Journal Article > ReviewFull Text
Int Health. 3 March 2025; DOI:10.1093/inthealth/ihaf013
Pandey DK, Alvar J, den Boer M, Jain S, Gill N, et al.
Int Health. 3 March 2025; DOI:10.1093/inthealth/ihaf013
The incidence and mortality of kala-azar (KA, visceral leishmaniasis) in India have fallen drastically in the past few years, and in 2023 the reported KA incidence reached the threshold for elimination as a public health problem (<1 case/10 000 of population at subdistrict level). One of the strategies adopted by India's kala-azar elimination program (KAEP) was the regular independent assessment of the program implementation by teams of experts. We present the findings of assessments undertaken in 2019, 2021 and 2023, when the KAEP was in the last mile of elimination. Factors that contributed to its success were political commitment, intensified implementation, a strong network of KA partners and committed donors. Bottlenecks were observed in disease surveillance, data utilization, vector-control operations and program management at implementation. To sustain the gains and achieve validation of elimination, the KAEP should continue the following minimal essential services: optimized active and passive case detection and management of KA, post-KA dermal leishmaniasis, KA-HIV coinfection and relapse supported by vector-control interventions. Long-term measures that will sustain elimination are overall socioeconomic development, including improved living conditions, parallel with efficient surveillance and operational research that is aligned with the changing epidemiology of the disease.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 20 June 2024; Volume 18 (Issue 6); e0012242.; DOI:10.1371/journal.pntd.0012242
Sundar S, Pandey K, Mondal D, Madhukar M, Kamal Topno R, et al.
PLoS Negl Trop Dis. 20 June 2024; Volume 18 (Issue 6); e0012242.; DOI:10.1371/journal.pntd.0012242
BACKGROUND
In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF.
METHODOLOGY/PRINCIPAL FINDINGS
An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred.
CONCLUSIONS/SIGNIFICANCE
Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia.
In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF.
METHODOLOGY/PRINCIPAL FINDINGS
An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred.
CONCLUSIONS/SIGNIFICANCE
Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia.
Journal Article > Research
Medical and Veterinary Entomology. 4 August 2023; Online ahead of print; DOI: 10.1111/mve.12683
Jibreel T, Khogali A, Jiménez M, Raiyed A, Dakein O, et al.
Medical and Veterinary Entomology. 4 August 2023; Online ahead of print; DOI: 10.1111/mve.12683
Visceral leishmaniasis (VL, kala azar), caused by Leishmania donovani, transmitted by Phlebotomus orientalis, is a serious systemic disease that causes high morbidity and mortality rates in Sudan and other parts of East Africa and the world. Despite progress in understanding the epidemiology of the disease in East Africa, little is known about the host preference of P. orientalis in kala azar endemic villages of Sudan, which have some of the highest VL incidence rates in the world. The present study used host choice experiments and blood-meal identification approaches to determine the host preference of P. orientalis in kala azar endemic villages in Gedarif state, eastern Sudan. In the host choice experiment, tent traps were used to compare the attractiveness of cows, donkeys, sheep and goats for host-seeking P. orientalis. In the blood-meal identification study, blood-fed P. orientalis females, captured inside houses and peri-domestic habitats, were subjected to molecular typing using cytochrome b gene (cyt b) amplification and sequence analysis. Cows and donkeys were the most attractive to blood-seeking P. orientalis, followed by goats. Similarly, the blood-meal analysis of P. orientalis showed that the vector preferentially feeds on cows, followed by donkeys, humans and goats. The human blood index of P. orientalis was 19.4% (42/216), indicating a high zoophilic habit of the vector, both inside and outside the houses. Although the order of host preference varied by location, it was clear that cows are the most preferred host of P. orientalis in the area. Results are discussed in relation to the role of domestic/livestock animals in VL zoopotentiation and zooprophylaxis. Inference is made on the potential impact of insecticide treatment of cows in control of the vector and the transmission of VL in Sudan and other parts of East Africa.
Conference Material > Slide Presentation
Solomos A, Musa AM, Mbui J, Mohammed R, Olobo J, et al.
MSF Scientific Day International 2023. 7 June 2023; DOI:10.57740/81jj-tz57
Conference Material > Abstract
Solomos A, Musa AM, Mbui J, Mohammed R, Olobo J, et al.
