Efficacy Trial of Ambisome Given Alone and Ambisome Given in Combination With Miltefosine for the Treatment of VL HIV Positive Ethiopian Patients.

A Randomized Trial of Ambisome Monotherapy and Combination of Ambisome and Miltefosine for the Treatment of VL in HIV Positive Patients in Ethiopia Followed by Secondary VL Prophylactic Treatment With Pentamidine.

The overall objective of this trial is to identify a safe and effective treatment for visceral leishmaniasis (VL) in HIV co-infected Ethiopian patients.

Patients will receive either Ambisome alone or Ambisome in combination with Miltefosine.

Patients who do not undergo treatment failure will be given a VL prophylactic treatment with Pentamidine one month after the end of the study treatment.

Visceral Leishmaniasis (VL) is a neglected disease which is fatal if left untreated. Ethiopia is one of the countries where the majority of cases occur. With spread of HIV in VL endemic areas an increase in co-infected cases has been reported in Ethiopia.

HIV and VL mutually influence each other as they both affect cellular immunity. The most important features of co-infection include poor outcome, increased drug toxicity and relapse of treatment with the need for maintenance therapy.

There are few studies in co-infected patients. There are no specific recommendations for HIV-VL co-infected patients in Ethiopia.

This protocol will evaluate the efficacy and safety of the combination of Ambisome with Miltefosine and Ambisome monotherapy (high dose) in Ethiopia.

It is designed as a randomised, parallel arm, open-label trial. No comparator will be included.

The randomization will be stratified according to centre as well as wether VL is a primary case or a relapse. The study will be analysed according to group-sequential methods, specifically the triangular test. Data from each arm will be analysed after every 10 patients reach the primary endpoint of final cure at day 29. The data will be analysed as proportions according to an intention to treat and per protocol analysis for each arm.In order to address potential heterogeneity of the population, a test will be performed when a treatment is stopped. Depending on the outcome of this test for heterogeneity, recruitment may be continued into one stratum.

The treatment duration will be 28 days or 56 days in case of extended treatment.

• If at Day 29 assessment, tissue aspirate is parasite negative, the patient will be eligible for secondary prophylaxis (Pentamidine 4mg/kg IM (intramuscular) once a month up to a maximum of 18 months) and enter the 1 year follow up phase.
• If at day 29 assessment, tissue aspirate is positive but the patient is well, he/she will receive another complete course of treatment (but classified as treatment failure). The patient will be evaluated again on day 58. Those who still have a parasite positive tissue aspirate will be offered a rescue treatment. Those who are negative will be offered secondary prophylaxis if eligible (Pentamidine 4mg/kg IM once a month up to a maximum of 18 months).
• If at day 29 assessment, tissue aspirate is positive and the patient is unwell, he/she will be treated with rescue treatment (and considered as treatment failure)
• All patients, independently of their outcome at day 29 and/or day 58 will enter the follow-up assessments at day 210 and day 390.

Rescue treatment will also be given in case of relapse during the follow-up period and in case of occurence of severe grade 2 or grade 3 PKDL or PKDL with mucosal and/or eye involvement after treatment period.

All patients who are not yet on antiretroviral treatment (ART) at inclusion will commence ART once they have completed routine voluntary counselling and testing procedures. Patients who are already on ART at diagnosis of VL will continue ART throughout the study.

Inclusion Criteria:

• Confirmed HIV positive test (2 rapid diagnostics tests (RDTs) followed by a confirmatory ELISA test).
• Diagnosis of VL (first episode or relapse) confirmed by bone marrow or spleen aspirate.
• Male and female age: 18-60 years.
• Written informed consent from the patient.

Exclusion Criteria:

• Women of child-bearing potential (defined as women who have achieved menarche) who are not using an assured method of contraception or are unwilling to use an assured method of contraception for the duration of treatment and four months after.
• Pregnant women or breast-feeding mothers.
• Patients with grade 2 or 3 post kala-azar dermal leishmaniasis (PKDL) lesions.
• Clinical or biological evidence of severe cardiac, renal or hepatic impairment.
• Known hypersensitivity to AmBisome® and/or miltefosine.
• Patients receiving allopurinol treatment