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  • Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis

    Abongomera, C; van Henten, S; Vogt, F; Buyze, J; Verdonck, K; van Griensven, J (Public Library of Science, 2020-05-15)
    Background Visceral leishmaniasis (VL) is a vector-borne disease that is deadly if left untreated. Understanding which factors have prognostic value may help to focus clinical management and reduce case fatality. However, information about prognostic factors is scattered and conflicting. We conducted a systematic review and meta-analysis to identify prognostic factors for mortality among VL patients in East Africa. Methodology/Principal findings The review protocol was registered in PROSPERO (CRD42016043112). We included studies published in English after 1970 describing VL patients treated in East African health facilities. To be included, studies had to report on associations between clinical or laboratory factors and mortality during admission or during VL treatment, with a minimal study size of ten patients. Conference abstracts and evaluations of genetic or immunological prognostic factors were excluded. We searched for studies in MEDLINE and four other databases in December 2018. To assess the risk of bias in observational studies and clinical trials, we used the Quality in Prognostic Studies (QUIPS) tool. We included 48 studies in the systematic review, describing 150,072 VL patients of whom 7,847 (5.2%) died. Twelve prognostic factors were evaluated in five or more studies and these results were submitted to meta-analysis producing one pooled crude odds ratio (OR) per prognostic factor. The following factors were strongly (OR>3) and significantly (P-value<0.05) associated with mortality: jaundice (OR = 8.27), HIV (OR = 4.60), tuberculosis (OR = 4.06), age >45 years (OR = 3.69), oedema (OR = 3.52), bleeding (OR = 3.37), and haemoglobin ≤6.5 g/dl (OR = 3.26). Factors significantly and moderately (OR between one and three) associated with death were severe malnutrition, long duration of illness, young age (<5 years), and large spleen size. Conclusions/Significance These prognostic factors can be identified by health professionals in resource-constrained settings. They should be considered as “core” prognostic factors in future studies that aim at improving the prognosis of VL patients.
  • Prognostic factors for mortality among patients with visceral leishmaniasis in East Africa: Systematic review and meta-analysis

    Abongomera, C; van Henten, S; Vogt, F; Buyze, J; Verdonck, K; van Griensven, J (Public Library of Sciences, 2020-05-15)
    Background: Visceral leishmaniasis (VL) is a vector-borne disease that is deadly if left untreated. Understanding which factors have prognostic value may help to focus clinical management and reduce case fatality. However, information about prognostic factors is scattered and conflicting. We conducted a systematic review and meta-analysis to identify prognostic factors for mortality among VL patients in East Africa. Methodology/principal findings: The review protocol was registered in PROSPERO (CRD42016043112). We included studies published in English after 1970 describing VL patients treated in East African health facilities. To be included, studies had to report on associations between clinical or laboratory factors and mortality during admission or during VL treatment, with a minimal study size of ten patients. Conference abstracts and evaluations of genetic or immunological prognostic factors were excluded. We searched for studies in MEDLINE and four other databases in December 2018. To assess the risk of bias in observational studies and clinical trials, we used the Quality in Prognostic Studies (QUIPS) tool. We included 48 studies in the systematic review, describing 150,072 VL patients of whom 7,847 (5.2%) died. Twelve prognostic factors were evaluated in five or more studies and these results were submitted to meta-analysis producing one pooled crude odds ratio (OR) per prognostic factor. The following factors were strongly (OR>3) and significantly (P-value<0.05) associated with mortality: jaundice (OR = 8.27), HIV (OR = 4.60), tuberculosis (OR = 4.06), age >45 years (OR = 3.69), oedema (OR = 3.52), bleeding (OR = 3.37), and haemoglobin ≤6.5 g/dl (OR = 3.26). Factors significantly and moderately (OR between one and three) associated with death were severe malnutrition, long duration of illness, young age (<5 years), and large spleen size. Conclusions/significance: These prognostic factors can be identified by health professionals in resource-constrained settings. They should be considered as "core" prognostic factors in future studies that aim at improving the prognosis of VL patients.
  • Male predominance in reported Visceral Leishmaniasis cases: Nature or nurture? A comparison of population-based with health facility-reported data

