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Diagnostic advances in visceral leishmaniasis include the development of the rK39 and rK28 rapid diagnostic test. The direct agglutination test is also increasingly used, as well as conventional and real-time polymerase chain reaction, which also performs well on peripheral blood. The choice of treatment for visceral leishmaniasis depends on the geographic region where the infection is acquired. Liposomal amphotericin B is generally found to be safe and effective in most endemic regions of the world; antimonials still remain to be the most effective in eastern Africa despite its high toxicity. Combination therapy is increasingly explored. Immunosuppressed patients require adapted diagnostic and therapeutic strategies., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The long-term treatment outcome of visceral leishmaniasis (VL) patients with HIV co-infection is complicated by a high rate of relapse, especially when the CD4 count is low. Although use of secondary prophylaxis is recommended, it is not routinely practiced and data on its effectiveness and safety are limited., Methods: A prospective cohort study was conducted in Northwest Ethiopia from August 2014 to August 2017 (NCT02011958). HIV-VL patients were followed for up to 12 months. Patients with CD4 cell counts below 200/μL at the end of VL treatment received pentamidine prophylaxis starting one month after parasitological cure, while those with CD4 count ≥200 cells/μL were followed without secondary prophylaxis. Compliance, safety and relapse-free survival, using Kaplan-Meier analysis methods to account for variable time at risk, were summarised. Risk factors for relapse or death were analysed., Results: Fifty-four HIV patients were followed. The probability of relapse-free survival at one year was 50% (95% confidence interval [CI]: 35-63%): 53% (30-71%) in 22 patients with CD4 ≥200 cells/μL without pentamidine prophylaxis and 46% (26-63%) in 29 with CD4 <200 cells/μL who started pentamidine. Three patients with CD4 <200 cells/μL did not start pentamidine. Amongst those with CD4 ≥200 cells/μL, VL relapse was an independent risk factor for subsequent relapse or death (adjusted rate ratio: 5.42, 95% CI: 1.1-25.8). Except for one case of renal failure which was considered possibly related to pentamidine, there were no drug-related safety concerns., Conclusion: The relapse-free survival rate for VL patients with HIV was low. Relapse-free survival of patients with CD4 count <200cells/μL given pentamidine secondary prophylaxis appeared to be comparable to patients with a CD4 count ≥200 cells/μL not given prophylaxis. Patients with relapsed VL are at higher risk for subsequent relapse and should be considered a priority for secondary prophylaxis, irrespective of their CD4 count., Competing Interests: The authors have declared that no competing interests exist.

Leishmania aethiopica is the main causative species for cutaneous leishmaniasis (CL) in Ethiopia. Despite its considerable burden, L. aethiopica has been one of the most neglected Leishmania species. In this review, published evidence on L. aethiopica history, geography, vector, reservoir, epidemiology, parasitology, and immunology is discussed and knowledge gaps are outlined. L. aethiopica endemic regions are limited to the highland areas, although nationwide studies on CL prevalence are lacking. Phlebotomus pedifer and P. longipes are the sandfly vectors and hyraxes are considered to be the main reservoir, but the role of other sandfly species and other potential reservoirs requires further investigation. Where and how transmission occurs exactly are also still unknown. Most CL patients in Ethiopia are children and young adults. Lesions are most commonly on the face, in contrast to CL caused by other Leishmania species which may more frequently affect other body parts. CL lesions caused by L. aethiopica seem atypical and more severe in their presentation as compared to other Leishmania species. Mucocutaneous leishmaniasis and diffuse cutaneous leishmaniasis are relatively common, and healing of lesions caused by L. aethiopica seems to take longer than that of other species. A thorough documentation of the natural evolution of L. aethiopica as well as in depth studies into the immunological and parasitological characteristics that underpin the atypical and severe clinical presentation are needed. Better understanding of CL caused by this parasite species will contribute to interventions related to transmission, prevention, and treatment.

Human Immunodeficiency Virus (HIV) co-infection drastically increases the risk of developing overt visceral leishmaniasis (VL). The asymptomatic Leishmania infection window constitutes an opportunity to identify those HIV patients at highest risk by defining early markers associated with disease susceptibility or resistance. As intracellular parasite killing is essential, we investigated whether serum markers of macrophage activation were notably affected in HIV patients with an asymptomatic Leishmania infection or overt visceral leishmaniasis disease. Serum levels of soluble CD40 ligand and neopterin were assessed in 24 active VL-HIV patients, 35 HIV patients with asymptomatic Leishmania infection and 35 HIV endemic controls. All patients were recruited in L. donovani endemic regions of North-West Ethiopia. The serum levels of sCD40L and neopterin significantly decreased and increased in HIV patients with active VL compared to HIV patients with asymptomatic Leishmania infection, respectively. No statistically significant differences could be detected in neopterin and sCD40L levels between Leishmania asymptomatically infected HIV patients and endemic HIV control patients. However, an inverse trend, between Leishmania antibody positivity or VL development and neopterin levels could be seen. The CD4+ T-cell count was inversely correlated with serum neopterin levels, but not with sCD40L levels. Our results in HIV coinfected patients, correspond with the postulated protective role of sCD40L in VL and underline the importance of the CD40-CD40L pathway in resistance against the parasite. Neopterin levels suggest an increased macrophage activation upon infection and could have a value in clinical algorithms to, although non-specifically, improve prediction of VL development in HIV patients with asymptomatic Leishmania infection.

Introduction: During the 2014 Ebola Virus Disease (EVD) epidemic, the Ebola-Tx trial evaluated the use of convalescent plasma (CP) in Guinea. The effectiveness of plasmapheresis trials depends on the recruitment of plasma donors. This paper describes what motivated or deterred EVD survivors to donate CP, providing insights for future plasmapheresis trials and epidemic preparedness., Methods: This qualitative study, part of Ebola-Tx, researched and addressed emergent trial difficulties through interviewing, participant observation and focus group discussions. Sampling was theoretical and retroductive analysis was done in NVivo 10., Results: Willingness or hesitance to participate in plasma donation depended on factors at the interface of pre-existing social dynamics; the impact of the disease and the consequent emergency response including the trial set-up. For volunteers, motivation to donate was mainly related to the feeling of social responsibility inspired by having survived EVD and to positive perceptions of plasmapheresis technology despite still unknown trial outcomes. Conversely, confidentiality concerns when volunteering due to stigmatization of survivors and perceived decrease in vital strength and in antibodies when donating, leading to fears of loss in protection against EVD, were main deterrents. The dynamic (dis)trust in Ebola Response Actors and in other survivors further determined willingness to participate and lead to the emergence/decline of rumours related to blood stealing and treatment effectiveness. Historic inter-ethnic relations in the health care setting further defined volunteering along socio-economic and ethnic lines. Finally, lack of follow-up and of dedicated care further impacted on motivation to volunteer., Conclusions: Ebola-Tx was the first trial to solicit and evaluate blood-product donation as an experimental treatment on a large scale in Sub-Saharan Africa. An effective donation system requires directly engaging with emergent social barriers and providing an effective ethical response, including improved and transparent communication, effective follow-up after donation, assuring confidentiality and determining ethical incentives., Competing Interests: The authors have declared that no competing interests exist.

