Generalizing boundaries for triangular designs, and efficacy estimation at extended follow-ups.

BACKGROUND: Visceral leishmaniasis (VL) is a parasitic disease transmitted by sandflies and is fatal if left untreated. Phase II trials of new treatment regimens for VL are primarily carried out to evaluate safety and efficacy, while pharmacokinetic data are also important to inform future combination treatment regimens. The efficacy of VL treatments is evaluated at two time points, initial cure, when treatment is completed and definitive cure, commonly 6 months post end of treatment, to allow for slow response to treatment and detection of relapses. This paper investigates a generalization of the triangular design to impose a minimum sample size for pharmacokinetic or other analyses, and methods to estimate efficacy at extended follow-up accounting for the sequential design and changes in cure status during extended follow-up. METHODS: We provided R functions that generalize the triangular design to impose a minimum sample size before allowing stopping for efficacy. For estimation of efficacy at a second, extended, follow-up time, the performance of a shrinkage estimator (SHE), a probability tree estimator (PTE) and the maximum likelihood estimator (MLE) for estimation was assessed by simulation. RESULTS: The SHE and PTE are viable approaches to estimate an extended follow-up although the SHE performed better than the PTE: the bias and root mean square error were lower and coverage probabilities higher. CONCLUSIONS: Generalization of the triangular design is simple to implement for adaptations to meet requirements for pharmacokinetic analyses. Using the simple MLE approach to estimate efficacy at extended follow-up will lead to biased results, generally over-estimating treatment success. The SHE is recommended in trials of two or more treatments. The PTE is an acceptable alternative for one-arm trials or where use of the SHE is not possible due to computational complexity. TRIAL REGISTRATION: NCT01067443 , February 2010

Characteristics and contraceptive outcomes of women seeking medical or surgical abortion in reproductive health clinics in Cambodia.

BACKGROUND: Since the approval of medical abortion in Cambodia in 2010, the proportion of women reporting an abortion has increased. We describe the characteristics and contraceptive outcomes of women seeking medical abortion compared to surgical abortion at four reproductive health clinics in Cambodia. METHODS: Secondary data analysis using data collected in the MObile Technology for Improved Family Planning (MOTIF) trial, a single blind, randomized trial of a personalized, mobile phone-based intervention designed to support post-abortion family planning in Cambodia. Baseline interviews were conducted after women had received post-abortion family planning counselling at the clinic, and follow-up interviews were conducted at 4 and 12 months. We used multivariable logistic regression to assess associations between abortion type and baseline characteristics, contraceptive uptake, repeat pregnancy and repeat abortion. We conducted an exploratory analysis to compare the timing of initiation of long-acting (LA) contraception between women having medical versus surgical abortion over the four-month post-abortion period. RESULTS: Of the 500 women who participated in the trial, 41% had a medical abortion. In multivariate analyses, women undergoing medical abortion were more likely to be urban residents, have a higher level of education, be undecided or not intending to use family planning, and be undecided or intending to have another child. There was no association between type of abortion and contraceptive uptake, repeat pregnancy or repeat abortion. Women who had medical abortion initiated LA contraception post abortion later than women who had surgical abortion. CONCLUSIONS: Our results suggest women having a medical abortion in Cambodia have different baseline characteristics and had delayed uptake of contraception compared to women having a surgical abortion. However, we cannot draw conclusions on the direction of associations and causality. Further research is recommended to explore reasons for the observed findings with view to increasing access to abortion and post-abortion contraception

Implementation of patient charges at primary care facilities in Kenya: implications of low adherence to user fee policy for users and facility revenue.

With user fees now seen as a major hindrance to universal health coverage, many countries have introduced fee reduction or elimination policies, but there is growing evidence that adherence to reduced fees is often highly imperfect. In 2004, Kenya adopted a reduced and uniform user fee policy providing fee exemptions to many groups. We present data on user fee implementation, revenue and expenditure from a nationally representative survey of Kenyan primary health facilities. Data were collected from 248 randomly selected public health centres and dispensaries in 2010, comprising an interview with the health worker in charge, exit interviews with curative outpatients, and a financial record review. Adherence to user fee policy was assessed for eight tracer conditions based on health worker reports, and patients were asked about actual amounts paid. No facilities adhered fully to the user fee policy across all eight tracers, with adherence ranging from 62.2% for an adult with tuberculosis to 4.2% for an adult with malaria. Three quarters of exit interviewees had paid some fees, with a median payment of US dollars (USD) 0.39, and a quarter of interviewees were required to purchase additional medical supplies at a later stage from a private drug retailer. No consistent pattern of association was identified between facility characteristics and policy adherence. User fee revenues accounted for almost all facility cash income, with average revenue of USD 683 per facility per year. Fee revenue was mainly used to cover support staff, non-drug supplies and travel allowances. Adherence to user fee policy was very low, leading to concerns about the impact on access and the financial burden on households. However, the potential to ensure adherence was constrained by the facilities' need for revenue to cover basic operating costs, highlighting the need for alternative funding strategies for peripheral health facilities

Epidemiology of coinfection with soil transmitted helminths and Plasmodium falciparum among school children in Bumula District in western Kenya.

