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Background: Visceral leishmaniasis (VL) in human immunodeficiency virus (HIV) co-infected patients requires special case management. AmBisome monotherapy at 40 mg/kg is recommended by the World Health Organization. The objective of the study was to assess if a combination of a lower dose of AmBisome with miltefosine would show acceptable efficacy at the end of treatment. Methodology/Principal findings: An open-label, non-comparative randomized trial of AmBisome (30 mg/kg) with miltefosine (100 mg/day for 28 days), and AmBisome monotherapy (40 mg/kg) was conducted in Ethiopian VL patients co-infected with HIV (NCT02011958). A sequential design was used with a triangular continuation region. The primary outcome was parasite clearance at day 29, after the first round of treatment. Patients with clinical improvement but without parasite clearance at day 29 received a second round of the allocated treatment. Efficacy was evaluated again at day 58, after completion of treatment. Recruitment was stopped after inclusion of 19 and 39 patients in monotherapy and combination arms respectively, as per pre-specified stopping rules. At D29, intention-to-treat efficacy in the AmBisome arm was 70% (95% CI 45–87%) in the unadjusted analysis, and 50% (95% CI 27–73%) in the adjusted analysis, while in the combination arm, it was 81% (95% CI 67–90%) and 67% (95% CI 48–82%) respectively. At D58, the adjusted efficacy was 55% (95% CI 32–78%) in the monotherapy arm, and 88% (95% CI 79–98%) in the combination arm. No major safety concerns related to the study medication were identified. Ten SAEs were observed within the treatment period, and 4 deaths unrelated to the study medication. Conclusions/Significance: The extended treatment strategy with the combination regimen showed the highest documented efficacy in HIV-VL patients; these results support a recommendation of this regimen as first-line treatment strategy for HIV-VL patients in eastern Africa. Trial registration number: . [ABSTRACT FROM AUTHOR]

Background. There are concerns that the evidence from studies showing noninferiority of oral amoxicillin to benzyl penicillin for severe pneumonia may not be generalizable to high-mortality settings. Methods. An open-label, multicenter, randomized controlled noninferiority trial was conducted at 6 Kenyan hospitals. Eligible children aged 2-59 months were randomized to receive amoxicillin or benzyl penicillin and followed up for the primary outcome of treatment failure at 48 hours. A noninferiority margin of risk difference between amoxicillin and benzyl penicillin groups was prespecified at 7%. Results. We recruited 527 children, including 302 (57.3%) with comorbidity. Treatment failure was observed in 20 of 260 (7.7%) and 21 of 261 (8.0%) of patients in the amoxicillin and benzyl penicillin arms, respectively (risk difference, -0.3% [95% confidence interval, -5.0% to 4.3%]) in per-protocol analyses. These findings were supported by the results of intention-to-treat analyses. Treatment failure by day 5 postenrollment was 11.4% and 11.0% and rising to 13.5% and 16.8% by day 14 in the amoxicillin vs benzyl penicillin groups, respectively. The most frequent cause of cumulative treatment failure at day 14 was clinical deterioration within 48 hours of enrollment (33/59 [55.9%]). Four patients died (overall mortality 0.8%) during the study, 3 of whom were allocated to the benzyl penicillin group. The presence of wheeze was independently associated with less frequent treatment failure. Conclusions. Our findings confirm noninferiority of amoxicillin to benzyl penicillin, provide estimates of risk of treatment failure in Kenya, and offer important additional evidence for policy making in sub-Saharan Africa. Clinical Trial Registration. NCT01399723 [ABSTRACT FROM AUTHOR]

Background: The World Health Organization recommends at least 3 annual antibiotic mass drug administrations (MDA) where the prevalence of trachoma is >10% in children ages 1–9 years, with coverage at least at 80%. However, the additional value of higher coverage targeted at children with multiple rounds is unknown. Trial Design: 2×2 factorial community randomized, double blind, trial. Trial methods: 32 communities with prevalence of trachoma ≥20% were randomized to: annual MDA aiming for coverage of children between 80%–90% (usual target) versus aiming for coverage>90% (enhanced target); and to: MDA for three years versus a rule of cessation of MDA early if the estimated prevalence of ocular C. trachomatis infection was less than 5%. The primary outcome was