Left untreated, visceral leishmaniasis (VL) is fatal. The highest burden of VL worldwide is
      in eastern Africa where field-adapted diagnostic and test-of-cure tools and treatment are
      lacking. The current laboratory tool to help assessing cure, treatment failure and relapse is
      microscopy, based on invasive sampling (e.g. splenic or bone marrow aspirate). Non-invasive,
      more sensitive tools will enable these assessments with minimum risk and discomfort to
      patients.

      This study aims to evaluate immunological and molecular tests to predict cure and relapse,
      and to replace with these the current invasive methods.

      The study will be conducted at the Leishmaniasis Research and Treatment Centre (LRTC), Gondar
      University Hospital, Ethiopia It will be a non-intervention study, the tools under evaluation
      will be considered as index tests; their results will not influence patient management during
      the duration of the study. Patient management will follow the national guidelines for VL
      diagnosis and management in Ethiopia.

Evaluation of Less Invasive Procedures for Visceral Leishmaniasis Treatment Efficacy Monitoring Test of Cure

Visceral Leishmaniasis

CONTEXT Visceral leishmaniasis (VL), or kala-azar, is caused by parasitic protozoa of the
      Leishmania donovani species complex, which are transmitted by the bite of infected female
      phlebotomine sand flies. VL has a worldwide distribution throughout Asia, eastern Africa,
      South America and the Mediterranean basin. A proportion of infected individuals present with
      insidiously evolving symptoms, with splenomegaly, irregular fever, anaemia or pancytopaenia,
      weight loss and weakness, occurring progressively over a period of weeks or even months. And
      the disease can be fatal without treatment in up to 90% of cases.

      In 1990, the worldwide incidence of VL was estimated at 500,000 cases annually. Since then,
      it has significantly decreased. A WHO report on the 14 high-burden countries (> 100
      cases/year) reported 30,758 new cases of VL in 2014, with under-reporting between 1.2- and
      4-fold. This drastic reduction in the last decades is largely attributed to a sharp decline
      in incidence in Southeast Asia, from approximately 50,000 reported cases in 2006-2007, to
      10,311 in 2014. A successful elimination campaign, natural fluctuations in incidence and
      improvements in local living conditions have contributed to the decrease. Currently, the
      highest burden of VL worldwide is in eastern Africa, where there is a lack of appropriate
      diagnostic tools and treatment. Most of the cases are observed in Ethiopia, Kenya, Somalia,
      Sudan, South Sudan and Uganda. Of the six countries currently representing 91% of the overall
      VL burden worldwide, four are in eastern Africa - Ethiopia, South Sudan, Sudan and Somalia.

      With targets for VL elimination being reached in Southeast Asia, the WHO has recently
      encouraged partners to improve the tools for better control and eventual elimination of VL in
      specific foci in eastern Africa. Important challenges for disease control include:
      inconsistent performance of RDTs in different regions; suboptimal efficacy of treatment with
      potentially toxic injectable medicines; lack of drug resistance monitoring; insufficient
      access to early diagnosis and treatment; and lack of a test-of-cure and prediction of
      relapses. All this has a significant impact on morbidity, mortality, loss of quality of life
      and economic development. We believe that improving access to diagnostic and treatment
      monitoring tools for VL is the cornerstone of successful VL control/elimination approaches.

      New drugs and drug combinations for VL are being evaluated by DNDi and LEAP partners at
      several study sites, who showed that in Eastern Africa, sodium stibogluconate (SSG) and
      paromomycine (PM) in combination offer an advantage compared to the previous SSG monotherapy.
      Close patient monitoring during treatment and follow-up, provides a unique opportunity for
      evaluating new tools and markers of cure and relapses, as we propose in this study.

      STUDY RATIONALE In VL clinical trials, patients fulfilling pre-defined inclusion criteria are
      enrolled based on diagnosis by Leishmania positive tissue aspirate (spleen, bone marrow or
      lymph node) and microscopy, which is also the method used as the parasitological test-of-cure
      at the end of treatment. Although sensitive (variable depending on the tissue sample), this
      traditional method bears limitations, warranting new improved non-invasive tools. Spleen
      aspiration and microscopy also have limitations, including difficulty in harmonizing
      microscopy results, as tissue aspirates are not homogeneous, reflecting inaccurate
      assessments of parasite load. In many patients, the spleen shrinks with treatment, making
      monitoring by splenic aspiration at the end of treatment difficult. In these cases, bone
      marrow aspirates are often analysed for test-of-cure, which makes quantitative comparisons of
      parasite loads before and after treatment even more difficult. Finally, splenic aspiration is
      invasive with risk of severe complications.

