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.

BACKGROUND

Visceral leishmaniasis (VL) is a vector-borne disease caused by Leishmania parasites and transmitted by sand fly bites, targeted for elimination in India. VL primarily affects rural, low-income populations with limited health care access. In South Asia, few studies have explored patients’ perspectives, diagnoses, and treatment experiences; particularly lacking an understanding about the patients’ life experiences outside of clinical research settings.

METHODOLOGY/PRINCIPAL FINDINGS

A qualitative study was conducted in Bihar, India, using moderator-facilitated, protocol-defined discussion. Eighteen adult patients and 12 caregivers of children diagnosed with and treated for VL within the last 12 months were identified by self-report. Mean time from symptom onset to diagnosis was 13.8 days. Challenges of the early patient life experience included lack of urgency by health care professionals, delayed diagnosis, and no guarantee of treatment at the location of their VL diagnosis (63% had to switch to a different center for treatment, at times delaying treatment). Key barriers identified in previous studies that were re-confirmed in this study include out-of-pocket financial burden, absence from work/home duties, and long-distance travel to hospitals. Patients and caregivers (n = 29/30) expressed a preference for a potential oral treatment that could be taken close to home.

CONCLUSIONS/SIGNIFICANCE

This study reveals new insights about the patient life experience and reconfirms previous research indicating that access to care for patients with VL in the Bihar area remains a challenge. Although most patients with VL seek care early, diagnosis often requires multiple visits to a health care facility. Despite access to therapy in public hospitals, some patients reported a preference for private care. Even if diagnosis takes place in a government-funded public setting, some patients reported needing to move from the location of diagnosis to another center to receive therapy, creating an additional burden for patients. As a potential alternative to current parenteral treatment, adult patients and caregivers of pediatric patients expressed interest in a potential oral therapy because it may reduce barriers to access care.

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).

BACKGROUND

Visceral leishmaniasis (VL) is an important public health problem, which mainly affects the poor rural dwelling communities in Low- and Middle-Income Countries. However, little is known about the health and economic burdens of this disease in East Africa, including Ethiopia. The aim of this study was to assess the household level economic burden of VL among affected communities in Tigray, Northern Ethiopia.

METHODS

Between April and August 2020, a cross-sectional household survey was conducted on 96 patients who had been treated for VL within 12 months prior to the survey, in six districts of Tigray. Data on households’ health seeking behavior, direct and indirect costs and coping strategies were collected using a structured questionnaire and the responses were analyzed using SPSS software.

RESULTS

Most (82%) of the patients surveyed were males and the majority (74%) of them were between 16 and 30 years of age. The education level of participants was very low: over 33% had not received any form of education; 48% of patients were farmers dependent on subsistence agriculture and about 32% were daily laborers. Just under half of household families (46%) resided in “poor houses” with structures made from entirely local materials. Forty-one percent of patients from the surveyed households had traveled 48 to 72 kilometers to reach VL treatment hospitals. The median total household cost for one VL episode was estimated to be US$ 214. This is equated to 18% of the mean total annual household income or 72.5% of annual per capita income of the study population. More than 80% of the households surveyed incurred catastrophic costs of VL, where this is defined as exceeding 10% of annual household income. The median delay between the onset of symptoms and arrival at a care provider hospital was 37 days; once the patient arrived at hospital, the median delay during diagnosis was 3 days. Direct and indirect costs represented 44% and 56% of the total costs incurred, respectively. To cope with VL treatment costs, 43% of the households used more than one coping strategy: 48% took out loans, 43% sold livestock and 31% of households mobilized cash savings.

CONCLUSIONS

VL in Tigray is concentrated among young males with low educational background and mostly engaged in subsistence economic activities. Despite the free diagnostic and treatment provisions that were available at public hospitals at the time of the study, our work shows that the household economic burden of the disease had significant impact among VL-affected communities in Tigray. Initiating community awareness towards prevention, early treatment seeking and decentralization of VL treatment centers are strongly recommended. In addition, we recommend efforts to reduce household treatment costs through transport and food provisions for patients (and their accompanying carers where possible) or through cash reimbursement for patients who complete treatment at public hospitals, in order to reduce the barriers to seeking treatment for this life-threatening disease.

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.