Safety and Efficacy of Single Dose versus Multiple Doses of AmBisome® for Treatment of Visceral Leishmaniasis in Eastern Africa: A Randomised Trial

Khalil, E. A. G.; Weldegebreal, Teklu; Younis, Brima M.; Omollo, Raymond; Musa, Ahmed; Hailu, Workagegnehu; Abuzaid, Abuzaid A.; Dorlo, Thomas P. C.; Hurissa, Zewdu; Yifru, Sisay; Haleke, William; Smith, P. G.; Ellis, Sally; Balasegaram, Manica; Elhassan, Ahmed M.; Schoone, Gerard J.; Wasunna, Monique; Kimutai, Robert; Edwards, Tansy; Hailu, Asrat

doi:10.1371/journal.pntd.0002613

Cited by 76 publications

(77 citation statements)

References 21 publications

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“…In E. Africa, monotherapies have proven less efficacious and with greater regional variability than seen in S. Asia (den Boer et al, 2009;Mueller et al, 2007;Khalil et al, 2014). Since AmBisome requires a cold chain and is very expensive with limited availability, it is considered a second line treatment, but under continued evaluation (Khalil et al, 2014).…”

Section: Feeding Behaviourmentioning

confidence: 99%

“…Since AmBisome requires a cold chain and is very expensive with limited availability, it is considered a second line treatment, but under continued evaluation (Khalil et al, 2014). One concern with monotherapies is the potential development of parasite resistance, particularly MIL and PM, because they require long treatment courses, lowering compliance.…”

Section: Feeding Behaviourmentioning

confidence: 99%

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Progress in the Mathematical Modelling of Visceral Leishmaniasis

Rock¹,

Quinnell²,

Medley³

et al. 2016

Advances in Parasitology

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The leishmaniases comprise a complex of diseases characterised by clinical outcomes that range from self-limiting to chronic, disfiguring and stigmatising, to life-threatening. Diagnostic methods, treatments, and vector and reservoir control options exist, but deciding the most effective interventions requires a quantitative understanding of the population level infection and disease dynamics. The effectiveness of any set of interventions has to be determined within the context of operational conditions, including economic and political commitment. Mathematical models are the best available tools for studying quantitative systems crossing disciplinary spheres (biology, medicine, economics) within environmental and societal constraints.In 2005, the World Health Assembly and government health ministers of India, Nepal, and Bangladesh signed a Memorandum of Understanding to eliminate the life threatening form of leishmaniasis, visceral leishmaniasis (VL), on the Indian subcontinent by 2015 through a combination of early case detection, improved treatments, and vector control. The elimination target is <1/10,000 population at the district or subdistrict level compared to the current 20/10,000 in the regions of highest transmission.Towards this goal, this chapter focuses on mathematical models of VL, and the biology driving those models, to enable realistic predictions of the * Corresponding author Email address: orin.courtenay@warwick.ac.uk (Orin Courtenay)Preprint submitted to Advances in Parasitology July 18, 2016 best combination of interventions. Several key issues will be discussed which have affected previous modelling of VL and the direction future modelling may take. Current understanding of the natural history of disease, immunity (and loss of immunity), as well as stages of infection and their durations are considered particularly for humans, but also for dogs. Asymptomatic and clinical infection are discussed in the context of their relative roles in Leishmania transmission, as well as key components of the parasite-sandfly-vector interaction and intervention strategies including diagnosis, treatment and vector control. Gaps in current biological knowledge and potential avenues to improve model structures and mathematical predictions are identified. Underpinning the marriage between biology and mathematical modelling, the content of this chapter represents the first step towards developing the next generation of models for VL.

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Section: Feeding Behaviourmentioning

confidence: 99%

Section: Feeding Behaviourmentioning

confidence: 99%

Progress in the Mathematical Modelling of Visceral Leishmaniasis

Rock¹,

Quinnell²,

Medley³

et al. 2016

Advances in Parasitology

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“…The parasite load in blood rapidly decreases upon initiation of treatment, in parallel with clinical improvement (14)(15)(16)(17). qPCR of blood of East African VL patients reflected differences in treatment responses to different AmBisome dosages (27); however, the sensitivity of the assay was lower than for Indian VL patients (28).…”

Section: Identified Biomarkersmentioning

confidence: 99%

“…While this method measures the parasite directly and therefore is theoretically the most promising biomarker, there are some issues. First, the sensitivity of this marker for VL is relatively low (ϳ80%) and seems to vary between geographical regions (27,28). The parasite loads appear to decrease with clinical cure but are undetectable before clinical cure can be established.…”