Diagnosis of visceral leishmaniasis (VL) and assessment of treatment response in human immunodeficiency virus (HIV)-coinfected patients still relies on invasive tissue aspiration. This hampers scale-up and decentralization of care in resource-limited settings. Noninvasive diagnostics are urgently needed. KATEX is a frequently used latex agglutination test for Leishmania antigen in urine that has never been evaluated in HIV-coinfected individuals from Leishmania donovani -endemic areas. This was an exploratory sub-study embedded within the screening phase of a trial in highly endemic northwestern Ethiopia. All patients were HIV-positive and aspirate-confirmed VL cases. We assessed diagnostic accuracy of KATEX for VL diagnosis and as test of cure at end of treatment, using tissue aspirate parasite load as reference methods. We also described the evolution of weekly antigen levels during treatment. Most of the 87 included patients were male (84, 97%), young (median age 31 years), and had poor immune status (median cluster of differentiation type 4 count 56 cells/μL). KATEX had moderate sensitivity (84%) for VL diagnosis. KATEX had moderate sensitivity (82%) and a moderate negative predictive value (87%) but only low specificity (49%) and a low positive predictive value (40%) for the assessment of treatment outcomes. Weekly antigen levels showed characteristic patterns during treatment of patients with different initial parasite loads and treatment outcomes. Antigen detection in urine using KATEX can contribute to improved VL diagnosis in HIV-coinfected patients but has limited use for monitoring of treatment response. Better noninvasive diagnostics are needed to reduce reliance on invasive methods and thus to expand and improve clinical care for VL in resource-limited settings.

Background: North-west Ethiopia faces the highest burden world-wide of visceral leishmaniasis (VL) and HIV co-infection. VL-HIV co-infected patients have higher (initial) parasitological failure and relapse rates than HIV-negative VL patients. Whereas secondary prophylaxis reduces the relapse rate, parasitological failure rates remain high with the available antileishmanial drugs, especially when administered as monotherapy. We aimed to determine the initial effectiveness (parasitologically-confirmed cure) of a combination of liposomal amphotericin B (AmBisome) and miltefosine for treatment of VL in HIV co-infected patients., Methodology/principal Findings: We conducted a retrospective cohort study at a Médecins Sans Frontières-supported health center in north-west Ethiopia. We included VL-HIV co-infected adults, treated for VL between January 2011 and August 2014, with AmBisome infusion (30 mg/kg total dose) and miltefosine orally for 28 days (100 mg/day). Proportions of initial treatment outcome categories were calculated. Predictors of initial parasitological failure and of death were determined using multivariable logistic regression. Of the 173 patients included, 170 (98.3%) were male and the median age was 32 years. The proportion of patients with primary VL (48.0%) and relapse VL (52.0%) were similar. The majority had advanced HIV disease (n = 111; 73.5%) and were on antiretroviral therapy prior to VL diagnosis (n = 106; 64.2%). Initial cure rate was 83.8% (95% confidence interval [CI], 77.6-88.6); death rate 12.7% (95% CI, 8.5-18.5) and parasitological failure rate 3.5% (95% CI, 1.6-7.4). Tuberculosis co-infection at VL diagnosis was predictive of parasitological failure (adjusted odds ratio (aOR), 8.14; p = 0.02). Predictors of death were age >40 years (aOR, 5.10; p = 0.009), hemoglobin ≤6.5 g/dL (aOR, 5.20; p = 0.002) and primary VL (aOR, 8.33; p = 0.001)., Conclusions/significance: Initial parasitological failure rates were very low with AmBisome and miltefosine combination therapy. This regimen seems a suitable treatment option. Knowledge of predictors of poor outcome may facilitate better management. These findings remain to be confirmed in clinical trials., Competing Interests: The authors have declared that no competing interests exist.

Immunosuppression contributes significantly to the caseload of visceral leishmaniasis (VL). HIV coinfection, solid organ transplantation, malnutrition, and helminth infections are the most important immunosuppression-related factors. This review briefly describes the challenges of these associations. East Africa and the Indian subcontinent are the places where HIV imposes the highest burden in VL. In the highlands of Northern Ethiopia, migrant rural workers are at a greater risk of coinfection and malnutrition, while in India, HIV reduces the sustainability of a successful elimination programme. As shown from a longitudinal cohort in Madrid, VL is an additional threat to solid organ transplantation. The association with malnutrition is more complex since it can be both a cause and a consequence of VL. Different regimes for therapy and secondary prevention are discussed as well as the role of nutrients on the prophylaxis of VL in poverty-stricken endemic areas.

Background: Passive therapy with convalescent plasma provides an early opportunity to intervene in Ebola virus disease (EVD). Methods for field screening and selection of potential donors and quantifying plasma antibody are needed., Study Design and Methods: Recombinant Ebola virus glycoprotein (EBOV GP) was formatted into immunoglobulin G-capture, competitive, and double-antigen bridging enzyme immunoassays (EIAs). EVD survivors in Freetown, Sierra Leone, were recruited as potential plasma donors and assessed locally using sera alone and/or paired sera and oral fluids (ORFs). Uninfected controls comprised unexposed Gambians and communities in Western Area, Sierra Leone. Antibody neutralization in selected sera was measured retrospectively in a pseudotype virus assay., Results: A total of 115 potential donors were considered for enrollment: 110 plasma samples were concordantly reactive in the three EIAs; three were concordantly unreactive and two were reactive in two of three EIAs (98.2% agreement; 95% confidence interval [CI], 93.9%-99.8%). In 88 donors with paired ORF and plasma, G-capture EIA reactivity correlated well in the two analytes (R 2  = 0.795). Plasma and ORF from 44 Gambians were unreactive. ORF samples from 338 of 339 unexposed Western Area community controls were unreactive (specificity, 99.7%; 95% CI, 98.4%-99.7%); ORF samples from 113 of 116 Kerry Town EVD survivors were reactive (sensitivity, 97.4%; 95% CI, 92.5%-99.5%). Strong reactivity in G-capture and/or competitive EIAs identified donors with high plasma EBOV GP antibody levels in the double-antigen bridging assay, correlating with high levels of neutralizing antibody., Conclusions: In-field testing can qualify convalescent donors for providing high-titer antibody., (© 2018 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.)

Background: Biomarkers predicting the risk of VL treatment failure and relapse in VL/HIV coinfected patients are needed. Nested within a two-site clinical trial in Ethiopia (2011-2015), we conducted an exploratory study to assess whether (1) levels of Leishmania antigenuria measured at VL diagnosis were associated with initial treatment failure and (2) levels of Leishmania antigenuria at the end of treatment (parasitologically-confirmed cure) were associated with subsequent relapse. Methods: Leishmania antigenuria at VL diagnosis and cure was determined using KAtex urine antigen test and graded as negative (0), weak/moderate (grade 1+/2+) or strongly-positive (3+). Logistic regression and Kaplan-Meier methods were used to assess the association between antigenuria and (1) initial treatment failure, and (2) relapse over the 12 months after cure, respectively. Results: The analysis to predict initial treatment failure included sixty-three coinfected adults [median age: 30 years interquartile range (IQR) 27-35], median CD4 count: 56 cells/μL (IQR 38-113). KAtex results at VL diagnosis were negative in 11 (17%), weak/moderate in 17 (27%) and strongly-positive in 35 (36%). Twenty (32%) patients had parasitologically-confirmed treatment failure, with a risk of failure of 9% (1/11) with KAtex-negative results, 0% (0/17) for KAtex 1+/2+ and 54% (19/35) for KAtex 3+ results. Compared to KAtex-negative patients, KAtex 3+ patients were at increased risk of treatment failure [odds ratio 11.9 (95% CI 1.4-103.0); P : 0.025]. Forty-four patients were included in the analysis to predict relapse [median age: 31 years (IQR 28-35), median CD4 count: 116 cells/μL (IQR 95-181)]. When achieving VL cure, KAtex results were negative in 19 (43%), weak/moderate (1+/2+) in 10 (23%), and strongly positive (3+) in 15 patients (34%). Over the subsequent 12 months, eight out of 44 patients (18%) relapsed. The predicted 1-year relapse risk was 6% for KAtex-negative results, 14% for KAtex 1+/2+ and 42% for KAtex 3+ results [hazard ratio of 2.2 (95% CI 0.1-34.9) for KAtex 1+/2+ and 9.8 (95% CI 1.8-82.1) for KAtex 3+, compared to KAtex negative patients; P : 0.03]. Conclusion: A simple field-deployable Leishmania urine antigen test can be used for risk stratification of initial treatment failure and VL relapse in HIV-patients. A dipstick-format would facilitate field implementation.

