• Diagnostic accuracy of two rK39 antigen-based dipsticks and the formol gel test for rapid diagnosis of visceral leishmaniasis in northeastern Uganda.

      Chappuis, F; Mueller, Y; Nguimfack, A; Rwakimari, J; Couffignal, S; Boelaert, M; Cavailler, P; Loutan, L; Piola, P; Travel and Migration Medicine Unit, Geneva University Hospital, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland. francois.chappuis@hcuge.ch (American Society for Microbiology, 2005-12)
      The development of an accurate, practical, and affordable diagnostic test is essential to improve the management of visceral leishmaniasis (VL) in remote health centers. We evaluated the Formol Gel test (FGT) and two rK39 antigen-based dipsticks, the DUAL-IT L/M, and the Kalazar Detect for VL diagnosis in Amudat Hospital in Uganda. The DUAL-IT L/M was also evaluated for the diagnosis of malaria. All patients clinically suspect of VL were prospectively included in the study between October 2003 and March 2004. The gold standard used to define a VL case was a positive spleen aspirate or a direct agglutination test titer of >1:12,800 with an appropriate clinical response to antileishmanial therapy. A total of 131 VL and 112 non-VL patients were included in the analysis. The DUAL IT L/M was found to be more sensitive than the Kalazar Detect: 97% (95% confidence interval [95%CI] = 92 to 99%) versus 82% (95%CI = 74 to 87%). The Kalazar Detect and the DUAL IT L/M were highly specific (99% [95%CI = 95 to 100%] and 97% [95%CI = 92 to 99%], respectively). The FGT lacked both sensitivity (66% [95%CI = 57 to 73%]) and specificity (90% [95%CI = 83 to 94%]). The sensitivity of the DUAL IT L/M for malaria was only 57% (95%CI = 37 to 76%). The two rK39 dipsticks can be used for diagnostic confirmation of VL in this region. The DUAL-IT L/M without its malaria diagnostic component (DiaMed-IT LEISH) will be adopted as first-line test for VL in Uganda.
    • Drug policy for visceral leishmaniasis: a cost-effectiveness analysis.

      Vanlerberghe, V; Diap, G; Guerin, P J; Meheus, F; Gerstl, S; Van der Stuyft, P; Boelaert, M; Epidemiology and Disease Control Unit, Prince Leopold Institute of Tropical Medicine, Antwerp, Belgium. vvanlerberghe@itg.be (2007-02)
      OBJECTIVE: To facilitate the choice of the best visceral leishmaniasis (VL) treatment strategy for first-line health services in (VL)-endemic areas, we compared in a formal decision analysis the cost and the cost-effectiveness of the different available options. METHODS: We selected four drug regimens for VL on the basis of frequency of use, feasibility and reported efficacy studies. The point estimates and the range of plausible values of effectiveness and cost were retrieved from a literature review. A decision tree was constructed and the strategy minimizing the cost per death averted was selected. RESULTS: Treatment with amphotericin B deoxycholate was the most effective approach in the baseline analysis and averted 87.2% of all deaths attributable to VL. The least expensive and the most cost-effective treatment was the miltefosine regimen, and the most expensive and the least cost-effective was AmBisome treatment. The cost of drug and medical care are the main determinants of the cost-effectiveness ranking of the alternative schemes. Sensitivity analysis showed that antimonial was competitive with miltefosine in the low-resistance regions. CONCLUSION: In areas with >94% response rates to antimonials, generic sodium stibogluconate remains the most cost-effective option for VL treatment, mainly due to low drug cost. In other regions, miltefosine is the most cost-effective option of treatment, but its use as a first-line drug is limited by its teratogenicity and rapid resistance development. AmBisome in mono- or combination therapy is too expensive to compete in cost-effectiveness with the other regimens.
    • Epidemiology and Clinical Features of Patients with Visceral Leishmaniasis Treated by an MSF Clinic in Bakool Region, Somalia, 2004-2006.