    Cloots, K; Burza, S; Malaviya, P; Hasker, E; Kansal, S; Mollett, G; Chakravarty, J; Roy, N; Lal, BK; Rijal, S; et al. (Public Library of Science, 2020-01-29)
    BACKGROUND: Bangladesh, India, and Nepal aim for the elimination of Visceral Leishmaniasis (VL), a systemic parasitic infectious disease, as a public health problem by 2020. For decades, male patients have comprised the majority of reported VL cases in this region. By comparing this reported VL sex ratio to the one observed in population-based studies conducted in the Indian subcontinent, we tested the working hypothesis that mainly socio-cultural gender differences in healthcare-seeking behavior explain this gender imbalance. METHODOLOGY/PRINCIPAL FINDINGS: We compared the observed sex ratio of male versus female among all VL cases reported by the health system in Nepal and in the two most endemic states in India with that observed in population-based cohort studies in India and Nepal. Also, we assessed male sex as a potential risk factor for seroprevalence at baseline, seroconversion, and VL incidence in the same population-based data. The male/female ratio among VL cases reported by the health systems was 1.40 (95% CI 1.37-1.43). In the population cohort data, the age- and study site-adjusted male to female risk ratio was 1.27 (95% CI 1.08-1.51). Also, males had a 19% higher chance of being seropositive at baseline in the population surveys (RR 1.19; 95% CI 1.11-1.27), while we observed no significant difference in seroconversion rate between both sexes at the DAT cut-off titer defined as the primary endpoint. CONCLUSIONS/SIGNIFICANCE: Our population-based data show that male sex is a risk factor for VL, and not only as a socio-cultural determinant. Biological sex-related differences likely play an important role in the pathogenesis of this disease.
  • Outcomes of visceral leishmaniasis in pregnancy: A retrospective cohort study from South Sudan

    Pekelharing, JE; Gatluak, F; Harrison, T; Maldonado, F; Siddiqui, MR; Ritmeijer, K (Public Library of Science, 2020-01-24)
    INTRODUCTION: Visceral leishmaniasis (VL) is endemic in South Sudan, where outbreaks occur frequently. Because of changes in the immune system during pregnancy, pregnant women are considered particularly vulnerable for developing complications of VL disease, including opportunistic infections. There is limited evidence available about clinical aspects and treatment outcomes of VL in pregnancy. We describe characteristics, maternal and pregnancy outcomes from a cohort of pregnant women with VL. METHODS: We conducted a retrospective analysis using routine programme data from a MSF health facility in Lankien, Jonglei State, South Sudan, between Oct 2014 and April 2018. Records were extracted of women diagnosed with VL while pregnant, and those symptomatic during pregnancy but diagnosed during the first two weeks postpartum. Records were matched with a random sample of non-pregnant women of reproductive age (15-45 years) with VL from the same period. RESULTS: We included 113 women with VL in pregnancy, and 223 non-pregnant women with VL. Women with VL in pregnancy presented with more severe anaemia, were more likely to need blood transfusion (OR 9.3; 95%CI 2.5-34.2) and were more often prescribed antibiotics (OR 6.0; 95%CI 3.4-10.6), as compared to non-pregnant women with VL. Adverse pregnancy outcomes, including miscarriage and premature delivery, were reported in 20% (16/81) where VL was diagnosed in pregnancy, and 50% 13/26) where VL was diagnosed postpartum. Postpartum haemorrhage was common. Pregnant women were more likely to require extension of treatment to achieve cure (OR 10.0; 95%CI 4.8-20.9), as compared to non-pregnant women with VL. Nevertheless, overall initial cure rates were high (96.5%) and mortality was low (1.8%) in this cohort of pregnant women with VL. CONCLUSION: This is the largest cohort in the literature of VL in pregnancy. Our data suggest that good maternal survival rates are possible in resource-limited settings, despite the high incidence of complications.
  • Failure of an Innovative Low-Cost, Noninvasive Thermotherapy Device for Treating Cutaneous Leishmaniasis Caused by in Pakistan.

