Clinical trial NCT01360762: Prophylaxis of Visceral Leishmaniasis Relapses in HIV Co-infected Patients With Pentamidine: a Cohort Study
Official title: Secondary Prophylaxis of Visceral Leishmaniasis Relapses in HIV Co-infected Patients Using Pentamidine as a Prophylactic Agent: a Prospective Cohort Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Visceral Leishmaniosis
HIV-infection/Aids
Keywords: Secondary prophylaxis
Visceral leishmaniasis
Relapses
HIV co-infection
Pentamidine
Ethiopia
Lead sponsor: Institute of Tropical Medicine, Belgium
Sponsor class: OTHER
Collaborators: name: Addis Ababa University
name: University of Gondar
name: Tigray Regional Health Bureau, Tigray Region
name: Amhara Regional Health Bureau, Amhara Region
name: Medecins Sans Frontieres, Netherlands
name: Leishmania East Africa Platform (LEAP)
name: Drugs for Neglected Diseases
First posted: 2011-05-26
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Probability of Relapse-free Survival
timeFrame: up to 1 year after the start of the intervention (PSP)
measure: Number of Participants With Serious Adverse Events (SAEs)
timeFrame: 1 year
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 1 year
measure: Number of Treatment Discontinuations and Interruptions
timeFrame: 30 months
measure: Number of Required Additional Interventions
timeFrame: 30 months
Other outcomes:
Locations:
city: Abdurafi
country: Ethiopia
facility: Abdurafi Health Center/Médecins Sans Frontières
state: Amhara
city: Humera
country: Ethiopia
facility: Kahsay Abera Hospital
state: Tigray
city: Gondar
country: Ethiopia
facility: Leismania Research and Treatment Centre, University of Gondar Hospital
Study officials:
affiliation: University of Gondar, Ethiopia
name: Ermias Diro, MD
role: STUDY_DIRECTOR
affiliation: ITM
name: Johan Van Griensven, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Diro E, Ritmeijer K, Boelaert M, Alves F, Mohammed R, Abongomera C, Ravinetto R, De Crop M, Fikre H, Adera C, van Loen H, Tsoumanis A, Adriaensen W, Hailu A, Griensven JV. Long-term Clinical Outcomes in Visceral Leishmaniasis/Human Immunodeficiency Virus-Coinfected Patients During and After Pentamidine Secondary Prophylaxis in Ethiopia: A Single-Arm Clinical Trial. Clin Infect Dis. 2018 Jan 18;66(3):444-451. doi: 10.1093/cid/cix807.