      Raguenaud, M E; Jansson, A; Vanlerberghe, V; Van der Auwera, G; Deborggraeve, S; Dujardin, J C C; Orfanos, G; Reid, T; Boelaert, M; Médecins Sans Frontières, Medical Department, Brussels, Belgium. (Public Library of Science, 2007)
      BACKGROUND: There are few reports describing the epidemiology of visceral leishmaniasis (VL) in Somalia. Over the years 2002 to 2005, a yearly average of 140 patients were reported from the Huddur centre in Bakool region, whereas in 2006, this number rose to 1002 patients. Given the limited amount of information on VL and the opportunity to compare features with the studies done in 2000 in this part of Somalia, we describe the epidemiologic and clinical features of patients who presented to the Huddur treatment centre of Bakool region, Somalia, using data routinely collected over a five-year observation period (2002-2006). METHODOLOGY: Methods used included the analysis of routine data on VL cases treated in the Huddur treatment centre, a retrospective study of records of patients admitted between 2004 and 2006, community leaders interviews, and analysis of blood specimens taken for parasite species identification in Antwerp Institute of Tropical Medicine. PRINCIPAL FINDINGS: A total of 1671 VL patients were admitted to the Huddur centre from January 2002 until December 2006. Nearly all patients presented spontaneously to the health centre. Since 2002, the average patient load was stable, with an average of 140 admissions per year. By the end of 2005, the number of admissions dramatically increased to reach a 7-fold increase in 2006. The genotype of L. donovani identified in 2006 was similar to the one reported in 2002. 82% of total patients treated for VL originated from two districts of Bakool region, Huddur and Tijelow districts. Clinical recovery rate was 93.2% and case fatality rate 3.9%. CONCLUSIONS: After four years of low but constant VL case findings, a major increase in VL was observed over a 16-month period in the Huddur VL centre. The profile of the patients was pediatric and mortality relatively low. Decentralized treatment centers, targeted active screening, and community sensitization will help decrease morbidity and mortality from VL in this endemic area. The true magnitude of VL in Somalia remains unknown. Further documentation to better understand transmission dynamics and thus define appropriate control measures will depend on the stability of the context and safe access to the Somali population.
    • 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.
    • "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.
    • 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.
    • 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; et al. (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.
    • 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.
    • A neglected disease of humans: a new focus of visceral leishmaniasis in Bakool, Somalia.

      Marlet, M V L; Wuillaume, F; Jacquet, D; Quispe, K W; Dujardin, J C; Boelaert, M; Médecins sans Frontières, Dupréstraat 94, B-1090 Brussels, Belgium. (Elsevier, 2008-02-07)
      Visceral leishmaniasis (VL) was observed in children in Bakool region, Somalia, an area where VL has not been reported before. We describe the extent of the problem in this war- and famine-stricken area. A retrospective analysis was done of all cases admitted to a VL treatment centre between July 2000 and August 2001. Patients with longstanding fever, splenomegaly and a positive direct agglutination test (DAT; titre > 1:3200) were treated as suspected VL cases. A rapid epidemiological and entomological assessment was performed in the area. Species identification was attempted from blood samples by polymerase chain reaction-restriction fragment length polymorphism analysis of cysteine proteinase B genes. In 1 year, 230 serologically-positive cases were diagnosed as VL, and response to therapy was good in 91.6% of the 225 treated with sodium stibogluconate. Parasitological confirmation was attempted and obtained in 2 cases. Parasites were found to be most similar to Sudanese and Ethiopian reference strains of the Leishmania donovani complex. In a serological survey of 161 healthy displaced persons, 15% were positive by the leishmanin skin test and 3 (2%) were positive by the DAT. The sandfly captures showed Phlebotomus martini and P. vansomerenae. VL seems to be a longstanding and serious health problem in Bakool region. Food insecurity might have contributed to the emergence and detection of VL in this area.
    • 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.
    • Visceral leishmaniasis (kala-azar) outbreak in Somali refugees and Kenyan shepherds, Kenya.

      Boussery, G; Boelaert, M; van Peteghem, J; Ejikon, P; Henckaerts, K (2001)
    • 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.
    • Visceral Leishmaniasis-HIV Coinfection as a Predictor of Increased Transmission at the Village Level in Bihar, India.

      Cloots, K; Marino, P; Burza, S; Gill, N; Boelaert, M; Hasker, E (Frontiers Media, 2021-03-11)
      These findings indicate the importance of VL-HIV+ patients as infectious reservoirs for Leishmania, and suggest that they represent a threat equivalent to PKDL patients towards the VL elimination initiative on the Indian subcontinent, therefore warranting a similar focus.
    • 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.