    Kamink, S; Abdi, A; Kamau, C; Ashraf, S; Ansari, MA; Qureshi, NA; Schallig, H; Grobusch, MB; Fernhout, J; Ritmeijer, K (The American Society of Tropical Medicine and Hygiene, 2019-10-07)
    Cutaneous leishmaniasis (CL), a neglected parasitic skin disease, is endemic in Pakistan, where Leishmania tropica and Leishmania major are the causative protozoan species. Standard treatment with antimonial injections is long, painful, and costly; has toxic side effects; and is not always available in public hospitals. Small pilot studies have previously evaluated a low-cost and noninvasive hand-held exothermic crystallization thermotherapy (HECT-CL) device. We aimed to further establish the effectiveness, safety, and feasibility of HECT-CL in L. tropica. In a prospective observational study, patients with parasitological confirmation of CL were treated using the HECT-CL heat pack for 3 minutes with an initial temperature of 52-53°C for 7 consecutive days. Dried blood spot samples were taken for species identification by PCR. Effectiveness was assessed by using medical photographs and measurements of the lesion size at baseline and subsequent follow-up visits, for up to 180 days. We intended to enroll 317 patients. The HECT-CL treatment was easy to apply and well tolerated. Species identification demonstrated the presence of L. tropica. Interim analysis of 56 patients showed a failure rate of 91% at follow-up (median 45 days after treatment, interquartile range 30-60 days). Enrollment of patients was prematurely suspended because of futility. This study showed a high failure rate for HECT-CL thermotherapy in this setting. Leishmania tropica is known to be less sensitive to antileishmanial drugs, more temperature-resistant, and spontaneous healing is slower than that in L. major. More research is needed to identify low-cost, effective, and more patient-friendly treatment for L. tropica.
  • Field effectiveness of new visceral leishmaniasis regimens after 1 year following treatment within public health facilities in Bihar, India

    Goyal, V; Burza, S; Pandey, K; Singh, SN; Singh, RS; Strub-Wourgaft, N; Das, VNR; Bern, C; Hightower, A; Rijal, S; et al. (The Public Library of Science, 2019-09-26)
    BACKGROUND: An earlier open label, prospective, non-randomized, non-comparative, multi-centric study conducted within public health facilities in Bihar, India (CTRI/2012/08/002891) measured the field effectiveness of three new treatment regimens for visceral leishmaniasis (VL): single dose AmBisome (SDA), and combination therapies of AmBisome and miltefosine (AmB+Milt) and miltefosine and paromomycin (Milt+PM) up to 6 months follow-up. The National Vector Borne Disease Control Program (NVBDCP) recommended an extended follow up at 12 months post-treatment of the original study cohort to quantify late relapses. METHODS: The 1,761 patients enrolled in the original study with the three new regimens were contacted and traced between 10 and 36 months following completion of treatment to determine their health status and any occurrence of VL relapse. RESULTS: Of 1,761 patients enrolled in the original study, 1,368 were traced at the extended follow-up visit: 711 (80.5%), 295 (83.2%) and 362 (71.5%) patients treated with SDA, AmB+Milt and Milt+PM respectively. Of those traced, a total of 75 patients were reported to have relapsed by the extended follow-up; 45 (6.3%) in the SDA, 25 (8.5%) in the AmB+Milt and 5 (1.4%) in the Milt+PM arms. Of the 75 relapse cases, 55 had already been identified in the 6-months follow-up and 20 were identified as new cases of relapse at extended follow-up; 7 in the SDA, 10 in the AmB+Milt and 3 in the Milt+PM arms. CONCLUSION: Extending follow-up beyond the standard 6 months identified additional relapses, suggesting that 12-month sentinel follow-up may be useful as a programmatic tool to better identify and quantify relapses. With limited drug options, there remains an urgent need to develop effective new chemical entities (NCEs) for VL.
  • Epidemiological and molecular investigation of resurgent cutaneous leishmaniasis in Sudan.

