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

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.