the community prevalence of infection with C. trachomatis at 36 months. Results: Over the trial's course, no community met the MDA cessation rule, so all communities had the full 3 rounds of MDA. At 36 months, there was no significant difference in the prevalence of infection, 4.0 versus 5.4 (mean adjusted difference = 1.4%, 95% CI = −1.0% to 3.8%), nor in the prevalence of trachoma, 6.1 versus 9.0 (mean adjusted difference = 2.6%, 95% CI = −0.3% to 5.3%) comparing the usual target to the enhanced target group. There was no difference if analyzed using coverage as a continuous variable. Conclusion: In communities that had pre-treatment prevalence of follicular trachoma of 20% or greater, there is no evidence that MDA can be stopped before 3 annual rounds, even with high coverage. Increasing coverage in children above 90% does not appear to confer additional benefit. Author Summary: The World Health Organization recommends at least 3 annual antibiotic mass drug administrations (MDA) where the prevalence of trachoma is >10% in children ages 1–9 years, with coverage at least at 80%. However, the additional value of higher coverage targeted at children with multiple rounds is unknown. We randomized 32 communities in Kongwa, Tanzania, with starting prevalence estimated at >20% to four arms: annual MDA aiming for coverage of children between 80%–90% (usual target) versus aiming for coverage>90% (enhanced target); and to: MDA for three years versus a rule of cessation of MDA early if the estimated prevalence of ocular C. trachomatis infection was less than 5%. After three rounds of MDA, infection with C. trachomatis and trachoma had declined significantly from baseline but no communities had treatment stopped. There was no difference in infection or in trachoma at three years comparing the usual coverage communities to the enhanced coverage communities. We conclude that in communities that had pre-treatment prevalence of follicular trachoma of 20% or greater, there is no evidence that MDA can be stopped before 3 annual rounds, even with high coverage. Increasing coverage in children above 90% does not appear to confer additional benefit. [ABSTRACT FROM AUTHOR]

Background: Trachoma, caused by ocular Chlamydia trachomatis infection, is the leading infectious cause of blindess, but its prevalence is now falling in many countries. As the prevalence falls, an increasing proportion of individuals with clinical signs of follicular trachoma (TF) is not infected with C. trachomatis. A recent study in Tanzania suggested that other bacteria may play a role in the persistence of these clinical signs. Methodology/Principal Findings: We examined associations between clinical signs of TF and ocular colonization with four pathogens commonly found in the nasopharnyx, three years after the initiation of mass azithromycin distribution. Children aged 0 to 5 years were randomly selected from 16 Gambian communitites. Both eyes of each child were examined and graded for trachoma according to the World Health Organization (WHO) simplified system. Two swabs were taken from the right eye: one swab was processed for polymerase chain reaction (PCR) using the Amplicor test for detection of C. trachomatis DNA and the second swab was processed by routine bacteriology to assay for the presence of viable Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella catarrhalis. Prevalence of TF was 6.2% (96/1538) while prevalence of ocular C. trachomatis infection was 1.0% (16/1538). After adjustment, increased odds of TF were observed in the presence of C. trachomatis (OR = 10.4, 95%CI 1.32–81.2, p = 0.03), S. pneumoniae (OR = 2.14, 95%CI 1.03–4.44, p = 0.04) and H. influenzae (OR = 4.72, 95% CI 1.53–14.5, p = 0.01). Conclusions/Significance: Clinical signs of TF can persist in communities even when ocular C. trachomatis infection has been controlled through mass azithromycin distribution. In these settings, TF may be associated with ocular colonization with bacteria commonly carried in the nasopharnyx. This may affect the interpretation of impact surveys and the determinations of thresholds for discontinuing mass drug administration. Author Summary: Trachoma, the world's leading infectious cause of blindness, is caused by ocular infection with the bacterium Chlamydia trachomatis. In low-prevalence settings and following mass treatment campaigns, clinically active follicular trachoma (TF) can be found in the absence of C. trachomatis infection. We carried out this study to investigate associations between ocular carriage of non-chlamydial pathogens and a clinical diagnosis of TF following a mass treatment campaign in The Gambia. We found that children who carried Streptococcus pneumoniae or Haemophilus influenza in their eyes were more likely to have been diagnosed with TF than children who did not carry these pathogens. In The Gambia, non-chlamydial pathogens may be inducing or exacerbating TF in the absence of C. trachomatis infection. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization has recommended three rounds of mass drug administration (MDA) with antibiotics in districts where the prevalence of follicular trachoma (TF) is ≥10% in children aged 1–9 years, with treatment coverage of at least 80%. For districts at 5–10% TF prevalence it was recommended that TF be assessed in 1–9 year olds in each community within the district, with three rounds of MDA provided to any community where TF≥10%. Worldwide, over 40 million people live in districts whose TF prevalence is estimated to be between 5 and 10%. The best way to treat these districts, and the optimum role of testing for infection in deciding whether to initiate or discontinue MDA, are unknown. Methods: In a community randomized trial with a factorial design, we randomly assigned 48 communities in four Gambian districts, in which the prevalence of trachoma was known or suspected to be above 10%, to receive annual mass treatment with expected coverage of 80–89% ("Standard"), or to receive an additional visit in an attempt to achieve coverage of 90% or more ("Enhanced"). The same 48 communities were randomised to receive mass treatment annually for three years ("3×"), or to have treatment discontinued if Chlamydia trachomatis (Ct) infection was not detected in a sample of children in the community after mass treatment (stopping rule("SR")). Primary outcomes were the prevalence of TF and of Ct infection in 0–5 year olds at 36 months. Results: The baseline prevalence of TF and of Ct infection in the target communities was 6.5% and 0.8% respectively. At 36 months the prevalence of TF was 2.8%, and that of Ct infection was 0.5%. No differences were found between the arms in TF or Ct infection prevalence either at baseline (Standard-3×: TF 5.6%, Ct 0.7%; Standard-SR: TF 6.1%, Ct 0.2%; Enhanced-3×: TF 7.4%, Ct 0.9%; and Enhanced-SR: TF 6.2%, Ct 1.2%); or at 36 months (Standard-3×: TF 2.3%, Ct 1.0%; Standard-SR TF 2.5%, Ct 0.2%; Enhanced-3× TF 3.0%, Ct 0.2%; and Enhanced-SR TF 3.2%, Ct 0.7%). The implementation of the stopping rule led to treatment stopping after one round of MDA in all communities in both SR arms. Mean treatment coverage of children aged 0–9 in communities randomised to standard treatment was 87.7% at baseline and 84.8% and 88.8% at one and two years, respectively. Mean coverage of children in communities randomized to enhanced treatment was 90.0% at baseline and 94.2% and 93.8% at one and two years, respectively. There was no evidence of any difference in TF or Ct prevalence at 36 months resulting from enhanced coverage or from one round of MDA compared to three. Conclusions: The Gambia is close to the elimination target for active trachoma. In districts prioritised for three MDA rounds, one round of MDA reduced active trachoma to low levels and Ct infection was not detectable in any community. There was no additional benefit to giving two further rounds of MDA. Programmes could save scarce resources by determining when to initiate or to discontinue MDA based on testing for Ct infection, and one round of MDA may be all that is necessary in some settings to reduce TF below the elimination threshold. Author Summary: Trachoma, which results from infection with a bacterium Chlamydia trachomatis(Ct), is a leading cause of preventable blindness in the world. One of the currently used control methods is mass drug administration (MDA) with azithromycin, which is initiated according to rates of follicular trachoma(TF) in children. This study was a clinical trial done to determine whether testing communities for Ct infection will prevent unnecessary rounds of MDA. This was done by allowing communities to stop treatment if their infection had been reduced below a threshold. The study compared the effects of one round of mass treatment to three and found that there was no difference in either follicular trachoma or infection rates after three years. One round of treatment reduced TF to a low level. Tests for infection could be used to decide when to start or discontinue MDA and to prevent unnecessary treatment rounds in settings like The Gambia. [ABSTRACT FROM AUTHOR]