Background: Visceral leishmaniasis (VL)-human immunodeficiency virus (HIV) coinfection remains a major problem in Ethiopia, India, and Brazil. Tuberculosis (TB), a treatable factor, could contribute to high mortality (up to 25%) in VL-HIV coinfection. However, the current evidence on the prevalence and clinical impact of TB in VL-HIV coinfection is very limited. In previous reports on routine care, TB prevalence ranged from 5.7% to 29.7%, but information on how and when TB was diagnosed was lacking., Methods: Field observations suggest that TB work-up is often not done systematically, and it is only done in patients who do not respond well to VL treatment. Here, we advocate high-quality diagnostic studies in VL-HIV-coinfected patients, during which all patients are systematically screened for TB, including a comprehensive work-up, to obtain reliable estimates., Results: Cost-effective and feasible diagnostic algorithms can be developed for field use, and this can be integrated in VL clinical guidelines., Conclusions: An accurate diagnosis of TB can allow clinicians to assess its clinical impact and evaluate the impact of early TB diagnosis.

The approach to treatment of visceral leishmaniasis (VL)-HIV co-infection in East Africa has not been systematically examined. Although antiretroviral treatment (ART) should be initiated for all co-infected persons, the extent of ART prescription is not known. We conducted a retrospective cohort study including all VL-HIV co-infected adults at selected referral and district hospitals in northwest Ethiopia from 2010 to 2015. Purposes of the study were to compare the proportion of VL diagnoses made in previously diagnosed HIV-patients versus diagnosis concurrent with HIV diagnosis and to quantify utilization of ART. We included 112 patients and 58 patients at the referral and district hospital, respectively (median age: 30 years, 98% males). Of all VL cases, 56% (63/112) and 19% (11/58) occurred in known HIV patients at the referral and district hospital, respectively, with a median CD4 count at VL diagnosis of 45 cells/µL and 248 cells/µL at the referral and district hospital, respectively. Seventy-six percent (56/44) were on ART at VL diagnosis and nine (12%) started ART after VL diagnosis. The remaining 96 (56%) patients had both infections diagnosed concurrently, with a median CD4 count of 56 and 143 cells/µL at the referral and district hospital, respectively. Among cured patients, ART initiation was 67% and 36% at the referral and district hospital, respectively. A substantial proportion of VL-HIV cases occur while in HIV care, requiring further evaluation of preventive strategies. Among newly diagnosed VL-HIV co-infected patients, ART initiation was low. The reasons, including poor documentation and information exchange, should be assessed.

Patients with visceral leishmaniasis (VL)-human immunodeficiency virus (HIV) coinfection experience increased drug toxicity and treatment failure rates compared to VL patients, with more frequent VL relapse and death. In the era of VL elimination strategies, HIV coinfection is progressively becoming a key challenge, because HIV-coinfected patients respond poorly to conventional VL treatment and play an important role in parasite transmission. With limited chemotherapeutic options and a paucity of novel anti-parasitic drugs, new interventions that target host immunity may offer an effective alternative. In this review, we first summarize current views on how VL immunopathology is significantly affected by HIV coinfection. We then review current clinical and promising preclinical immunomodulatory interventions in the field of VL and discuss how these may operate in the context of a concurrent HIV infection. Caveats are formulated as these interventions may unpredictably impact the delicate balance between boosting of beneficial VL-specific responses and deleterious immune activation/hyperinflammation, activation of latent provirus or increased HIV-susceptibility of target cells. Evidence is lacking to prioritize a target molecule and a more detailed account of the immunological status induced by the coinfection as well as surrogate markers of cure and protection are still required. We do, however, argue that virologically suppressed VL patients with a recovered immune system, in whom effective antiretroviral therapy alone is not able to restore protective immunity, can be considered a relevant target group for an immunomodulatory intervention. Finally, we provide perspectives on the translation of novel theories on synergistic immune cell cross-talk into an effective treatment strategy for VL-HIV-coinfected patients.

Background: East Africa, where Leishmania donovani is prevalent, faces the highest burden world-wide of visceral leishmaniasis (VL) and human immunodeficiency virus (HIV) coinfection. However, data on the risk and predictors of VL relapse are scarce. Such information is vital to target medical follow-up and interventions to those at highest risk., Methods: We conducted a retrospective cohort study at a Médecins Sans Frontières-supported health center in northwest Ethiopia. We included adult VL-HIV coinfected patients treated for VL and discharged cured between February 2008 and February 2013. The risk of relapse was calculated using Kaplan-Meier methods, and predictors were determined using Cox regression models., Results: Of the 146 patients included, 140 (96%) were male and the median age was 31 years. At the index VL diagnosis, 110 (75%) had primary VL, 57 (40%) were on antiretroviral therapy (ART), and the median CD4 count was 149 cells/µL. The median follow-up time after cure was 11 months, during which 44 (30%) patients relapsed. The risk of relapse was 15% at 6 months, 26% at 12 months, and 35% at 24 months. Predictors of relapse were: not being on ART at VL diagnosis, ART not initiated during VL treatment, and high tissue parasite load (parasite grade 6+) at VL diagnosis., Conclusions: The risk of VL relapse in coinfected patients was high, particularly in those not on ART or presenting with a high tissue parasite load. These patients should be preferentially targeted for secondary prophylaxis and/or regular medical follow-up. Timely ART initiation in all coinfected patients is crucial., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objective: Cutaneous leishmaniasis (CL) receives far less attention than visceral leishmaniasis. Nevertheless, CL is predominantly caused by a unique species in Ethiopia (L. aethiopica), which is known to cause severe forms such as diffuse (DCL) and mucocutaneous leishmaniasis (MCL). We report on the number and type of CL cases diagnosed, the clinical features, the treatments and treatment outcomes in North-West Ethiopia., Methods: This is a retrospective chart record analysis of CL patients treated at the Leishmania Research and Treatment Center (LRTC) of the University of Gondar, Ethiopia., Results: From 178 CL patients seen between January 2014 and December 2015, a total of 154 chart records were retrieved. These included 80 localised CL (LCL), 7 DCL and 67 MCL. The median age was 23 years; 71.4% were male. Most (n = 121, 78.6%) of the lesions were on the face. The median time since onset was 12 months (6-24 months), and 28.6% presented after a trial of traditional medicine. The treatment of all forms of CL mainly consisted of 30 days of IM antimonial injections. Of these, 51/133 (38.3%) required treatment extension or change due to nonresponse. Three cases were treated with liposomal amphotericin B or miltefosine (two received the combination), of which two responded well., Conclusion: CL was found to be complicated and difficult to treat. MCL was common, and patients presented after long delays. There is an urgent need to look for better treatment options for CL and improve access to care., (© 2017 John Wiley & Sons Ltd.)

