or appropriate for resource-limited settings. Even if the standard of care routinely delivered in industrialized settings cannot be replicated, antiretroviral treatment programs with less-intense monitoring have the potential to reduce morbidity and mortality from human immunodeficiency virus. Research to identify monitoring strategies that provide the greatest benefit to those living with human immunodeficiency virus in resource-limited settings and that use the available technologies and resources needs to be conducted within a conceptual and ethical framework that takes into account differences between rich and poor countries.