      Diagnosing VL using a sensitive diagnostic test based on peripheral blood is much more
      favourable. Nucleic acid amplification tests (NAAT) have proven sensitive for detection of
      Leishmania parasites in blood and have a potential role in the diagnostic algorithm of
      primary VL. However, in VL endemic settings, most NAAT are restricted to well-equipped
      laboratories. Recently, FIND, in collaboration with other partners, developed a robust NAAT,
      loop-mediated isothermal amplification (LAMP) that can be used at the basic laboratory level
      (e.g. microscopy laboratory). An additional advantage of LAMP is that by using a fluorimeter
      or turbidimeter, it could reproducibly semi-quantify parasite load, avoiding parasite grading
      based on microscopy of tissues obtained invasively. The WHO has recently recommended LAMP for
      the diagnosis of pulmonary tuberculosis.

      A top research priority highlighted by the WHO Expert Committee on the Control of
      Leishmaniasis is identification of a biomarker of treatment failure and relapses, as opposed
      to cure after chemotherapy [1]. New tools and biomarkers to monitor the immune response of VL
      patients during therapy, such as immunoglobulin isotypes or cytokines, and that can be used
      to predict relapses, are important in eastern Africa, given the high relapse rate and that
      VL/HIV co-infection is a major determinant of relapses [1,3]. New T-cell-based interferon-γ
      release assays have shown that IFN-γ in Leishmania-stimulated whole blood increases gradually
      and significantly after successful treatment of patients infected with L. donovani or L.
      infantum . Whole blood stimulation and cytokine release assay (CRA) and cell proliferation
      assay (CPA) have demonstrated their usefulness to predict relapses in immunodepressed
      patients. CRA and IFN-γ analysis helped to confirm cure and risk of relapses in solid organ
      transplant individuals, while CPA was a good predictive marker of non-appearance of relapses
      in HIV patients co-infected with Leishmania. On the other hand, with the use of simple
      serological tests (ELISA), a strong evidence has been presented for the use of
      anti-Leishmania IgG1 in monitoring treatment outcomes in VL [10]. We propose a collaboration
      between European and Ethiopian research institutions, with sound expertise on VL, which will
      capitalize on LEAP's working infrastructure to evaluate the usefulness of an ELISA test
      detecting anti-Leishmania IgG1 antibodies, Leishmania-specific lymphocyte proliferation,
      cytokine release assays and LAMP to predict treatment failure and relapse in VL patients.

      With targets for VL elimination being reached in Southeast Asia, the WHO has recently
      encouraged partners to improve the tools for better control and eventual elimination of VL in
      specific foci in eastern Africa. Important challenges for disease control include:
      inconsistent performance of RDTs in different regions; suboptimal efficacy of treatment with
      potentially toxic injectable medicines; lack of drug resistance monitoring; insufficient
      access to early diagnosis and treatment; and lack of a test-of-cure and prediction of
      relapses. All this has a significant impact on morbidity, mortality, loss of quality of life
      and economic development. Improving access to diagnosis and treatment monitoring tools for VL
      is the cornerstone of successful VL control/elimination approaches.

      OBJECTIVES The objective of the proposed study is to evaluate immunological (whole blood
      cytokine release assay, cell proliferation assay, IgG1 anti-Leishmania) and molecular
      (loop-mediated isothermal amplification) tests to predict cure and relapse, and to replace
      with these the current invasive methods.

ELISA, LAMP, Cytokine Release Assay

Sensitivity, specificity, positive and negative predictive values will be reported

After treatment completion Sensitivity, specificity, positive and negative predictive values will be reported

Evaluation of Less Invasive Procedures for Visceral Leishmaniasis Treatment Efficacy Monitoring Test of Cure

About this trial

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Type

Placebo

Accepting

Trial Timing

What is this trial about?

What are the participation requirements?

Locations

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