Background: As part of the WHO End TB strategy, national tuberculosis (TB) programs increasingly aim to engage all private and public TB care providers. Engagement of communities, civil society organizations and public and private care provider is the second pillar of the End TB strategy. In Myanmar, this entails the public-public and public-private mix (PPM) approach. The public-public mix refers to public hospital TB services, with reporting to the national TB program (NTP). The public-private mix refers to private general practitioners providing TB services including TB diagnosis, treatment and reporting to NTP. The aim of this study was to assess whether PPM activities can be scaled-up nationally and can be sustained over time., Methods: Using 2007-2014 aggregated program data, we collected information from NTP and non-NTP actors on 1) the number of TB cases detected and their relative contribution to the national case load; 2) the type of TB cases detected; 3) their treatment outcomes., Results: The total number of TB cases detected per year nationally increased from 133,547 in 2007 to 142,587 in 2014. The contribution of private practitioners increased from 11% in 2007 to 18% in 2014, and from 1.8% to 4.6% for public hospitals. The NTP contribution decreased from 87% in 2007 to 77% in 2014. A similar pattern was seen in the number of new smear (+) TB cases (31% of all TB cases) and retreatment cases, which represented 7.8% of all TB cases. For new smear (+) TB cases, adverse outcomes were more common in public hospitals, with more patients dying, lost to follow up or not having their treatment outcome evaluated. Patients treated by private practitioners were more frequently lost to follow up (8%). Adverse treatment outcomes in retreatment cases were particularly common (59%) in public hospitals for various reasons, predominantly due to patients dying (26%) or not being evaluated (10%). In private clinics, treatment failure tended to be more common (8%)., Conclusions: The contribution of non-NTP actors to TB detection at the national level increased over time, with the largest contribution by private practitioners involved in PPM. Treatment outcomes were fair. Our findings confirm the role of PPM in national TB programs. To achieve the End TB targets, further expansion of PPM to engage all public and private medical facilities should be targeted.

The epidemiology of hepatitis C in Cambodia is not well-known. We evaluated the prevalence of hepatitis C virus (HCV) and risk factors in the HIV cohort of Sihanouk Hospital Center of Hope in Phnom Penh to strengthen the evidence for suitable HCV testing strategies among people living with HIV (PLWH) in Cambodia. All consenting adult PLWH without a history of HCV treatment were tested for HCV between November 2014 and May 2016 according to the CDC algorithm (HCV antibody II electro-chemiluminescence immunoassay, followed by COBAS® AmpliPrep/COBAS® TaqMan® HCV PCR and INNO-LIA® HCV Score immunoblot end-testing). Genotyping was performed using the line probe assay Versant HCV genotype 2.0®. The study enrolled a total of 3045 patients (43% males, median age: 42.5 years, <1% high-risk). HCV antibodies were detected in 230 (7.6%; 95% confidence interval [CI] 6.6-8.5). Upon further testing, HCV antibodies were confirmed in 157 (5.2%; 95% CI 4.4-6.0) and active HCV in 106 (3.5%; 95% CI 2.8-4.2). Viremic prevalence peaked among men aged 50-55 years (7.3%) and women aged >55 years (11.2%). Genotype 1b (45%) and 6 (41%) were predominant. Coinfected patients had a higher aspartate-to-platelet ratio index, lower platelets, a lower HBsAg positivity rate and more frequent diabetes. Based on logistic regression, blood transfusion antecedents (adjusted odds ratio 2.9; 95% CI 1.7-4.9), unsafe medical injections (2.0; 1.3-3.2), and partner (3.4; 1.5-7.6) or household member (2.4; 1.3-3.2) with liver disease were independently associated with HCV in women. However, having a tattoo/scarification (1.9; 1.1-3.4) and household member (3.1; 1.3-7.3) with liver disease were associated with HCV in men. Thus, our study found intermediate endemicity of active hepatitis C in a large Cambodian HIV cohort and provides initial arguments for targeted HCV screening (>50 years, partner/household member with liver disease, diabetes, increased aspartate-to-platelet ratio index) as efficient way forward.

Background: Over the last decade, the availability and use of mobile phones have grown exponentially globally and in Cambodia. In the Sihanouk Hospital Centre of Hope(SHCH) in Cambodia about half of all tuberculosis patients referred out to peripheral health facilities for TB treatment initiation or continuation were lost to contact after referral ranging from 19 to 69% between 2008 and 2013. To address this, we implemented a mobile phone-based patient tracking intervention. Here, we report the number and proportion of referred TB patients who could be contacted through a mobile phone and retained in care after the introduction of mobile phone tracking., Methods: A descriptive study involving follow-up of TB patients referred out from SHCH to peripheral health facilities during May-October 2014. Standard operating procedures were used to contact individual patients and/or health facilities using a mobile phone., Results: Among 109 TB patients referred to peripheral health facilities, 107(98%) had access to a mobile phone of whom, 103(97%) could be contacted directly while 5(2%) were contacted through their health care providers. A total of 108(99%) of 109 referred TB patients in intervention period were thus placed on TB treatment., Conclusions: This study provides preliminary, but promising evidence that using mobile phones was accompanied with improved retention of referred TB patients compared to historical cohorts. Given the limitations associated with historical controls, we need better designed studies with larger sample size to strengthen the evidence before national scale-up.

Background: Bloodstream infections (BSI) caused by Salmonella Typhi and invasive non-Typhoidal Salmonella (iNTS) frequently affect children living in rural sub-Saharan Africa but data about incidence and serotype distribution are rare., Objective: The present study assessed the population-based incidence of Salmonella BSI and severe malaria in a Health and Demographic Surveillance System in a rural area with seasonal malaria transmission in Nanoro, Burkina Faso., Methods: Children between 2 months-15 years old with severe febrile illness were enrolled during a one-year surveillance period (May 2013-May 2014). Thick blood films and blood cultures were sampled and processed upon admission. Population-based incidences were corrected for non-referral, health seeking behavior, non-inclusion and blood culture sensitivity. Adjusted incidence rates were expressed per 100,000 person-years of observations (PYO)., Results: Among children < 5 years old, incidence rates for iNTS, Salmonella Typhi and severe malaria per 100,000 PYO were 4,138 (95% Confidence Interval (CI): 3,740-4,572), 224 (95% CI: 138-340) and 2,866 (95% CI: 2,538-3,233) respectively. Among those aged 5-15 years, corresponding incidence rates were 25 (95% CI: 8-60), 273 (95% CI: 203-355) and 135 (95% CI: 87-195) respectively. Most iNTS occurred during the peak of the rainy season and in parallel with the increase of Plasmodium falciparum malaria; for Salmonella Typhi no clear seasonal pattern was observed. Salmonella Typhi and iNTS accounted for 13.3% and 55.8% of all 118 BSI episodes; 71.6% of iNTS (48/67) isolates were Salmonella enterica serovar Typhimurium and 25.4% (17/67) Salmonella enterica serovar Enteritidis; there was no apparent geographical clustering., Conclusion: The present findings from rural West-Africa confirm high incidences of Salmonella Typhi and iNTS, the latter with a seasonal and Plasmodium falciparum-related pattern. It urges prioritization of the development and implementation of Salmonella Typhi as well as iNTS vaccines in this setting.