    Collis, S; El-Safi, S; Atia, AA; Bhattacharyya, T; Hammad, A; Den Boer, M; Le, H; Whitworth, JA; Miles, MA (Elsevier, 2019-08-20)
    OBJECTIVES: Local health personnel have drawn attention to an apparent increase in incidence and severity of cutaneous leishmaniasis (CL) in Sudan. The objective of this study was to investigate CL burden and surveillance. METHODS: Surveillance data were compiled from the KalaCORE programme, Leishmania coordinators in Northern Kordofan and Southern Darfur, and Khartoum Dermatology Hospital. CL lesions were sampled from 14 suspected cases from Northern Kordofan and the Hospital for Tropical Diseases in Omdurman. PCR-restriction fragment length polymorphism analysis and multilocus sequencing were used to characterize the disease agent. RESULTS: All sites reported substantial increases from 2014 to 2016/7, far exceeding World Health Organization case reports for 2014, consistent with a widespread outbreak. Single seasonal peak incidence was observed, except for two peaks in Southern Darfur. In Northern Kordofan, the odds ratio for CL in the 35-44 years age group was 2.6 times higher than in the >45 years age group (p<0.0001); in Southern Darfur, the OR was 2.38 greater in males than females (p<0.0001). Lesions included severe presentations, despite chemotherapy. Leishmania major was identified as the agent. CONCLUSIONS: Active surveillance is required to understand the extent of CL in Sudan, as well as training to standardize surveillance, diagnosis, reporting, and quality control. Point-of-care rapid diagnosis would be valuable. Genotyping and phenotyping are required to monitor the emergence of pathogenic strains, drug resistance, outbreaks, and changes in severity.
  • Exploring global and country-level barriers to an effective supply of leishmaniasis medicines and diagnostics in eastern Africa: a qualitative study.

    Sunyoto, T; Potet, J; den Boer, M; Ritmeijer, K; Postigo, JAR; Ravinetto, R; Alves, F; Picado, A; Boelaert, M (BMJ Publishing Group, 2019-05-30)
    OBJECTIVES: To understand stakeholders' perceptions of the access barriers to quality-assured diagnostics and medicines for leishmaniasis in the high-burden region of eastern Africa, and to identify key bottlenecks to improve the supply of commodities for neglected tropical diseases. DESIGN: Desk reviews and qualitative in-depth interview study with purposive sampling. METHODS: A landscape analysis through literature and desk review was performed. Next, 29 representatives from international organisations, non-governmental agencies, national control programmes from six countries (Ethiopia, Kenya, Somalia, South Sudan, Sudan and Uganda) and manufacturers were interviewed between May and July 2018. Participants were selected purposively and expanded through a snowballing technique.Data analysis was aided by NVivo, applying the framework method as a part of the thematic content analysis approach. RESULTS: The barriers along the visceral leishmaniasis (VL) supply chain were identified as emerging themes, grouped across supply chain activities and health systems component(s). Stakeholders expressed the perception of progress, but bottlenecks persist. VL medicines, in general, lack multisource production capacity and with small market volume, expansion of suppliers is difficult. Procurement is plagued by forecasting difficulties, complex regulatory policies and procedures, and distribution challenges. Weak communication and coordination across different levels resulted in shortages and loss of trust among different actors. Cross-cutting issues spanned from limited political and resource commitment due to low awareness and limited in-country capacity. However, study respondents were optimistic to pursue several remedies, most importantly to build bridges between supply and demand sides through continued dialogue and collaborations. Diagnostics supply has mostly been overlooked; thus, improved investment in this area is needed. CONCLUSIONS: Addressing supply barriers in eastern Africa requires consistent, specific efforts at the global and national levels, progressing from current partnerships and agreements. Priority actions include pooled procurement, improved forecast, and increased commitment and resources. Sustainability remains an elusive goal, yet to be integrated into discussions moving forward.
  • Long term outcomes and prognostics of visceral leishmaniasis in HIV infected patients with use of pentamidine as secondary prophylaxis based on CD4 level: a prospective cohort study in Ethiopia

    Diro, E; Edwards, T; Ritmeijer, K; Fikre, H; Abongomera, c; Kibret, A; Bardonneau, C; Soipei, P; Mutinda, B; Omollo, R; et al. (Public Library of Science, 2019-02-21)
    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.
  • Severe post-kala-azar dermal leishmaniasis successfully treated with miltefosine in an Ethiopian HIV patient.

