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).

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.

Background

People with human immunodeficiency virus (PWH) with recurrent visceral leishmaniasis (VL) could potentially drive Leishmania transmission in areas with anthroponotic transmission such as East Africa, but studies are lacking. Leishmania parasitemia has been used as proxy for infectiousness.

Methods

This study is nested within the Predicting Visceral Leishmaniasis in HIV-InfectedPatients (PreLeisH) prospective cohort study, following 490 PWH free of VL at enrollment for up to 24–37 months in northwest Ethiopia. Blood Leishmania polymerase chain reaction (PCR) was done systematically. This case series reports on 10 PWH with chronic VL (≥3 VL episodes during follow-up) for up to 37 months, and 3 individuals with asymptomatic Leishmania infection for up to 24 months.

Results

All 10 chronic VL cases were male, on antiretroviral treatment, with 0–11 relapses before enrollment. Median baseline CD4 count was 82 cells/µL. They displayed 3–6 VL treatment episodes over a period up to 37 months. Leishmania blood PCR levels were strongly positive for almost the entire follow-up (median cycle threshold value, 26 [interquartile range, 23–30]), including during periods between VL treatment. Additionally, we describe 3 PWH with asymptomatic Leishmania infection and without VL history, with equally strong Leishmania parasitemia over a period of up to 24 months without developing VL. All were on antiretroviral treatment at enrollment, with baseline CD4 counts ranging from 78 to 350 cells/µL.

Conclusions

These are the first data on chronic parasitemia in PWH from Leishmania donovani–endemic areas. PWH with asymptomatic and symptomatic Leishmania infection could potentially be highly infectious and constitute Leishmania superspreaders. Xenodiagnosis studies are required to confirm infectiousness.