Non-cases are suspect Ebola Virus Disease (EVD) cases testing negative by EVD RT-PCR after admission to an Ebola Treatment Centre (ETC). Admitting non-cases to an ETC prompts concerns on case- and workload in the ETC, risk for nosocomial EVD infection, and delays in diagnosis and disease-specific treatment. We retrospectively analysed characteristics, outcomes and determinants of death of EVD cases and non-cases admitted to the Conakry ETC in Guinea between 03/2014 and 09/2015. Of the 2362 admitted suspects who underwent full confirmatory PCR testing, 1540 (65.2%) were non-cases; among them 727 needed repeated confirmatory PCR testing resulting in 2.5 days (average) in the ETC isolation ward. Twenty-one patients tested positive on the repeat test, most in a period of flawed sampling for the initial test and none after introduction of PCR confirmation with geneXpert. No readmissions following nosocomial EVD infection were recorded. No combination of symptoms yielded acceptable sensitivity and specificity to allow differentiating confirmed from non-cases. Symptoms as ocular bleeding/redness have high specificity, but limited usefulness as not common. Admission delay and age distribution were not different for both groups. In total, 98 (20.6%) of 475 deaths in the ETC were non-cases. Most died within 24 hours after admission. Living in Conakry (aOR 1.78 (1.08-2.96)) was the strongest risk factor for death. Weeks with higher admission load had lower case fatality among non-cases, probably because more acute (and treatable) illnesses of contacts of known cases were admitted. These findings show high numbers of potentially critically ill non-cases need to be considered when setting up triage and referral of EVD suspect cases. Symptoms and risk factors alone do not allow differentiating the non-cases. Integration of highly-sensitive EVD diagnostic methods with short turnaround time in the triage of peripheral hospitals and dropping the systematic 2nd PCR for symptomatic early presenters could limit delays in access to adapted care of cases and seriously ill non-cases. Whether feasible without compromising outbreak control, and under which conditions, should be further assessed.

Background: In Ethiopia, case fatality rates among subgroups of visceral leishmaniasis (VL) patients are high. A clinical prognostic score for death in VL patients could contribute to optimal management and reduction of these case fatality rates. We aimed to identify predictors of death from VL, and to develop and externally validate a clinical prognostic score for death in VL patients, in a high HIV co-infection burden area in Ethiopia., Methodology/principal Findings: We conducted a retrospective cohort study in north west Ethiopia. Predictors with an adjusted likelihood ratio ≥1.5 or ≤0.67 were retained to calculate the predictor score. The derivation cohort consisted of 1686 VL patients treated at an upgraded health center and the external validation cohort consisted of 404 VL patients treated in hospital. There were 99 deaths in the derivation cohort and 53 deaths in the external validation cohort. The predictors of death were: age >40 years (score +1); HIV seropositive (score +1); HIV seronegative (score -1); hemoglobin ≤6.5 g/dl (score +1); bleeding (score +1); jaundice (score +1); edema (score +1); ascites (score +2) and tuberculosis (score +1). The total predictor score per patient ranged from -1 to +5. A score of -1, indicated a low risk of death (1.0%), a score of 0 an intermediate risk of death (3.8%) and a score of +1 to +5, a high risk of death (10.4-85.7%). The area under the receiver operating characteristic curve was 0.83 (95% confidence interval: 0.79-0.87) in derivation, and 0.78 (95% confidence interval: 0.72-0.83) in external validation., Conclusions/significance: The overall performance of the score was good. The score can enable the early detection of VL cases at high risk of death, which can inform operational, clinical management guidelines, and VL program management. Implementation of focused strategies could contribute to optimal management and reduction of the case fatality rates.

Background: This study examined evolving malaria profiles from January, 2010 to December, 2014 to evaluate achievements and challenges of implementing measures to prevent and control spread of artemisinin resistance in Myanmar., Methods: Using National Malaria Control Programme (NMCP) data, a cross-sectional descriptive study of 52 townships in artemisinin-resistant containment areas in Myanmar was conducted. Annual program data were analysed, and trends over time are graphically presented., Results: In the 52 study townships populated by 8.7 million inhabitants, malaria incidence showed a decreasing trend from 10.54 per 1 000 population in 2010 to 2.53 in 2014, and malaria mortalities also decreased from 1.83 per 100 000 population in 2010 to 0.17 in 2014. The proportion of confirmed to total tested malaria cases also decreased from 6 to 1%, while identification of cases improved. All cases from all parasites species, including Plasmodium falciparum, decreased. Coverage of LLIN (long-lasting insecticidal net)/ITN (insecticide-treated mosquito nets) and indoor residual spraying (IRS) was high in targeted areas with at-risk persons, even though the total population was not covered. In addition to passive case detection (PCD), active case detection (ACD) was conducted in hard-to-reach areas and worksites where mobile migrant populations were present. ACD improved in most areas from 2012 to 2014, but continues to need to be strengthened., Conclusions: The findings provide useful data on the malaria situation in artemisinin-resistant initiative areas, which may be useful for the NMCP to meet its elimination goal. These profiles could contribute to better planning, implementation, and evaluation of intervention activities.

Background: Age-specific retention challenges make antiretroviral therapy (ART) initiation in adolescents difficult, often requiring a lengthy preparation process. This needs to be balanced against the benefits of starting treatment quickly. The optimal time to initiation duration in adolescents is currently unknown., Objective: To assess the effect of time to ART initiation on mortality and loss to follow-up (LTFU) among treatment eligible adolescents., Methods: We conducted a retrospective cohort analysis among 1499 ART eligible adolescents aged ≥10 to <19 years registered in a public sector HIV program in Bulawayo, Zimbabwe, between 2004 and 2011. Hazard ratios (HR) for mortality and LTFU were calculated for different time to ART durations using multivariate Cox regression models., Results: Median follow-up duration was 1.6 years. Mortality HRs of patients who initiated at 0 to ≤7 days, >14 days to ≤1 month, >1 to ≤2 months, >2 months, and before initiation were 1.59, 1.19, 1.56, 1.08, and 0.94, respectively, compared with the reference group of >7 to ≤14 days. LTFU HRs were 1.02, 1.07, 0.85, 0.97, and 3.96, respectively. Among patients not on ART, 88% of deaths and 85% of LTFU occurred during the first 3 months after becoming ART eligible, but only 37% and 29% among adolescents on ART, respectively., Conclusions: Neither mortality or LTFU was associated with varying time to ART. The initiation process can be tailored to the adolescents' needs and individual life situations without risking to increase poor treatment outcomes. Early mortality was high despite rapid ART initiation, calling for earlier rather than faster initiation through HIV testing scale-up.

Background: National tuberculosis (TB) programs increasingly engage with international non-governmental organizations (INGOs), especially to provide TB care in complex settings where community involvement might be required. In Myanmar, however, there is limited data on how such INGO community-based programs are organized and how effective they are. In this study, we describe four INGO strategies for providing community-based TB care to hard-to-reach populations in Myanmar, and assess their contribution to TB case detection., Methods: We conducted a descriptive study using program data from four INGOs and the National TB Program (NTP) in 2013-2014. For each INGO, we extracted information on its approach and key activities, the number of presumptive TB cases referred and undergoing TB testing, and the number of patients diagnosed with TB and their treatment outcomes. The contribution of INGOs to TB diagnosis in their selected townships was calculated as the proportion of INGO-diagnosed new TB cases out of the total NTP-diagnosed new TB cases in the same townships., Results: All four INGOs implemented community-based TB care in challenging contexts, targeting migrants, post-conflict areas, the urban poor, and other vulnerable populations. Two recruited community volunteers via existing community health volunteers or health structures, one via existing community leaderships, and one directly involved TB infected/affected individuals. Two INGOs compensated volunteers via performance-based financing, and two provided financial and in-kind initiatives. All relied on NTP laboratories for diagnosis and TB drugs, but provided direct observation treatment support and treatment follow-up. A total of 21 995 presumptive TB cases were referred for TB diagnosis, with 7 383 (34%) new TB cases diagnosed and almost all (98%) successfully treated. The four INGOs contributed to the detection of, on average, 36% (7 383/20 663) of the total new TB cases in their respective townships (range: 15-52%)., Conclusion: Community-based TB care supported by INGOs successfully achieved TB case detection in hard-to-reach and vulnerable populations. This is vital to achieving the World Health Organization End TB Strategy targets. Strategies to ensure sustainability of the programs should be explored, including the need for longer-term commitment of INGOs.