Background: Blinding trachoma, caused by ocular infection with Chlamydia trachomatis, is targeted for global elimination by 2020. Knowledge of risk factors can help target control interventions. Methodology/Principal Findings: As part of a cluster randomised controlled trial, we assessed the baseline prevalence of, and risk factors for, active trachoma and ocular C. trachomatis infection in randomly selected children aged 0–5 years from 48 Gambian and 36 Tanzanian communities. Both children's eyes were examined according to the World Health Organization (WHO) simplified grading system, and an ocular swab was taken from each child's right eye and processed by Amplicor polymerase chain reaction to test for the presence of C. trachomatis DNA. Prevalence of active trachoma was 6.7% (335/5033) in The Gambia and 32.3% (1008/3122) in Tanzania. The countries' corresponding Amplicor positive prevalences were 0.8% and 21.9%. After adjustment, risk factors for follicular trachoma (TF) in both countries were ocular or nasal discharge, a low level of household head education, and being aged ≥1 year. Additional risk factors in Tanzania were flies on the child's face, being Amplicor positive, and crowding (the number of children per household). The risk factors for being Amplicor positive in Tanzania were similar to those for TF, with the exclusion of flies and crowding. In The Gambia, only ocular discharge was associated with being Amplicor positive. Conclusions/Significance: These results indicate that although the prevalence of active trachoma and Amplicor positives were very different between the two countries, the risk factors for active trachoma were similar but those for being Amplicor positive were different. The lack of an association between being Amplicor positive and TF in The Gambia highlights the poor correlation between the presence of trachoma clinical signs and evidence of C. trachomatis infection in this setting. Only ocular discharge was associated with evidence of C. trachomatis DNA in The Gambia, suggesting that at this low endemicity, this may be the most important risk factor. Trial Registration: ClinicalTrials.gov NCT00792922 Author Summary: Trachoma is caused by Chlamydia trachomatis and is the leading infectious cause of blindness. The World Health Organization's (WHO) control strategy includes antibiotic treatment of all community members, facial cleanliness, and environmental improvements. By determining how prevalent trachoma is, decisions can be made whether control activities need to be put in place. Knowing what factors make people more at risk of having trachoma can help target trachoma control efforts to those most at risk. We looked at the prevalence of active trachoma and C. trachomatis infection in the eyes of children aged 0–5 years in The Gambia and Tanzania. We also measured risk factors associated with having active trachoma or infection. The prevalence of both active trachoma and infection was lower in The Gambia (6.7% and 0.8%, respectively) than in Tanzania (32.3% and 21.9%, respectively). Risk factors for active trachoma were similar in the two countries. For infection, the risk factors in Tanzania were similar to those for TF, whereas in The Gambia, only ocular discharge was associated with infection. These results show that although the prevalence of active trachoma and infection is very different between the two countries, the risk factors for active trachoma are similar but those for infection are different. [ABSTRACT FROM AUTHOR]

Background: Mass treatment to trachoma endemic communities is a critical part of the World Health Organization SAFE strategy. However, non-participation may not be at random, affecting coverage surveys and effectiveness if infection is differential. Methodology/Principal Findings: As part of the Partnership for Rapid Elimination of Trachoma (PRET), 32 communities in Tanzania, and 48 in The Gambia had a detailed census taken followed by mass treatment with azithromycin. The target coverage in each community was >80% of children ages <10 years. Community treatment assistants observed treatment and recorded compliance, thus coverage at the community, household, and individual level could be determined. Within each community, we determined the actual proportions of households where all, some, or none of the children were treated. Assuming the coverage in children <10 years of the community was as observed and non-participation was at random, we did 500 simulations to derive expected proportions of households where all, some, or none of the children were treated. Clustering of household treatment was detected comparing greater-than-expected proportions of households where none