Serious adverse events and mortality following antileishmanial chemotherapy

Serious adverse events and mortality following antileishmanial chemotherapy

A systematic review of published studies for estimating the baseline risk of serious adverse events and mortality in patients treated with antileishmanial therapies

Leishmaniasis. Credit: CDC
Leishmaniasis. Credit: CDC

Data extraction and analysis was complete in summer 2020. The manuscript was submitted in late 2020 and published in March 2021.

Read the manuscript: Serious adverse events following treatment of visceral leishmaniasis: A systematic review and meta-analysis

Key findings

The review included 157 published studies enrolling 35,376 patients in 347 treatment arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only).  Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal amphotericin B (L-AmB) in 52 (15.0%), amphotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), amphotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms.

During the first 30 days of treatment initiation, there were 285 deaths with the overall incidence rate of death (IRD) estimated at 0.068 [95% confidence interval (CI): 0.041 – 0.114; I2=81.4%; 95% prediction interval (PI): 0.001 – 2.779] per 1,000 person-days.

The derived estimated varied by region and the drug regimens used. The estimate was 0.628 [95% CI: 0.368– 1.021; I2 = 82.5%;] in Eastern Africa, and 0.041 [95% CI: 0.021 – 0.081; I2 = 68.1%] in the Indian Subcontinent. After stratifying by drug regimen tested, the IRD was 0.069 [95% CI: 0.023–0.207;I2 = 66.5%; 47 arms; 5,250 patients] per 1,000 person-days for amphotericin b deoxycholate; 0.052 [95% CI: 0.013 – 0.210; I2 = 0.0%; 29 arms; 1,267 patients] for amphotericin b with fat/lipid/colloid/cholesterol; 0.017 [95% CI: 0.002 – 0.128; I2 = 26.1; arms; 3,271 patients] for single-dose L-AmB, and 0.068 [95% CI: 0.010 –0.435; I2 =68.9%; 49 arms; 1,451 patients] for multiple-dose L-AmB.

These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared.


Pentavalent antimonial has been the front-line drug for the treatment of Visceral Leishmaniasis (VL) for over 70 years until the discovery of antileishmanial activity in the well-known anti-fungal agent, Amphotericin B. The encapsulation of Amphotericin B in liposome was first shown to effectively cure VL in 1991 leading to a successful development of the lipid form, which is now the drug of choice for the treatment of VL. The lipid associated amphotericin B has been tested in three different formulations: colloidal dispersion amphotericin B, lipid complex amphotericin B, and liposomal amphotericin B (LAmB). The latter is available either as a single dose regimen or as a multiple dose regimen administered over a treatment period often lasting over one month.

The practical advantages offered by the single dose LAmB regimen has meant that this has been the drug of choice in the VL elimination programme in India, Bangladesh and Nepal, and is currently deployed as a 10mg/kg single dose (or in some cases as 2–5mg/kg doses) with patients followed-up at 1, 6 and 12 months post-treatment. While this drug regimen has demonstrated high efficacy, the tolerability profile hasn’t been well-understood. Antileishmanial therapies have been historically associated with a poor tolerability profile. However, there is a paucity of information regarding the expected rate of incidence of the severe adverse events and deaths following antileishmanial chemotherapies. This review was conducted to address this research gap.


The overarching aim of this review is to quantify the incidence risk of severe adverse events during the treatment and during the ensuing follow-up period for antileishmanial therapies. The specific objectives are:

  1. To estimate the risk of treatment emergent serious adverse event (SAE) and death for all antileishmanial drugs.
  2. To estimate the relative risk of SAE including death when treated with LAmB (alone or combined) versus comparator treatment within same studies (head to head trials).
  3. To estimate relative risk of SAE/death in LAmB (alone or combined) versus comparator treatment across different studies (indirect analysis via common comparator, if feasible).
Inclusion criteria for studies

This review builds upon a recently published systematic review which identified clinical trials in VL from 1983 to 2015 (Bush 2017). An update of the review has been completed (up to September 2018) by retaining the same search terms, databases and inclusion and exclusion criteria (Table 1).

Table 1: Systematic Review inclusion and exclusion criteria

Study Inclusion Criterion

Studies reporting VL treatment outcomes

Study Exclusion Criteria

Studies focusing on: cutaneous leishmaniasis, post kala-azar dermal leishmaniasis (PKDL), canine VL, vector control, nets, prevalence estimation, diagnostic tests, vaccines or prophylaxis

Non-intervention studies, case reports, retrospective studies

Individual studies enrolling fewer than six patients

Databases, WHO International

Clinical Trials Registry Platform (ICTRP), the Cochrane Library and PubMed

Search Terms

((kala AND azar) OR (visceral AND leishmaniasis)) AND (pentamidine OR ambisome OR amphotericin OR paromomycin OR miltefosine OR pentavalent OR sodium)


Data extraction and statistical analysis

A standardised, pre-piloted form was used to extract data from the studies meeting the eligibility criteria. In addition to the information extracted in the previous review, data on the following aspects has been extracted from studies that met the inclusion criteria:

  1. Study design and allocation
  2. Study location
  3. Follow-up duration
  4. Participants enrolled
  5. Information on study arms
  6. Drug posology (dose, duration, frequency, mode of administration, and supervision)
  7. Adverse events
  8. Serious adverse events
  9. Allergic reaction
  10. Deaths

A descriptive summary of the studies identified in the review will be provided including the proportion of the serious adverse events observed in each of the studies. The incidence risk of death following antileishmanial therapies will be estimated using theoretical exposure time and the rate will be expressed per 1,000-person days. Meta-analysis of the incidence rate ratio of death will be carried out by accounting for the structural zeros. The assessment of risk of bias in the included studies will be carried out using the Cochrane risk-of-bias tool.


For further information on this research activity, email Sauman Singh ( or Prabin Dahal (


Bush JT, Wasunna M, Alves F, Alvar J, Olliaro PL, Otieno M, et al. Systematic review of clinical trials assessing the therapeutic efficacy of visceral leishmaniasis treatments: A first step to assess the feasibility of establishing an individual patient data sharing platform. PLoS Neglected Tropical Diseases. 2017;11:1–16.