Background: While community distribution of topical repellents has been proposed as an additional malaria control intervention, the safety of this intervention at the population level remains poorly evaluated. We describe the safety of mass distribution of the picaridin repellent during a cluster-randomised trial in rural Cambodia in 2012-2013., Methods: The repellent was distributed among 57 intervention villages with around 25,000 inhabitants by a team of village distributors. Information on individual adverse events, reported by phone by the village distributors, was obtained through home visits. Information on perceived side effects, reported at the family level, was obtained during two-weekly bottle exchange. Adverse events were classified as adverse reactions (events likely linked to the repellent), cases of repellent abuse and events not related to the repellent use, and classified as per Common Terminology Criteria for Adverse Events., Findings: Of the 41 adverse events notified by phone by the village distributors, there were 22 adverse reactions, 11 cases of repellent abuse (6 accidental, 5 suicide attempts) and 8 non-related events. All adverse reactions were mild, occurred in the first few months of use, and mainly manifested as skin conditions. Of the 11 cases of abuse, 2 were moderate and 2 life-threatening. All cases with adverse reactions and repellent abuse recovered completely. 20% of families reported perceived side effects, mainly itching, headache, dizziness and bad smell, but few discontinued repellent use., Conclusions: Adverse reactions and abuse during mass use of picaridin were uncommon and generally mild, supporting the safety of the picaridin repellent for malaria control.

Objective: To describe the experience of Guinean Ebola virus disease (EVD) survivors in Guinea, up to ten months after discharge from the Ebola treatment unit., Methods: Cross-sectional study using a standardised semistructured questionnaire among survivors from Conakry and Coyah districts in 2015 in Guinea. We used proportions, mean (standard deviation) and median (interquartile range) to summarise the variables. The McNemar chi-square test was used to compare proportions., Results: The 121 EVD survivors interviewed had a median reintegration time from discharge of 18 weeks (IQR: 14-32 weeks). Most survivors were aged 15-44 years (87.6%) with secondary to higher level of education (68.6%), and 25.6% were healthcare workers. The majority reported a lower socio-economic status (90%), a less favourable work situation (79%) and psychological status (60%). About 31% reported physical health problems. Most survivors reported lower levels of reintegration with friends and at work place (72%) and lower acceptance by others in general (71%) in the period after the EVD as compared to the period before the EVD. Only 55 survivors (45.5%) were involved in one or more activities of the EVD response: participation in clinical studies on the EVD (44 survivors, 36.4%), community sensitisation (28 survivors, 23.1%) or work in Ebola treatment and/or transit centres (23 survivors, 21.7%)., Conclusion: There is a need for a long-term follow-up of EVD survivors in Guinea and more efforts to support their social, professional and economic reintegration, especially in rural areas., (© 2016 John Wiley & Sons Ltd.)

Facility-based antiretroviral therapy (ART) provision for stable patients with HIV congests health services in resource-limited countries. We assessed outcomes and risk factors for attrition after decentralization to community-based ART refill centers among 2603 patients with HIV in Kinshasa, Democratic Republic of Congo, using a multilevel Poisson regression model. Death, loss to follow-up, and transfer out were 0.3%, 9.0%, and 0.7%, respectively, at 24 months. Overall attrition was 5.66/100 person-years. Patients with >3 years on ART, >500 cluster of differentiation type-4 count, body mass index >18.5, and receiving nevirapine but not stavudine showed reduced attrition. ART refill centers are a promising task-shifting model in low-prevalence urban settings with high levels of stigma and poor ART coverage., Competing Interests: The authors have no funding or conflicts of interest to disclose.

Visceral leishmaniasis (VL) is a fatal parasitic disease. Unfortunately, diagnosis of VL in east Africa currently relies on aspiration of tissue from the spleen or bone marrow, which is painful and potentially dangerous. We sought to determine whether peripheral blood could be used instead of invasive tissue aspirates to diagnose VL, using three parasite concentration techniques. Three hundred and one consecutive people suspected of having VL were recruited. Compared with microscopy of tissue aspirates, the diagnostic accuracy of peripheral blood microscopy was as follows: whole blood thin smear sensitivity 1.5% (95% confidence interval [CI] 0.0-8.3) and specificity 100% (95% CI 76.8-100); buffy-coat smear sensitivity 19.5% (95% CI 14.3-25.6) and specificity 98.9% (95% CI 94.1-100); peripheral blood mononuclear cell (PBMC) smear sensitivity 33.7% (95% CI 27.3-40.5) and specificity 95.7% (95% CI 89.6-98.6). Sensitivity of PBMC smears was significantly higher in human immunodeficiency virus (HIV)-coinfected patients (N = 48/301); two-sample test of proportions, P = 0.0097; sensitivity 55.9% (95% CI 37.9-72.8) and specificity 92.9% (95% CI 66.1-99.8), and correlated with the degree of parasite load in the tissue. Combining the results from smears of both PBMC and buffy coat yielded a sensitivity and specificity of 67.6% (95% CI 49.1-82.6) and 92.9% (95% CI 66.1-99.8), respectively, in HIV-coinfected patients. In this setting, VL could be ruled-in with peripheral blood microscopy in a substantial number of VL suspects and may reduce the number of tissue aspirations performed, particularly in HIV-coinfected patients. More sensitive and logistically feasible methods than light microscopy are needed to detect Leishmania donovani parasites present in blood., (© The American Society of Tropical Medicine and Hygiene.)

Background: The 2014/2015 Ebola outbreak was the most sustained in history. In Guinea, we compared trends in family planning, antenatal care, and institutional deliveries over the period before, during and after the outbreak., Methods: We carried out an ecological study involving all the health facilities during pre-Ebola (1 March 2013 to 28 February 2014), intra-Ebola (1 March 2014 to 28 February 2015) and post-Ebola (1 March to 31 July 2016) periods in Macenta district., Results: Utilization of family planning declined from a monthly average of 531 visits during the pre-Ebola period to 242 visits in the peak month of the Ebola outbreak (51% decline) but recovered in the post-Ebola period. From a monthly average of 2053 visits pre-Ebola, antenatal care visits declined by 41% during Ebola and then recovered to only 63% of the pre-Ebola level (recovery gap of 37%, p<0.001). From a monthly average of 1223 deliveries pre-Ebola, institutional deliveries also declined during Ebola and then recovered to only 66% of the pre-Ebola level (p<0.001)., Conclusions: All services assessed were affected by Ebola. Family planning recovered post-Ebola; however, shortfalls were observed in recovery of antenatal care and institutional deliveries. We call for stronger political will, international support and generous funding to change the current state of affairs., (© The Author 2017. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

By using data from a 2015 clinical trial on Ebola convalescent-phase plasma in Guinea, we assessed the prevalence of electrolyte and metabolic abnormalities at admission and their predictive value to stratify patients into risk groups. Patients underwent testing with a point-of-care device. We used logistic regression to construct a prognostic model and summarized the predictive value with the area under the receiver operating curve. Abnormalities were common among patients, particularly hypokalemia, hypocalcemia, hyponatremia, raised creatinine, high anion gap, and anemia. Besides age and PCR cycle threshold value, renal dysfunction, low calcium levels, and low hemoglobin levels were independently associated with increased risk for death. A prognostic model using all 5 factors was highly discriminatory (area under the receiver operating curve 0.95; 95% CI 0.90-0.99) and enabled the definition of risk criteria to guide targeted care. Most patients had a very low (<5%) or very high (>80%) risk for death.