BACKGROUND: Many school children living in Africa are infected with plasmodia and helminth species and are consequently at risk of coinfection. However, the epidemiology of such coinfection and the implications of coinfection for children's health remain poorly understood. This study describes the epidemiology of Ascaris lumbricoides-Plasmodium and hookworm-Plasmodium coinfection among school children living in western Kenya and investigates the associated risk factors. METHODS: As part of a randomized trial, a baseline cross-sectional survey was conducted among school children aged 5-18 years in 23 schools in Bumula District. Single stool samples were collected to screen for helminth infections using the Kato-Katz technique and malaria parasitaemia was determined from a finger prick blood sample. Demographic and anthropometric data were also collected. RESULTS: Overall, 46.4% of the children were infected with Plasmodium falciparum while 27.6% of the children were infected with at least one soil transmitted helminth (STH) species, with hookworm being the most common (16.8%) followed by A. lumbricoides (15.3%). Overall 14.3% of the children had STH-Plasmodium coinfection, with hookworm-Plasmodium (9.0%) coinfection being the most common. Geographical variation in the prevalence of coinfection occurred between schools. In multivariable logistic regression analysis, hookworm was positively associated with P. falciparum infection. In stratified analysis, hookworm infection was associated with increased odds of P. falciparum infection among both boys (P < 0.001) and girls (P = 0.01), whereas there was no association between A. lumbricoides and P. falciparum. CONCLUSION: These findings demonstrate STH infections are still prevalent, despite the ongoing national deworming programme in Kenya, and that malaria parasitaemia is widespread, such that coinfection occurs among a proportion of children. A subsequent trial will allow us to investigate the implications of coinfection for the risk of clinical malaria

Trachoma in Western Equatoria State, Southern Sudan: Implications for National Control

Baseline data on trachoma prevalence is a prerequisite for intervention. Prior to the present study, all surveys in Southern Sudan reported trachoma prevalences that exceeded the threshold for large-scale intervention. This gave rise to the notion that the disease may be endemic throughout the country. The present study was conducted under the auspices of the National Program for Integrated Control of Neglected Tropical Diseases, to verify whether prevalences in two counties west of the Nile exceeded the WHO recommended intervention threshold for mass drug administration (MDA) of antibiotic treatment. The results show that trachoma prevalence at county level was below this threshold. However, prevalences in some communities within the county were above the threshold, meaning that they should be targeted with MDA of antibiotics, as well as with other interventions such as trichiasis surgery, health promotion and improved water and sanitation. This finding reminds us of the need for geographical targeting of resources, both for surveys and subsequent intervention. Current resources are insufficient to conduct population-based prevalence surveys for trachoma throughout Southern Sudan. Further surveys should thus be conducted in areas where collection of additional information will be most informative. We propose that a combination of risk-mapping and rapid assessments is used to identify such areas

Time to reconsider the role of ribavirin in Lassa fever

Ribavirin is the only available Lassa fever treatment. The rationale for using ribavirin is based on one clinical study conducted in the early 1980s. However, reanalysis of previous unpublished data reveals that ribavirin may actually be harmful in some Lassa fever patients. An urgent reevaluation of ribavirin is therefore needed

Effect of Repeated Anthelminthic Treatment on Malaria in School Children in Kenya: A Randomized, Open-Label, Equivalence Trial.

BACKGROUND: School children living in the tropics are often concurrently infected with plasmodium and helminth parasites. It has been hypothesized that immune responses evoked by helminths may modify malaria-specific immune responses and increase the risk of malaria. METHODS: We performed a randomized, open-label, equivalence trial among 2436 school children in western Kenya. Eligible children were randomized to receive either 4 repeated doses or a single dose of albendazole and were followed up during 13 months to assess the incidence of clinical malaria. Secondary outcomes were Plasmodium prevalence and density, assessed by repeat cross-sectional surveys over 15 months. Analysis was conducted on an intention-to-treat basis with a prespecified equivalence range of 20%. RESULTS: During 13 months of follow-up, the incidence rate of malaria was 0.27 episodes/person-year in the repeated treatment group and 0.26 episodes/person-year in the annual treatment group (incidence difference, 0.01; 95% confidence interval, -.03 to .06). The prevalence and density of malaria parasitemia did not differ by treatment group at any of the cross-sectional surveys. CONCLUSIONS: Our findings suggest that repeated deworming does not alter risks of clinical malaria or malaria parasitemia among school children and that school-based deworming in Africa may have no adverse consequences for malaria. CLINICAL TRIALS REGISTRATION: NCT01658774

Non-participation during azithromycin mass treatment for trachoma in The Gambia: heterogeneity and risk factors.

BACKGROUND: There is concern that untreated individuals in mass drug administration (MDA) programs for neglected tropical diseases can reduce the impact of elimination efforts by maintaining a source of transmission and re-infection. METHODOLOGY/PRINCIPAL FINDINGS: Treatment receipt was recorded against the community census during three MDAs with azithromycin for trachoma in The Gambia, a hypo-endemic setting. Predictors of non-participation were investigated in 1-9 year olds using random effects logistic regression of cross-sectional data for each MDA. Two types of non-participators were identified: present during MDA but not treated (PNT) and eligible for treatment but absent during MDA (EBA). PNT and EBA children were compared to treated children separately. Multivariable models were developed using baseline data and validated using year one and two data, with a priori adjustment for previous treatment status. Analyses included approximately 10000 children at baseline and 5000 children subsequently. There was strong evidence of spatial heterogeneity, and persistent non-participation within households and individuals. By year two, non-participation increased significantly to 10.4% overall from 6.2% at baseline, with more, smaller geographical clusters of non-participating households. Multivariable models suggested household level predictors of non-participation (increased time to water and household head non-participation for both PNT and EBA; increased household size for PNT status only; non-inclusion in a previous trachoma examination survey and younger age for EBA only). Enhanced coverage efforts did not decrease non-participation. Few infected children were detected at year three and only one infected child was EBA previously. Infected children were in communities close to untreated endemic areas with higher rates of EBA non-participation during MDA. CONCLUSIONS/SIGNIFICANCE: In hypo-endemic settings, with good coverage and no association between non-participation and infection, efforts to improve participation during MDA may not be required. Further research could investigate spatial hotspots of infection and non-participation in other low and medium prevalence settings before allocating resources to increase participation