    Abongomera, C; Battaglioli, T; Adera, C; Ritmeijer, K (Elsevier, 2019-02-18)
    Post-kala-azar dermal leishmaniasis (PKDL) is a neglected tropical disease characterized by a dermatosis which often appears after successful treatment of visceral leishmaniasis caused by Leishmania donovani. PKDL treatment options are few and have severe limitations. In East- Africa, the standard treatment of PKDL is with daily painful potentially toxic sodium stibogluconate injections, administered for a prolonged duration of 30-60 days. In the Indian subcontinent, PKDL is mainly treated with miltefosine, a safer orally administered drug. However, in East-Africa, there is very limited experience in the use of miltefosine for treatment of severe PKDL, with only one published case report. Here we report a severe PKDL case in an Ethiopian HIV patient successfully treated with oral miltefosine (100 milligrams/day for 28 days). Miltefosine was efficacious, safe and well tolerated, suggesting that it can play an important role in the treatment of severe PKDL also in East-African patients. Further research is warranted.
  • A Randomized Trial of AmBisome Monotherapy and AmBisome and Miltefosine Combination to Treat Visceral leishmaniasis in HIV Co-infected Patients in Ethiopia

    Diro, E; Blesson, S; Edwards, T; Ritmeijer, K; Fikre, H; Admassu, H; Kibret, A; Ellis, SJ; Bardonneau, C; Zijlstra, EE; et al. (Public Library of Science, 2019-01-17)
    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.
  • Barriers to access to visceral leishmaniasis diagnosis and care among seasonal mobile workers in Western Tigray, Northern Ethiopia: A qualitative study

    Coulborn, RM; Gebrehiwot, TG; Schneider, M; Gerstl, S; Adera, C; Herrero, M; Porten, K; den Boer, M; Ritmeijer, K; Alvar, J; et al. (PLoS, 2018-11-08)
    Ethiopia bears a high burden of visceral leishmaniasis (VL). Early access to VL diagnosis and care improves clinical prognosis and reduces transmission from infected humans; however, significant obstacles exist. The approximate 250,000 seasonal mobile workers (MW) employed annually in northwestern Ethiopia may be particularly disadvantaged and at risk of VL acquisition and death. Our study aimed to assess barriers, and recommend interventions to increase access, to VL diagnosis and care among MWs.
  • Uncharted territory of the epidemiological burden of cutaneous leishmaniasis in sub-Saharan Africa-A systematic review

    Sunyoto, T; Verdonck, K; El Safi, S; Potet, J; Picado, A; Boelaert, M (Public Library of Science, 2018-10-25)
    Cutaneous leishmaniasis (CL) is the most frequent form of leishmaniasis, with 0.7 to 1.2 million cases per year globally. However, the burden of CL is poorly documented in some regions. We carried out this review to synthesize knowledge on the epidemiological burden of CL in sub-Saharan Africa.
  • Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India

    Goyal, Vi; Mahajan, R; Pandey, K; Singh, SN; Singh, RS; Strub-Wourgaft, N; Alves, F; Rabi Das, VN; Topno, RK; Sharma, B; et al. (Public Library of Science, 2018-10-22)
    In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions.
  • Leishmaniasis

    Burza, S; Croft, SL; Boelaert, M (Elsevier, 2018-08-17)
    Leishmaniasis is a poverty-related disease with two main clinical forms: visceral leishmaniasis and cutaneous leishmaniasis. An estimated 0·7-1 million new cases of leishmaniasis per year are reported from nearly 100 endemic countries. The number of reported visceral leishmaniasis cases has decreased substantially in the past decade as a result of better access to diagnosis and treatment and more intense vector control within an elimination initiative in Asia, although natural cycles in transmission intensity might play a role. In east Africa however, the case numbers of this fatal disease continue to be sustained. Increased conflict in endemic areas of cutaneous leishmaniasis and forced displacement has resulted in a surge in these endemic areas as well as clinics across the world. WHO lists leishmaniasis as one of the neglected tropical diseases for which the development of new treatments is a priority. Major evidence gaps remain, and new tools are needed before leishmaniasis can be definitively controlled.
  • New insights into leishmaniasis in the immunosuppressed

    Akuffo, H; Costa, C; van Griensven, J; Burza, S; Moreno, J; Herrero, M (Public Library of Science, 2018-05-10)
    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.
  • Why miltefosine-a life-saving drug for leishmaniasis-is unavailable to people who need it the most