Although convalescent plasma (CP) transfusion was prioritized among potential Ebola treatments by the World Health Organization, there were concerns on the feasibility of its implementation. We report on the successful organization of donor mobilization and plasma collection as part of the Ebola-Tx clinical trial from November 2014 to July 2015 in Conakry, Guinea. Project implementation registers, tools and reports, mission reports, and minutes of research team meetings were used to reconstruct the sequence of events on how donor mobilization was organized, plasmapheresis was set up, and how effective this approach was in collecting CP. An initial needs assessment of the Guinean National Blood Transfusion Center resulted in targeted training of staff on site, resulting in autonomy and independent production of CP within 3 months. The Conakry Ebola Survivors Association played a direct role in donor mobilization and organization of CP donations. A total of 98 Ebola survivors were screened for plasma donation, of which 84 were found eligible for plasmapheresis. Of these, 26 (30.9%) were excluded. The remaining 58 donors made a total of 90 donations, corresponding to 50.9 L of CP. This sufficed to treat the 99 eligible patients enrolled in the trial. Within a poor resource emergency context, transfusion capacity could be rapidly improved through the strengthening of local capacities and gradual transfer of skills coupled with active involvement of Ebola survivors. However, large-scale plasma collection or multisite studies may require further adaptations of both strategy and logistics. The Ebola-Tx trial was funded by the European Union and others., (© The American Society of Tropical Medicine and Hygiene.)

Quantitative measurement of viral load is an important parameter in the management of filovirus disease outbreaks because viral load correlates with severity of disease, survival, and infectivity. During the ongoing Ebola virus disease outbreak in parts of Western Africa, most assays used in the detection of Ebola virus disease by more than 44 diagnostic laboratories yielded qualitative results. Regulatory hurdles involved in validating quantitative assays and the urgent need for a rapid Ebola virus disease diagnosis precluded development of validated quantitative assays during the outbreak. Because of sparse quantitative data obtained from these outbreaks, opportunities for study of correlations between patient outcome, changes in viral load during the course of an outbreak, disease course in asymptomatic individuals, and the potential for virus transmission between infected patients and contacts have been limited. We strongly urge the continued development of quantitative viral load assays to carefully evaluate these parameters in future outbreaks of filovirus disease., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Leishmania aethiopica is the etiological agent of cutaneous leishmaniasis (CL) in Ethiopia and can cause severe and complicated cases such as diffuse CL (DCL), mucocutaneous leishmaniasis or extensive CL, requiring systemic treatment. Despite the substantial burden, evidence-based treatment guidelines are lacking. We conducted a systematic review of clinical studies reporting on treatment outcomes of CL due to L aethiopica in order to help identify potentially efficacious medications on CL that can be taken forward for clinical trials. We identified a total of 24 records reporting on 506 treatment episodes of CL presumably due to L aethiopica. The most commonly used drugs were antimonials (n = 201), pentamidine (n = 150) and cryotherapy (n = 103). There were 20 case reports/series, with an overall poor study quality. We only identified two small and/or poor quality randomized controlled trials conducted a long time ago. There were two prospective non-randomized studies reporting on cryotherapy, antimonials and pentamidine. With cryotherapy, cure rates were 60-80%, and 69-85% with antimonials. Pentamidine appeared effective against complicated CL, also in cases non-responsive to antimonials. However, all studies suffered from methodological limitations. Data on miltefosine, paromomycin and liposomal amphotericin B are extremely scarce. Only a few studies are available on DCL. The only potentially effective treatment options for DCL seem to be antimonials with paromomycin in combination or pentamidine, but none have been properly evaluated. In conclusion, the evidence-base for treatment of complicated CL due to L aethiopica is extremely limited. While antimonials remain the most available CL treatment in Ethiopia, their efficacy and safety in CL should be better defined. Most importantly, alternative first line treatments (such as miltefosine or paromomycin) should be explored. High quality trials on CL due to L aethiopica are urgently needed, exploring group sequential methods to evaluate several options in parallel.

The Ebola virus disease outbreak in 2014-2015 led to a huge caseload with a high case fatality rate. No specific treatments were available beyond supportive care for conditions such as dehydration and shock. Evaluation of treatment with convalescent plasma from Ebola survivors was identified as a priority. We evaluated this intervention in an emergency setting, where randomization was unacceptable. The original trial design was an open-label study comparing patients receiving convalescent plasma and supportive care to patients receiving supportive care alone. The comparison group comprised patients recruited at the start of the trial before convalescent plasma became available, as well as patients presenting during the trial for whom there was insufficient blood group-compatible plasma or no staffing capacity to provide additional transfusions. However, during the trial, convalescent plasma was available to treat all new patients. The design was changed to use a comparator group comprising patients previously treated at the same Ebola treatment center prior to the start of the trial. In the analysis, it was planned to adjust for any differences in prognostic variables between intervention and comparison groups, specifically baseline polymerase chain reaction cycle threshold and age. In addition, adjustment was planned for other potential confounders, identified in the analysis, such as patient presenting symptoms and time to treatment seeking. Because plasma treatment started up to 3 days after diagnosis and we could not define a similar time-point for the comparator group, patients who died before the third day after confirmation of diagnosis were excluded from both intervention and comparison groups in a per-protocol analysis. Some patients received additional experimental treatments soon after plasma treatment, and these were excluded. We also analyzed mortality including all patients from the time of confirmed diagnosis, irrespective of whether those in the trial series actually received plasma, as an intention-to-treat analysis. Per-protocol and intention-to-treat approaches gave similar conclusions. An important caveat in the interpretation of the findings is that it is unlikely that all potential sources of confounding, such as any variation in supportive care over time, were eliminated. Protocols and electronic data capture systems have now been extensively field-tested for emergency evaluation of treatment with convalescent plasma. Ongoing studies seek to quantify the level of neutralizing antibodies in different plasma donations to determine whether this influences the response and survival of treated patients., (© The Author(s) 2016.)

Background: In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea., Methods: In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group., Results: A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed., Conclusions: The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union's Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171.).