or all of children were treated, and the intraclass correlation (ICC) was calculated. Tanzanian and Gambian mass treatment coverages for children <10 years of age ranged from 82–100% and 62–99%, respectively. Clustering of households where all children were treated or no children were treated was greater than expected. Compared to model simulations, all Tanzanian communities and 44 of 48 (91.7%) Gambian communities had significantly higher proportions of households where all children were treated. Furthermore, 30 of 32 (93.8%) Tanzanian communities and 34 of 48 (70.8%) Gambian communities had a significantly elevated proportion of households compared to the expected proportion where no children were treated. The ICC for Tanzania was 0.77 (95% CI 0.74–0.81) and for The Gambia was 0.55 (95% CI 0.51–0.59). Conclusions/Significance: In programs aiming for high coverage, complete compliance or non-compliance with mass treatment clusters within households. Non-compliance cannot be assumed to be at random. Author Summary: Trachoma, an infectious disease, continues to cause blindness. A great deal of the trachoma burden is concentrated in developing countries. The World Health Organization recommends mass treatment for entire communities in trachoma-endemic regions. In 32 Tanzanian and 48 Gambian communities with trachoma, mass treatment was directly observed following a census. Community coverage was mostly greater than 80%. Larger-than-expected proportions of households where all children were treated and where none of the children were treated were found in each country. Household clustering of treatment was higher in Tanzania compared to The Gambia. However, children who were not treated were not more likely to be infected compared to children who were treated. We found that treatment and non-treatment within communities does not occur at random but rather clusters within households. These findings impact the design of future coverage surveys and suggest that further research evaluate factors that are associated with familial non-compliance. [ABSTRACT FROM AUTHOR]

Background: A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days. Methods: This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg. Findings: 42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively). Conclusion: Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa. [ABSTRACT FROM AUTHOR]

Background: Trachoma is thought to be common over large parts of Southern Sudan. However, many areas of the country, particularly west of the Nile, have not yet been surveyed. The aim of this study was to confirm whether trachoma extends into Western Equatoria State from neighboring Central Equatoria, where trachoma is highly prevalent, and whether intervention with the SAFE strategy is required. Methods and Findings: Population-based cross-sectional surveys were conducted using a two-stage cluster random sampling method to select the study population. Subjects were examined for trachoma by experienced graders using the World Health Organization (WHO) simplified grading scheme. Two counties thought to be most likely to have trachoma were surveyed, Maridi and Mundri. In Maridi, prevalence of one of the signs of active trachoma (trachomatous inflammationfollicular (TF)) in children aged 1-9 years was 0.4% (95% confidence interval (CI), 0.0%-0.8%), while no children showing the other possible sign, trachomatous inflammation-intense (TI), were identified. No trachomatous trichiasis (TT) was found in those aged under 15, and prevalence was 0.1% (95% CI, 0.0%-0.4%) in those aged 15 years and above. In Mundri, active trachoma was also limited to signs of TF, with a prevalence of 4.1% (95% CI, 1.4%-6.9%) in children aged 1-9 years. Again, no TT was found in those aged under 15, and prevalence in those aged 15 years and above was 0.3% (95% CI, 0.0%-0.8%). Conclusion: Trachoma prevalence in the east of Western Equatoria State is below the WHO recommended intervention threshold for mass drug administration of antibiotic treatment in all villages. However, the prevalence of TF and TT in some villages, particularly in Mundri County, is sufficiently high to warrant targeted interventions at the community level. These results demonstrate that trachoma is not a major public health problem throughout Southern Sudan. Further studies will be required to determine trachoma prevalence in other areas, particularly west of the Nile, but there are presently no resources to survey each county. Studies should thus be targeted to areas where collection of new data would be most informative. [ABSTRACT FROM AUTHOR]