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  • 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; van Griensven, J; Zijlstra, EE; Wasunna, M; Alves, F; Alvar, J; Hailu, A; Alexander, N; Blesson, S (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; Soipei, P; Mutinda, B; Omollo, R; Kimutai, R; Omwalo, G; Wasunna, M; Tadesse, F; Alves, F; Strub-Wourgaft, N; Hailu, A; Alexander, N; Alvar, J (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; Hassen, A; Mulugeta, A (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; Balasegaram, M; Bern, C; Hightower, A; Rijal, S; Ellis, S; Sunyoto, T; Burza, S; Lima, N; Das, P; Alvar, J (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; Picado, A; Boelaert, M (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; Diro, E (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.
  • A Clinical Severity Scoring System for Visceral Leishmaniasis in Immunocompetent Patients in South Sudan

    Kämink, SS; Collin, SM; Harrison, T; Gatluak, F; Mullahzada, AW; Ritmeijer, K (Public Library of Science, 2017-10-02)
    South Sudan is one of the most endemic countries for visceral leishmaniasis (VL), and is frequently affected by large epidemics. In resource-limited settings, clinicians require a simple clinical tool to identify VL patients who are at increased risk of dying, and who need specialised treatment with liposomal amphotericin B and other supportive care. The aim of this study was to develop and validate a clinical severity scoring system based on risk factors for death in VL patients in South Sudan.
  • Long-term Clinical Outcomes in Visceral Leishmaniasis-HIV Co-infected Patients during and after Pentamidine Secondary Prophylaxis in Ethiopia: a single-arm clinical trial

    Diro, E; Ritmeijer, K; Boelaert, M; Alves, F; Mohammed, R; Abongomera, C; Ravinetto, R; De Crop, M; Fikre, H; Adera, C; van Loen, H; Tsoumanis, A; Adriaensen, W; Hailu, A; van Griensven, J (Oxford University Press, 2017-09-13)
    We have conducted a single-arm trial evaluating monthly pentamidine secondary prophylaxis (PSP) to prevent visceral leishmaniasis (VL) relapse in Ethiopian HIV-patients. Outcomes at 12 months of PSP have been previously reported, supporting PSP effectiveness and safety. However, remaining relapse-free after PSP discontinuation is vital. We now report outcomes and associated factors for a period of upto 2.5 years after initiating PSP, including one year follow-up after PSP discontinuation.
  • The Risk and Predictors of Visceral Leishmaniasis Relapse in HIV Co-infected Patients in Ethiopia: A Retrospective Cohort Study

    Abongomera, C; Diro, E; Vogt, F; Tsoumanis, A; Mekonnen, Z; Admassu, H; Colebunders, R; Mohammed, R; Ritmeijer, K; van Griensven, J (Oxford University Press, 2017-07-20)
  • Development and External Validation of a Clinical Prognostic Score for Death in Visceral Leishmaniasis Patients in a High HIV Co-Infection Burden Area in Ethiopia

    Abongomera, C; Ritmeijer, K; Vogt, F; Buyze, J; Mekonnen, Z; Admassu, H; Colebunders, R; Mohammed, R; Lynen, L; Diro, E; van Griensven, J (Public Library of Science, 2017-06-05)
    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.
  • Visceral Leishmaniasis in Somalia: A Review of Epidemiology and Access to Care

    Sunyoto, T; Potet, J; Boelaert, M (Public Library of Science, 2017-03-09)
    Somalia, ravaged by conflict since 1991, has areas endemic for visceral leishmaniasis (VL), a deadly parasitic disease affecting the rural poor, internally displaced, and pastoralists. Very little is known about VL burden in Somalia, where the protracted crisis hampers access to health care. We reviewed evidence about VL epidemiology in Somalia and appraised control options within the context of this fragile state's health system. VL has been reported in Somalia since 1934 and has persisted ever since in foci in the southern parts of the country. The only feasible VL control option is early diagnosis and treatment, currently mostly provided by nonstate actors. The availability of VL care in Somalia is limited and insufficient at best, both in coverage and quality. Precarious security remains a major obstacle to reach VL patients in the endemic areas, and the true VL burden and its impact remain unknown. Locally adjusted, innovative approaches in VL care provision should be explored, without undermining ongoing health system development in Somalia. Ensuring VL care is accessible is a moral imperative, and the limitations of the current VL diagnostic and treatment tools in Somalia and other endemic settings affected by conflict should be overcome.
  • Does Timing of Antiretroviral Treatment Influence Treatment Outcomes of Visceral Leishmaniasis in Northwest Ethiopia?

    Aderie, E; Diro, E; Zachariah, R; da Fonseca, M; Abongomera, C; Dolamo, B; Ritmeijer, K (Oxford University Press, 2017-03-01)
    Visceral leishmaniasis (VL) patients with HIV co-infection should receive antiretroviral treatment (ART). However, the best timing for initiation of ART is not known. Among such individuals, we assessed the influence of ART timing on VL outcomes.
  • Safety and Effectiveness of Sodium Stibogluconate and Paromomycin Combination for the Treatment of Visceral Leishmaniasis in Eastern Africa: Results from a Pharmacovigilance Programme

    Kimutai, R; Musa, AM; Njoroge, S; Omollo, R; Alves, F; Hailu, A; Khalil, EAG; Diro, E; Soipei, P; Musa, B; Salman, K; Ritmeijer, K; Chappuis, F; Rashid, J; Mohammed, R; Jameneh, A; Makonnen, E; Olobo, J; Okello, L; Sagaki, P; Strub, N; Ellis, S; Alvar, J; Balasegaram, M; Alirol, E; Wasunna, M (Springer Link, 2017-01-09)
    In 2010, WHO recommended a new first-line treatment for visceral leishmaniasis (VL) in Eastern Africa. The new treatment, a combination of intravenous (IV) or intramuscular (IM) sodium stibogluconate (SSG) and IM paromomycin (PM) was an improvement over SSG monotherapy, the previous first-line VL treatment in the region. To monitor the new treatment's safety and effectiveness in routine clinical practice a pharmacovigilance (PV) programme was developed.
  • A Comparison of the Effectiveness of Sodium Stibogluconate Monotherapy to Sodium Stibogluconate and Paromomycin Combination for the Treatment of Severe Post Kala Azar Dermal Leishmaniasis in South Sudan - A Retrospective Cohort Study

    Abongomera, C; Gatluak, F; Buyze, J; Ritmeijer, K (Public Library of Science (PLoS), 2016-09-22)
    Post-kala-azar dermal leishmaniasis (PKDL) is a common dermatological complication following successful treatment of Visceral Leishmaniasis (VL) caused by Leishmania donovani. PKDL presents as macular, papular, nodular or mixed skin rash on sun-exposed body parts. Patients are not ill unless there are complications due to mucosal involvement or ulceration. As PKDL in East Africa is typically self-healing, and treatment is long and with significant adverse events, only severe and complicated cases are treated. Studies to determine optimal treatment of PKDL are rare and based on small cohorts. Since 1989, Médecins Sans Frontières is treating severe PKDL within VL treatment programmes in South Sudan. Treatment was initially with sodium stibogluconate (SSG) monotherapy and since 2002 with a combination of SSG and paromomycin (PM). SSG monotherapy (20 mg/kg/day for a minimum of 30 days) was provided in primary health units, and the combination of PM (15 mg sulphate/kg/day for 17 days) plus SSG (30 mg/kg/day for a minimum of 17 days) was provided in secondary health facilities.

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