Date Published: April 2, 2015
Publisher: Public Library of Science
Author(s): Emiliano Lucero, Simon M. Collin, Sujit Gomes, Fatima Akter, Asaduzzam Asad, Asish Kumar Das, Koert Ritmeijer, Marleen Boelaert. http://doi.org/10.1371/journal.pntd.0003699
Abstract: BackgroundBangladesh is one of the endemic countries for Visceral Leishmaniasis (VL). Médecins Sans Frontières (MSF) ran a VL treatment clinic in the most endemic district (Fulbaria) between 2010 and 2013 using a semi-ambulatory regimen for primary VL of 15mg/kg Liposomal Amphotericin-B (AmBisome) in three equal doses of 5mg/kg. The main objective of this study was to analyze the effectiveness and safety of this regimen after a 12 month follow-up period by retrospective analysis of routinely collected program data. A secondary objective was to explore risk factors for relapse.Methods and Principal FindingsOur analysis included 1521 patients who were initially cured, of whom 1278 (84%) and 1179 (77.5%) were followed-up at 6 and 12 months, respectively. Cure rates at 6 and 12 months were 98.7% (1262/1278) and 96.4% (1137/1179), respectively. Most relapses (26/39) occurred between 6 and 12 months after treatment. Serious adverse events (SAE) were recorded for 7 patients (0.5%). Odds of relapse at 12 months were highest in the youngest and oldest age groups. There was some evidence that spleen size measured on discharge (one month after initiation of treatment) was associated with risk of relapse: OR=1.25 (95% CI 1.01 to 1.55) per cm below lower costal margin (P=0.04).ConclusionsOur study demonstrates that 15mg/kg AmBisome in three doses of 5mg/kg is an effective (>95% cure rate) and safe (<1% SAE) treatment for primary VL in Bangladesh. The majority of relapses occurred between 6 and 12 months, justifying the use of a longer follow-up period when feasible. Assessment of risk of relapse based on easily measured clinical parameters such as spleen size could be incorporated in VL treatment protocols in resource-poor settings where test-of-cure is not always feasible.
Partial Text: Visceral Leishmaniasis (VL), also known as Kala Azar, is a vector borne disease caused by parasites of the genus Leishmania, L. donovani—L. infantum complex, which are transmitted through the bite of an infected sand fly (mainly genus Phlebotomus, old world, and Lutzomya, new world), Leishmaniasis infection in humans presents as cutaneous, muco-cutaneous and visceral. The visceral form is fatal if untreated. VL progressively affects the immune system of the patient, and opportunistic infections are frequently the final cause of death [1,2]. VL is endemic in around 80 countries, with over 90% of cases found in India, Bangladesh, Sudan, South Sudan, Ethiopia and Brazil .
This retrospective analysis used routine patient data from the MSF VL clinic in Fulbaria, Bangladesh, collected from January 2010 to April 2014. We included all patients diagnosed with primary VL who received AmBisome 15 mg/kg in three separate doses (5mg/kg), and who were not referred to other institutions for treatment or follow-up. Relapse VL cases require treatment with a higher total dose of AmBisome, and were excluded from our analysis.
After applying the inclusion criteria, a total of 1521 patients who completed the treatment were included in our study (Fig 1). The first and last admissions occurred on May 17th 2010 and January 12th 2013, respectively. The last patient to complete their 12 month follow-up attended the clinic on February 10th 2014. Of the 1653 patients diagnosed with primary VL during this period, 40 complicated cases were transferred to tertiary care at Mymensingh Medical College. Of the 1613 patients treated at Fulbaria during the study period, 89 received other regimens: 18 patients with 5 x 3mg/kg had (suspected) impaired renal function and were treated with a lower dose more frequently over a longer period in accordance with protocol; 61 patients were treated with a single 10mg/kg dose as a new national protocol began to be introduced in 2013; and 10 patients were treated outside protocol for reasons which were not recorded in the database. The proportions of patients whose status was known at 6 and 12 months follow-up were 84.0% (1278/1521) and 77.5% (1179/1521), respectively. Data with which to analyze factors associated with risk of relapse at 12 months were available for 1106 patients.
Our study has shown that 15mg/kg AmBisome in three doses of 5mg/kg is an effective (96.4% cure rate) and safe (<1% SAE) treatment for primary VL in Bangladesh, when judged against internationally accepted parameters for effectiveness ≥95% and safety (SAE<5%) for VL treatment . We demonstrated that VL treatment studies in this setting require a follow-up period longer than 6 months if they are to capture the majority of relapses. Whether routine follow-up of discharged patients for this length of time is necessary depends on ease of access to re-treatment for patients who relapse. In settings where access to re-treatment is problematic, routine follow-up may be equally difficult (and costly), but it could help to achieve the VL elimination target (of <1 case per 10,000 people at upazila level in Bangladesh) set in the Regional Strategic Framework for Elimination of Kala-azar from South East Asia Region . We have also shown that residual splenomegaly is predictive of an increased risk of VL relapse, particularly in conjunction with low levels of hemoglobin. Our study has shown that 15mg/kg AmBisome in three doses of 5mg/kg is a safe and effective treatment for primary VL in Bangladesh, and could be an alternative to the current first line regimen of single dose 10mg/kg AmBisome. We have also shown that a follow-up period of 12 months is required to capture the majority of VL relapse cases, and that VL relapse is predicted by low Hb and large spleen size at the end of treatment. Until more evidence is gathered, we would recommend that follow-up be extended to 12 month for all patients or, where this is not feasible, 12-month follow-up could be targeted at patients who present with large spleen at the end of the treatment. Source: http://doi.org/10.1371/journal.pntd.0003699