Section: Selection Of Potential Pharmacodynamic Biomarkersmentioning

confidence: 99%

Systematic Review of Biomarkers To Monitor Therapeutic Response in Leishmaniasis

Kip

Balasegaram

Beijnen

et al. 2015

Antimicrob Agents Chemother

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e Recently, there has been a renewed interest in the development of new drugs for the treatment of leishmaniasis. This has spurred the need for pharmacodynamic markers to monitor and compare therapies specifically for visceral leishmaniasis, in which the primary recrudescence of parasites is a particularly long-term event that remains difficult to predict. We performed a systematic review of studies evaluating biomarkers in human patients with visceral, cutaneous, and post-kala-azar dermal leishmaniasis, which yielded a total of 170 studies in which 53 potential pharmacodynamic biomarkers were identified. In conclusion, the large majority of these biomarkers constituted universal indirect markers of activation and subsequent waning of cellular immunity and therefore lacked specificity. Macrophage-related markers demonstrate favorable sensitivity and times to normalcy, but more evidence is required to establish a link between these markers and clinical outcome. Most promising are the markers directly related to the parasite burden, but future effort should be focused on optimization of molecular or antigenic targets to increase the sensitivity of these markers. In general, future research should focus on the longitudinal evaluation of the pharmacodynamic biomarkers during treatment, with an emphasis on the correlation of studied biomarkers and clinical parameters.

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“…The definitive cure rate in eastern Africa was 85% in patients treated with multiple doses of liposomal formulation and only 40% in single doses. 25 It was also not successful to shorten the duration of IM paromomycin from 21 to 14 days in India and it was accompanied by significantly less cure rate (92% and 82%, respectively). 20 In the preliminary phase, defervescence after treatment of VL was strongly correlated with a decrease in the parasite load of the spleen.…”

Section: Discussionmentioning

confidence: 97%

Effectiveness of Short-Course Meglumine Antimoniate (Glucantime®) for Treatment of Visceral Leishmaniasis: A 13-Year, Multistage, Non-Inferiority Study in Iran

Alborzi

Pouladfar

Attar

et al. 2017

The American Society of Tropical Medicine and Hygiene

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Abstract. The World Health Organization's (WHO) recommendation is 28-day course of meglumine antimoniate (Glucantime ® , Sanofi Aventis, France) for the treatment of visceral leishmaniasis (VL). The aim of this study was to evaluate the effectiveness of a shorter duration of treatment in regions with low level of resistance to Glucantime. During 13 years, this study was conducted in three phases on 392 patients. In the pilot first phase, we performed splenic punctures in seven patients to assess the correlation between the changes in the parasite load during treatment with Glucantime and defervescence. With defervescence, parasite density was dramatically dropped (P = 0.014), propounding defervescence as a marker of parasitological response. On the basis of the results, we conducted a randomized trial on 75 patients, comparing the efficacy of continuation of Glucantime therapy for 1, 2, or 3 weeks after defervescence. The treatment course of 1 week after defervescence (mean = 11.7 days) was non-inferior to that of 3 weeks (final cure rate, 96% versus 100%; P = 0.023). The third phase was a retrospective cohort study of 302 patients treated either with the WHO's regimen or for 7 days after defervescence (intervention group). Relapse was detected in 8.3% patients of the intervention group and in 5% patients following the WHO's regimen (P = 0.006 for non-inferiority). The final duration of treatment in intervention group was significantly shorter than standard course (13.3 ± 2.6 versus 28 days; P < 0.001). In summary, treatment of VL with Glucantime for 1 week after defervescence was non-inferior to and appears to be an acceptable alternative to the standard 28-day course for patients in Iran who show a response to antimonial therapy.

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Safety and Efficacy of Single Dose versus Multiple Doses of AmBisome® for Treatment of Visceral Leishmaniasis in Eastern Africa: A Randomised Trial

Cited by 76 publications

References 21 publications

Progress in the Mathematical Modelling of Visceral Leishmaniasis

Progress in the Mathematical Modelling of Visceral Leishmaniasis

Systematic Review of Biomarkers To Monitor Therapeutic Response in Leishmaniasis

Effectiveness of Short-Course Meglumine Antimoniate (Glucantime®) for Treatment of Visceral Leishmaniasis: A 13-Year, Multistage, Non-Inferiority Study in Iran

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