    Sunyoto, T; Potet, J; Boelaert, M (BMJ Publishing Group, 2018-05-03)
    Miltefosine, the only oral drug approved for the treatment of leishmaniasis-a parasitic disease transmitted by sandflies-is considered as a success story of research and development (R&D) by a public-private partnership (PPP). It epitomises the multiple market failures faced by a neglected disease drug: patients with low ability to pay, neglect by authorities and uncertain market size. Originally developed as an anticancer agent in the 1990s, the drug was registered in India in 2002 to treat the fatal visceral leishmaniasis. At the time, miltefosine was considered a breakthrough in the treatment, making it feasible to eliminate a regional disease. Today, access to miltefosine remains far from secure. The initial PPP agreement which includes access to the public sector is not enforced. The reality on the ground has been challenging: shortages due to inefficient supply chains, and use of a substandard product which led to a high number of treatment failures and deaths. Miltefosine received orphan drug status in the USA; when it was registered there in 2014, a priority review voucher (PRV) was awarded. The PRV, meant to facilitate drug development for neglected disease, was subsequently sold to another company for US$125 million without, to date, any apparent impact on drug access. At the heart of these concerns are questions on how to protect societal benefit of a drug developed with public investment, while clinicians worldwide struggle with its lack of affordability, limited availability and sustainability of access. This article analyses the reasons behind the postregistration access failure of miltefosine and provides the lessons learnt.
  • "Kala-Azar is a Dishonest Disease": Community Perspectives on Access Barriers to Visceral Leishmaniasis (Kala-Azar) Diagnosis and Care in Southern Gadarif, Sudan

    Sunyoto, T; Adam, GK; Atia, AM; Hamid, Y; Babiker, RA; Abdelrahman, N; Vander Kelen, C; Ritmeijer, K; Alcoba, G; den Boer, M; et al. (American Society of Tropical Medicine and Hygiene, 2018-04-13)
    Early diagnosis and treatment is the principal strategy to control visceral leishmaniasis (VL), or kala-azar in East Africa. As VL strikes remote rural, sparsely populated areas, kala-azar care might not be accessed optimally or timely. We conducted a qualitative study to explore access barriers in a longstanding kala-azar endemic area in southern Gadarif, Sudan. Former kala-azar patients or caretakers, community leaders, and health-care providers were purposively sampled and thematic data analysis was used. Our study participants revealed the multitude of difficulties faced when seeking care. The disease is well known in the area, yet misconceptions about causes and transmission persist. The care-seeking itineraries were not always straightforward: "shopping around" for treatments are common, partly linked to difficulties in diagnosing kala-azar. Kala-azar is perceived to be "hiding," requiring multiple tests and other diseases must be treated first. Negative perceptions on quality of care in the public hospitals prevail, with the unavailability of drugs or staff as the main concern. Delay to seek care remains predominantly linked to economic constraint: albeit treatment is for free, patients have to pay out of pocket for everything else, pushing families further into poverty. Despite increased efforts to tackle the disease over the years, access to quality kala-azar care in this rural Sudanese context remains problematic. The barriers explored in this study are a compelling reminder of the need to boost efforts to address these barriers.
  • Leishmania Antigenuria to Predict Initial Treatment Failure and Relapse in Visceral Leishmaniasis/HIV Coinfected Patients: An Exploratory Study Nested Within a Clinical Trial in Ethiopia

    van Griensven, J; Mengesha, B; Mekonnen, T; Fikre, H; Takele, Y; Adem, E; Mohammed, R; Ritmeijer, K; Vogt, F; Adriaensen, W; et al. (Frontiers Media, 2018-03-29)
    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.
  • Safety and effectiveness of short-course AmBisome in the treatment of Post-Kala-azar Dermal Leishmaniasis (PKDL): a prospective cohort study in Bangladesh

    den Boer, M; Das, Asish K; Akhter, F; Burza, S; Ramesh, V; Ahmed, BN; Zijlstra, EE; Ritmeijer, K (Oxford University Press, 2018-03-15)
    A safe and effective short-course treatment regimen for Post Kala Azar Dermal Leishmaniasis (PKDL) is considered essential for achieving and sustaining elimination of visceral leishmaniasis (VL) in the Indian subcontinent.(1, 2) Here, single dose liposomal amphotericin B (AmBisome) has been adopted as a first line regimen for VL; however the effectiveness and safety of AmBisome for PKDL has not been formally evaluated.

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