MSF Scientific Day International 2023. 7 June 2023; DOI:10.57740/y4z2-pq54
INTRODUCTION
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
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
Journal Article > ResearchFull Text
Clin Infect Dis. 27 September 2022; Online ahead of print; ciac643.; DOI:10.1093/cid/ciac643
Musa AM, Mbui J, Mohammed R, Olobo J, Ritmeijer KKD, et al.
Clin Infect Dis. 27 September 2022; Online ahead of print; ciac643.; DOI:10.1093/cid/ciac643
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.
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.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 22 October 2018; Volume 12 (Issue 10); e0006830.; DOI:10.1371/journal.pntd.0006830
Goyal V, Mahajan R, Pandey K, Singh SN, Singh RS, et al.
PLoS Negl Trop Dis. 22 October 2018; Volume 12 (Issue 10); e0006830.; DOI:10.1371/journal.pntd.0006830
BACKGROUND
In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions.
METHODS
This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891.
RESULTS
Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related.
CONCLUSION
All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India.
In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions.
METHODS
This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891.
RESULTS
Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related.
CONCLUSION
All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India.
Journal Article > ResearchFull Text
Am J Trop Med Hyg. 1 August 2007; Volume 77 (Issue 2); 275-282.
Alvar J, Bashaye S, Argaw D, Cruz I, Aparicio P, et al.
Am J Trop Med Hyg. 1 August 2007; Volume 77 (Issue 2); 275-282.
In May 2005, visceral leishmaniasis (VL) was recognized for the first time in Libo Kemkem, Ethiopia. In October 2005, a rapid assessment was conducted using data from 492 patients with VL treated in the district health center and a household survey of 584 residents of four villages. One subdistrict accounted for 71% of early cases, but the incidence and number of affected subdistricts increased progressively throughout 2004-2005. In household-based data, we identified 9 treated VL cases, 12 current untreated cases, and 19 deaths attributable to VL (cumulative incidence, 7%). Thirty percent of participants were leishmanin skin test positive (men, 34%; women, 26%; P = 0.06). VL was more common in men than women (9.7% versus 4.5%, P < 0.05), possibly reflecting male outdoor sleeping habits. Molecular typing in splenic aspirates showed L. infantum (six) and L. donovani (one). Local transmission resulted from multiple introductions, is now well established, and will be difficult to eradicate.
Journal Article > ResearchFull Text
PLoS Negl Trop Dis. 8 November 2018; Volume 12 (Issue 11); DOI:10.1371/journal.pntd.0006778
Coulborn RM, Gebrehiwot TG, Schneider M, Gerstl S, Adera C, et al.
PLoS Negl Trop Dis. 8 November 2018; Volume 12 (Issue 11); DOI:10.1371/journal.pntd.0006778
Ethiopia bears a high burden of visceral leishmaniasis (VL). Early access to VL diagnosis and care improves clinical prognosis and reduces transmission from infected humans; however, significant obstacles exist. The approximate 250,000 seasonal mobile workers (MW) employed annually in northwestern Ethiopia may be particularly disadvantaged and at risk of VL acquisition and death. Our study aimed to assess barriers, and recommend interventions to increase access, to VL diagnosis and care among MWs.
Journal Article > ReviewFull Text
Lancet Global Health. 1 December 2021; Volume 9 (Issue 12); e1763-e1769.; DOI:10.1016/S2214-109X(21)00392-2
Alvar J, den Boer ML, Dagne DA
Lancet Global Health. 1 December 2021; Volume 9 (Issue 12); e1763-e1769.; DOI:10.1016/S2214-109X(21)00392-2
East Africa is the world region most affected by visceral leishmaniasis, accounting for 45% of cases globally that were reported to WHO in 2018, with an annual incidence that is only slightly decreasing. Unlike southeast Asia, east Africa does not have a regional approach to achieving elimination of visceral leishmaniasis as a public health problem. The goal of the WHO 2021-30 Neglected Tropical Diseases road map is to reduce mortality caused by the disease to less than 1%. To achieve this goal in east Africa, it will be necessary to roll out diagnosis and treatment at the primary health-care level and implement evidence-based personal protection methods and measures to reduce human-vector contact. Investment and collaboration to develop the necessary tools are scarce. In this Health Policy paper, we propose a strategic framework for a coordinated regional approach in east Africa for the elimination of visceral leishmaniasis as a public health problem.