Prophylaxis of Visceral Leishmaniasis Relapses in HIV Co-infected Patients With Pentamidine: a Cohort Study

Study Overview
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Brief Summary
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Visceral leishmaniosis (VL) is widely reported in Ethiopia, with about 30% of cases being associated with human immunodeficiency virus (HIV). In absence of antiretroviral treatment (ART), poor prognosis, high mortality and high relapse rates are characteristic of Ethiopian VL patients with HIV co-infection. Conversely, co-infection can be successfully managed via a combination of effective treatment of the initial episode, timely ART and prevention of relapses. Actually, until cellular immunity returns with ART, the patient is at risk of VL relapses, which can result in death, severe illness, reduced ART efficacy, drug-resistance and possibly transmission of drug-resistant Leishmania donovani. Patients most vulnerable to relapses are those with high levels of immunosuppression, with previous VL episodes, or with opportunistic infections (OIs). The most important factor to prevent relapses seems to be the clearance of visible parasites. Limited studies in Europe show that HIV co-infected patients may benefit from secondary prevention with antimonials (part of mainstay treatment for VL in Ethiopia) and pentamidine (PM), not used for VL treatment in Africa. Such maintenance treatment has not been studied in African VL, but the poor outcomes without secondary prevention highlight a need of better care to patients at risk of relapse. This prospective cohort study aims at documenting the patient's outcomes of secondary prophylaxis with PM in VL-HIV co-infection, in terms of time to relapse or death, safety and feasibility, before it can be considered for general use in Ethiopia. A placebo group is not included, due to the clear advantages of the intervention to the patient population.

Detailed Description
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Visceral leishmaniosis (VL) in Ethiopia has been reported in different parts of the country, with approximately 30% of cases being associated with human immunodeficiency virus (HIV). The ruralisation of HIV epidemic in VL endemic areas will hamper efforts to control VL. Clinical experience in Ethiopia has shown that anti-leishmanial treatment in the absence of anti-retroviral therapy (ART) does not result in favourable outcomes: poor prognosis, high mortality and relapse rates are characteristic of Ethiopian VL patients with HIV co-infection. The effective management of the initial VL episode, timely ART, and prevention of relapses should be the cornerstones of effective management of HIV/VL co-infection. However, parasitological cure of VL in HIV co-infected patients cannot easily be established, and until cellular immunity returns with ART, the patient is at risk of relapses of VL, which can result in death, severe illness, negative effect on ART efficacy leading to other opportunistic infections (OIs), emergence of drug-resistant parasites, and possibly to transmission of drug-resistant Leishmania donovani. Patients most vulnerable to relapses are 1) those with high levels of immunosuppression, 2) patients with previous VL episodes, and 3) patients with OIs. ART reduces the risk of VL relapse/recurrence by  50%, while the type of anti-leishmanial primary treatment has little effect on relapses; the most important factor seems to be clearance of visible parasites (if residual parasites are seen at the end of treatment, the relapse rate is 100%). Limited studies in Europe show that HIV co-infected patients may benefit from secondary prevention, by significantly prolonging the relapse-free period. The drugs studied for secondary prophylaxis in Europe have been meglumine antimoniate and AmBisome, which are part of mainstay treatment for VL in Ethiopia, and pentamidine (PM), which is not used for VL treatment in Africa. The effect of such maintenance treatment has not been studied in African VL, but the poor outcomes without secondary prevention highlight a clear need to offer better care to patients at high risk of relapse. Indeed, secondary prophylaxis is generally recommended in Europe and the United States (see the 2009 Center for Disease Control guidelines). PM 4 mg/kg intravenous (IV) every 3-4 weeks has been proposed as secondary prophylaxis, and it is already used in countries like United Kingdom and Spain. Consequently, this prospective cohort study aims at documenting the patient's outcomes of secondary prophylaxis with PM in VL-HIV co-infection, in terms of time to relapse or death, safety and feasibility, before it can be considered for more general use in Ethiopia. A placebo group is not included, due to the clear advantages of the intervention to the patient population targeted herewith. Furthermore as other available VL treatments are used as main line treatments, they cannot be considered as alternative comparators, given the potential risk of rapid emergence of drug resistance and subsequent spread in areas of anthroponotic VL.

Official Title
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Secondary Prophylaxis of Visceral Leishmaniasis Relapses in HIV Co-infected Patients Using Pentamidine as a Prophylactic Agent: a Prospective Cohort Study

Conditions
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Visceral Leishmaniosis, HIV-infection/Aids

Intervention / Treatment
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* Drug: Pentamidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed with Visceral Leishmaniosis (VL) during the recruitment period that are EITHER treated for VL relapse and have a documented negative test of cure (TOC), OR are treated for primary VL and have a documented CD4 <200 or WHO stage 4 disease during the recruitment period and have a documented negative TOC Patients treated for VL in the past with documented CD4 <200 or WHO stage 4 disease during the recruitment period AND documented negative TOC after the latest VL treatment and currently asymptomatic OR currently negative diagnostic test (microscopy) Patients agreeing to start or continue antiretroviral treatment (first or second line) Patients willing to provide written informed consent Exclusion Criteria: Patients with known hypersensitivity to pentamidine Patients with known renal failure Patients with diabetes mellitus (type I or II) Patients unlikely to attend follow-up visits/comply with study requirements Pregnant and lactating women Any other condition that could increase the risk of toxicity of pentamidine to such an extent outweighing the expected benefit (eg severe cardiac dysfunction).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pentamidine Secondary Prophylaxis (PSP)<br>Patients with co-infection of human immunodeficiency virus (HIV)and visceral leishmaniosis (VL), having being treated for VL, are allocated to pentamidine secondary prophylaxis, to prevent VL relapses. The treatment period is of 12 months, plus an extended treatment period of 0 to 6 months depending on the immunosuppression status, plus 12 months follow-up after the extended treatment period. | Drug: Pentamidine<br>* Pentamidine isethionate 300 mg for one vial for intramuscular or intravenous route(1 mg of pentamidine isethionate is equivalent to 0.57 mg of pentamidine base)<br>* Other names: PENTACARINAT 300 mg, by Sanofi-Aventis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Probability of Relapse-free Survival | Probability of relapse-free survival up to one year after the start of the intervention (PSP) (at month 6 and month 12) | up to 1 year after the start of the intervention (PSP) | 
| Number of Participants With Serious Adverse Events (SAEs) | Number of patients with SAEs which are possibly, probably or definitely drug-related following clinician's assessment or that lead to permanent drug discontinuations during the first year of pentamidine administration | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | During the first year of pentamidine administration for prophylaxis: participants with any drug-related non-serious adverse events (with drug-related defined as possibly, probably or definitely related to primary therapy following physicians assessment) as well as any serious adverse events (drug-related or not) | 1 year | 
| Number of Treatment Discontinuations and Interruptions | Number of treatment discontinuations and interruptions/missed doses. | 30 months | 
| Number of Required Additional Interventions | The number of required additional clinical interventions/therapeutic procedures | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ethiopia, Secondary prophylaxis, Visceral leishmaniasis, Relapses, HIV co-infection, Pentamidine