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Background: With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is crucial to improving treatment efficacy and predicting patient relapse in cases of VL. This study aimed to characterize the kinetics of circulating Leishmania parasites in the blood, during and after different antileishmanial therapies, and to find predictors for clinical relapse of disease. Methods: Data from three clinical trials, in which Eastern African VL patients received various antileishmanial regimens, were combined in this study. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during, and up to six months after treatment. An integrated population pharmacokinetic-pharmacodynamic model was developed using non-linear mixed effects modelling. Results: Parasite proliferation was best described by an exponential growth model, with an in vivo parasite doubling time of 7.8 days (RSE 12%). Parasite killing by fexinidazole, liposomal amphotericin B, sodium stibogluconate, and miltefosine was best described by linear models directly relating drug concentrations to the parasite elimination rate. After treatment, parasite growth was assumed to be suppressed by the host immune system, described by an Emax model driven by the time after treatment. No predictors for the high variability in onset and magnitude of the immune response could be identified. Model-based individual predictions of blood parasite load on Day 28 and Day 56 after start of treatment were predictive for clinical relapse of disease. Conclusion: This semi-mechanistic pharmacokinetic-pharmacodynamic model adequately captured the blood parasite dynamics during and after treatment, and revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could be a useful biomarker to assess treatment efficacy of a treatment regimen in a clinical trial setting. Author summary: After primary treatment of visceral leishmaniasis (VL), relapse of disease occurs in a proportion of patients. Understanding parasite dynamics is crucial to improving treatment efficacy and predicting disease relapse at an early stage. Leishmania kinetoplast DNA loads in blood from East African VL patients from three clinical trials, treated with five different treatment regimens, were used to develop a semi-mechanistic model to integrate in vivo parasite replication in the host, parasite clearance by different VL drug regimens, and suppression of parasite regrowth by the host immune system after treatment. This model deepened our understanding of the parasite-drug-host interaction and described the in vivo parasite growth rate in human for the first time. Moreover, the model revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could serve as a biomarker to predict long-term clinical outcome, an important new tool for optimizing future VL treatment regimens. [ABSTRACT FROM AUTHOR]

Background This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa. Methods An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months. Results Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], −6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, −0.3%; 97.5% CI, –7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug–related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (<12 years) and adults. Conclusions PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa. Clinical Trials Registration NCT03129646. [ABSTRACT FROM AUTHOR]

Background: Anti-leishmanial drug regimens that include a single dose AmBisome® could be suitable for eastern African patients with symptomatic visceral leishmaniasis (VL) but the appropriate single dose is unknown. Methodology: A multi-centre, open-label, non-inferiority, randomized controlled trial with an adaptive design, was conducted to compare the efficacy and safety of a single dose and multiple doses of AmBisome® for the treatment of VL in eastern Africa. The primary efficacy endpoint was definitive cure (DC) at 6 months. Symptomatic patients with parasitologically-confirmed, non-severe VL, received a single dose of AmBisome® 7.5 mg/kg body weight or multiple doses, 7 times 3 mg/kg on days 1–5, 14, and 21. If interim analyses, evaluated 30 days after the start of treatment following 40 or 80 patients, showed the single dose gave significantly poorer parasite clearance than multiple doses at the 5% significance level, the single dose was increased by 2·5 mg/kg. In a sub-set of patients, parasite clearance was measured by quantitative reverse transcriptase (qRT) PCR. Principal Findings: The trial was terminated after the third interim analysis because of low efficacy of both regimens. Based on the intention-to-treat population, DC was 85% (95%CI 73–93%), 40% (95%CI 19–64%), and 58% (95%CI 41–73%) in patients treated with multiple doses (n = 63), and single doses of 7·5 (n = 21) or 10 mg/kg (n = 40), respectively. qRT-PCR suggested superior parasite clearance with multiple doses as early as day 3. Safety data accorded with the drug label. Conclusions: The tested AmBisome® regimens would not be suitable for VL treatment across eastern Africa. An optimal single dose regimen was not identified. Trials Registration: www.clinicaltrials.govNCT00832208 Author Summary: Visceral leishmaniasis is a potentially fatal disease which affects 0.2–0.4 million people every year, principally in South-East Asia, Latin America or Eastern Africa. Currently the safest drug in use is AmBisome®, which cures 90% of patients in India at 5 mg/kg, and is even more effective at higher doses (10 mg/kg) or in combination with miltefosine or paromomycin. These regimens have been shown to be equally cost-effective in India. However, the drug requires a cold chain for storage and reconstitution prior to injection. Although it is licensed for use in eastern Africa, in practice it is mainly used as a second-line treatment. A small study carried out in Kenya indicated that a higher dose is necessary in eastern Africa in contrast to Asia. This study aimed to determine the minimum single dose that is safe and effective for treatment of eastern African VL patients so as to be used in simplified treatment regimens. However, the tested regimens were found to be ineffective, and an optimal single dose that could potentially be used in simplified treatment regimens was not identified. [ABSTRACT FROM AUTHOR]