The clinical evaluation of convalescent plasma (CP) for the treatment of Ebola virus disease (EVD) in the current outbreak, predominantly affecting Guinea, Sierra Leone, and Liberia, was prioritized by the World Health Organization in September 2014. In each of these countries, nonrandomized comparative clinical trials were initiated. The Ebola-Tx trial in Conakry, Guinea, enrolled 102 patients by 7 July 2015; no severe adverse reactions were noted. The Ebola-CP trial in Sierra Leone and the EVD001 trial in Liberia have included few patients. Although no efficacy data are available yet, current field experience supports the safety, acceptability, and feasibility of CP as EVD treatment. Longer-term follow-up as well as data from nontrial settings and evidence on the scalability of the intervention are required. CP sourced from within the outbreak is the most readily available source of anti-EVD antibodies. Until the advent of effective antivirals or monoclonal antibodies, CP merits further evaluation., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objective: Data on feasibility and completion rates of isoniazid preventive therapy (IPT) in HIV-infected patient in Asia are limited. Within a hospital-based HIV programme in Phnom Penh, Cambodia, we determined the proportion completing IPT and reasons for non-completion., Methods: Retrospective cohort study using HIV/IPT programme data, including all adults starting IPT (300 mg/day self-administered for 24 weeks) from February 2011 to March 2013. All patients underwent symptom screening and further investigations as indicated. After ruling out tuberculosis (TB), IPT was started, with monthly follow-up visits. As per national guideline, IPT was only prescribed for ART-naïve patients. IPT completion was defined as taking IPT for at least 22 of the planned 24 weeks. Stavudine/lamivudine/nevirapine was the preferential first-line ART regimen., Results: Among 445 ART-naïve patients starting IPT (median age: 35 years (IQR: 31-43), median CD4 count 354 cells/μl (IQR 215-545) and 288 (65%) were female), 214 (48%) started ART after a median of 4 weeks (IQR 2-6) on IPT ('concurrent ART'). Overall, 348 (78%) completed IPT. Among individuals with concurrent ART, the completion rate was 73% (157/214). Those without concurrent ART had a higher completion rate (83%; 191/231; P 0.017). The main reason for non-completion with concurrent ART was drug toxicity (mainly hepatotoxicity/rash), occurring in 22% (48/214). Without concurrent ART, the main reason for non-completion was loss to follow-up (16/231; 7%). Fourteen (3%) patients were diagnosed with TB while on IPT, of whom three had a positive TB culture at baseline. An additional 14 TB cases were diagnosed after IPT completion; four were bacteriologically confirmed., Conclusion: Although overall completion rates were acceptable, IPT discontinuation due to drug toxicity was common in patients subsequently initiating ART. Future studies should evaluate whether this relates to IPT, ARVs or both, and whether the increased toxicity would justify delaying IPT initiation until stabilisation on ART., (© 2015 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Objectives: Among patients with primary and relapse visceral leishmaniasis (VL) in eastern Sudan, we determined the proportion eligible for treatment with sodium stibogluconate and paromomycin (SSG/PM) and, of these, their demographic and clinical characteristics; initial treatment outcomes including adverse side effects requiring treatment discontinuation; treatment outcomes by 6 months; and risk factors associated with initial (slow responders) and late treatment failure (relapses and post-kala-azar dermal leishmaniasis, PKDL)., Methods: A retrospective cohort study in Tabarak Allah Hospital, Gedaref Province, eastern Sudan, from July 2011 to January 2014., Results: Of 1252 individuals diagnosed with VL (1151 primary and 101 relapses), 65% were eligible for SSG/PM including 83% children, almost half of them malnourished and anaemic. About 4% of individuals discontinued treatment due to side effects; 0.7% died during treatment. Initial cure was achieved in 93% of 774 primary cases and 77% of 35 relapse cases (P < 0.001). Among the 809 patients eligible for SSG/PM, 218 (27%) were lost to follow-up. Outcomes by six months among the 591 patients with available follow-up data were: definitive cure (n = 506; 86%), relapse (n = 38; 6%), treatment discontinuation (n = 33; 6%), PKDL (n = 7; 1%) and death (n = 7; 1%). Among those completing a full course of SSG/PM, relapses and under-fives were at significantly higher risk of early and late treatment failure, respectively., Conclusion: Whether SSG/PM as a first-line regimen is an undeniable progress compared to SSG monotherapy, it excluded a considerable proportion of VL patients due to drug safety concerns. We call for accelerated development of new drugs and treatment regimens to improve VL treatment in Sudan., (© 2015 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.)

Background: Early HIV diagnosis and enrolment in care is needed to achieve early antiretroviral treatment (ART) initiation. Studies on HIV disease stage at enrolment in care from Asian countries are limited. We evaluated trends in and factors associated with late HIV disease presentation over a ten-year period in the largest ART center in Cambodia., Methods: We conducted a retrospective analysis of program data including all ARV-naïve adults (> 18 years old) enrolling into HIV care from March 2003-December 2013 in a non-governmental hospital in Phnom Penh, Cambodia. We calculated the proportion presenting with advanced stage HIV disease (WHO clinical stage IV or CD4 cell count <100 cells/μL) and the probability of ART initiation by six months after enrolment. Factors associated with late presentation were determined using multivariate logistic regression., Results: From 2003-2013, a total of 5642 HIV-infected patients enrolled in HIV care. The proportion of late presenters decreased from 67% in 2003 to 44% in 2009 and 41% in 2013; a temporary increase to 52% occurred in 2011 coinciding with logistical/budgetary constraints at the national program level. Median CD4 counts increased from 32 cells/μL (IQR 11-127) in 2003 to 239 cells/μL (IQR 63-291) in 2013. Older age and male sex were associated with late presentation across the ten-year period. The probability of ART initiation by six months after enrolment increased from 22.6% in 2003-2006 to 79.9% in 2011-2013., Conclusion: Although a gradual improvement was observed over time, a large proportion of patients still enroll late, particularly older or male patients. Interventions to achieve early HIV testing and efficient linkage to care are warranted.

Background: Visceral leishmaniasis (VL) has become an important opportunistic infection in persons with HIV-infection in VL-endemic areas. The co-infection leads to profound immunosuppression and high rate of annual VL recurrence. This study assessed the effectiveness, safety and feasibility of monthly pentamidine infusions to prevent recurrence of VL in HIV co-infected patients., Methods: A single-arm, open-label trial was conducted at two leishmaniasis treatment centers in northwest Ethiopia. HIV-infected patients with a VL episode were included after parasitological cure. Monthly infusions of 4 mg/kg pentamidine-isethionate diluted in normal-saline were started for 12 months. All received antiretroviral therapy (ART). Time-to-relapse or death was the primary end point., Results: Seventy-four patients were included. The probability of relapse-free survival at 6 months and at 12 months was 79% and 71% respectively. Renal failure, a possible drug-related serious adverse event, occurred in two patients with severe pneumonia. Forty-one patients completed the regimen taking at least 11 of the 12 doses. Main reasons to discontinue were: 15 relapsed, five died and seven became lost to follow-up. More patients failed among those with a CD4+cell count ≤ 50 cells/μl, 5/7 (71.4%) than those with counts above 200 cells/μl, 2/12 (16.7%), (p = 0.005)., Conclusion: Pentamidine secondary prophylaxis led to a 29% failure rate within one year, much lower than reported in historical controls (50%-100%). Patients with low CD4+cell counts are at increased risk of relapse despite effective initial VL treatment, ART and secondary prophylaxis. VL should be detected and treated early enough in patients with HIV infection before profound immune deficiency installs.

Background: The World Health Organisation (WHO) introduced the twelve early warning indicators for monitoring and evaluating drug Procurement and Supply management (PSM) systems, intended to prevent drug stock-outs and overstocking. Nigeria--one of the high Multi Drug Resistant Tuberculosis (MDR-TB) burden countries, scaled-up treatment in 2012 with the concurrent implementation of a PSM system., Method: We evaluated how well this system functioned using the WHO indicators, including all seven MDR-TB treatment centres in the country that were functional throughout 2013., Results: The quantity of MDR-TB drugs ordered for 2013 matched the annual forecast and all central orders placed during the year were delivered in full and on time. Drug consumption was 81%-106% of the quantity allocated for routine consumption. Timely submission of complete inventory reports ranged from 86-100%, late submissions being 5-15 days late. Forty to 71% of treatment centres placed a drug order when stock was below the minimum level of three months. The proportion of drug orders received at the treatment centres in full and on time ranged from 29-80%, late orders being 1-19 days late., Conclusion: The PSM was found to be performing well in terms of forecasting and procurement of MDR-TB drugs, but there were shortcomings in drug distribution, reporting at treatment centre level and in drug order placements. Despite these gaps, there were no stock outs. These findings indicate that where it matters most, namely ensuring that no drug stock outs affect patient management, the PSM system is effective. Addressing the observed shortcomings will help to strengthen the existing PSM system in anticipation of a growing MDR-TB case burden in the country.