Treatment regimens for post-kala-azar dermal leishmaniasis (PKDL) are usually extrapolated from those for visceral leishmaniasis (VL), but drug pharmacokinetics (PK) can differ due to disease-specific variations in absorption, distribution, and elimination. This study characterized PK differences in paromomycin and miltefosine between 109 PKDL and 264 VL patients from eastern Africa. VL patients showed 0.55-fold (95%CI: 0.41-0.74) lower capacity for paromomycin saturable reabsorption in renal tubules, and required a 1.44-fold (1.23-1.71) adjustment when relating renal clearance to creatinine-based eGFR. Miltefosine bioavailability in VL patients was lowered by 69% (62-76) at treatment start. Comparing PKDL to VL patients on the same regimen, paromomycin plasma exposures were 0.74-0.87-fold, while miltefosine exposure until the end of treatment day was 1.4-fold. These pronounced PK differences between PKDL and VL patients in eastern Africa highlight the challenges of directly extrapolating dosing regimens from one leishmaniasis presentation to another.
BACKGROUND
Targeted preventive strategies in persons living with HIV (PLWH) require markers to predict visceral leishmaniasis (VL). We conducted a longitudinal study in a HIV-cohort in VL-endemic North-West Ethiopia to 1) describe the pattern of Leishmania markers preceding VL; 2) identify Leishmania markers predictive of VL; 3) develop a clinical management algorithm according to predicted VL risk levels.
METHODS
The PreLeisH study followed 490 adult PLWH free of VL at enrolment for up to two years (2017-2021). Blood RT-PCR targeting Leishmania kDNA, Leishmania serology and Leishmania urine antigen test (KAtex) were performed every 3-6 months. We calculated the sensitivity/specificity of the Leishmania markers for predicting VL and developed an algorithm for distinct clinical management strategies, with VL risk categories defined based on VL history, CD4 count and Leishmania markers (rK39 RDT & RT-PCR).
FINDINGS
At enrolment, 485 (99%) study participants were on antiretroviral treatment; 360/490 (73.5%) were male; the median baseline CD4 count was 392 (IQR 259-586) cells/μL; 135 (27.5%) had previous VL. Incident VL was diagnosed in 34 (6.9%), with 32 (94%) displaying positive Leishmania markers before VL. In those without VL history, baseline rK39 RDT had 60% sensitivity and 84% specificity to predict VL; in patients with previous VL, RT-PCR had 71% sensitivity and 95% specificity. The algorithm defined 442 (92.3%) individuals at low VL risk (routine follow-up), 31 (6.5%) as moderate risk (secondary prophylaxis) and six (1.2%) as high risk (early treatment).
INTERPRETATION
Leishmania infection markers can predict VL risk in PLWH. Interventional studies targeting those at high risk are needed.
FUNDING
The PreLeisH study was supported by grants from the Department of Economy, Science and Innovation of the Flemish Government, Belgium (757013) and the Directorate-General for Development Cooperation and Humanitarian Aid (DGD), Belgium (BE-BCE_KBO-0410057701-prg2022-5-ET).
Human immunodeficiency virus (HIV) co-infection is a major challenge for visceral leishmaniasis (VL) control, particularly in Ethiopia where the incidence of both pathogens is high. VL-HIV often leads to high rates of antileishmanial treatment failure and recurrent VL disease relapses. Considering the high prevalence of HIV and Leishmania in the Ethiopian population, preventing the progression of asymptomatic Leishmania infection to disease would be a valuable asset to VL disease control and to the clinical management of people living with HIV (PLWH). However, such a strategy requires good understanding of risk factors for VL development. In immunocompetent individuals living in Brazil, India, or Iran, the Human Leukocyte Antigen (HLA) gene region has been associated with VL development. We used NanoTYPE, an Oxford Nanopore Technologies sequencing-based HLA genotyping method, to detect associations between HLA genotype and VL development by comparing 78 PLWH with VL history and 46 PLWH that controlled a Leishmania infection, all living in a VL endemic region of North-West Ethiopia. We identified an association between HLA-A*03:01 and increased risk of VL development (OR = 3.89). These data provide candidate HLA alleles that can be further explored for inclusion in a potential Leishmania screen-and-treat strategy in VL endemic regions.
To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response.
METHODS
Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults.
RESULTS
Data from 265 patients (59% =12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0–24h 187 (162–203) and 242 (217–328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0–28 517 (464–552) and 524 (456–567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25–28) and 30 (28–32) days, respectively] were comparable to previously observed values in adults.
CONCLUSIONS
Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure–response and exposure–toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.
The parasitic disease visceral leishmaniasis (VL) is most commonly caused by Leishmania donovani in eastern Africa, currently the region with highest burden worldwide. Current treatment for VL comprises the combination of sodium stibogluconate and paromomycin, SSG/PM; this is toxic, painful, and requires hospitalisation and daily injections. Treatments are urgently needed that are safe, effective, and appropriate for use in remote areas.
METHODS
We conducted a phase III open-label randomised non-inferiority trial in Ethiopia, Kenya, Sudan, and Uganda. The trial used a parallel-arm design with two arms, comparing the combination regimen of 20 mg/kg/day paromomycin and allometric miltefosine (MF) for 14 days with the current 17-day standard of care, 20 mg/kg/day SSG and 15 mg/kg/day PM. We enrolled adults and children aged 4-50 years with primary VL, without HIV or severe concomitant disease co-infection. The primary endpoint was definitive cure at 6 months’ follow-up.
ETHICS
This study was approved by the MSF Ethics Review Board and by ethics committees at the Institute of Endemic Diseases, Khartoum, Sudan; Kenya Medical Research Institute, Nairobi, Kenya; Makerere University, Uganda; and the University of Gondar, Ethiopia. Clinicaltrials.gov registry number, NCT03129646.
RESULTS
439 predominantly male (80%) patients aged 4 to 50 years were recruited over a period of 29 months. A similar proportion of patients in the PM/MF and the SSG/PM arms achieved definitive cure at 6-month follow-up in primary efficacy analysis using modified intention-to-treat; mITT; 91.2% cure for PM/MF (97.5% confidence interval, CI, 85-98.6) and 91.8% for SSG/PM (97.5% CI, 85.6-99.2). Non-inferiority was not demonstrated in the mITT population, with the upper limit of the 97.5% CI, 7.4%, slightly exceeding the non-inferiority margin of 7%. However, the per protocol analysis did show non-inferiority, with 92% (97.5% CI, 85-98.5) cure in the PM/MF arm, as compared to 91.7% (97.5% CI, 84.7-98.2) in the SSG/PM arm. Most adverse drug reactions (ADR’s) were mild to moderate. The most common expected ADR’s were MF-related vomiting, and PM-related injection site pain and hypoacusis. ADR’s suggesting SSG-related cardiac toxicity were reported in 6.5% (11/170) of patients in the SSG/PM arm. Eighteen serious adverse events were reported in 13 patients, four of which were considered related to study drugs. Fatality rate in the trial was 0.9% (4/439), with one death judged due to SSG-related cardiotoxicity.
CONCLUSION
The results of this study demonstrate that the 14-day PM/MF regimen achieved a clinically meaningful rate of cure with very similar efficacy to the standard of care, SSG/PM. It was generally well tolerated, with ADR’s as expected, based on the known safety profiles of study drugs. The PM/MF regimen has one fewer painful injection per day, a 3-day shorter treatment duration, and with no risk of SSG-associated life threating cardiotoxicity, as compared to SSG/PM. This regimen may therefore provide a more patient-friendly alternative for adults and children with VL in eastern Africa.
CONFLICTS OF INTEREST
None declared
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.