Visceral leishmaniasis & HIV co-infection in Bangladesh: Investigating prevalence and policy recommendations.

Postkala-Azar Dermal and Visceral Leishmaniasis in a Patient from Bangladesh.

Studies pertaining to Visceral leishmaniasis (VL) and its dermal sequel, Post Kala-azar Dermal Leishmaniasis (PKDL) are usually restricted to their immunopathogenesis, but the role, if any, regarding metabolic dysfunction of lymphocytes remains unanswered, and was the focus of this study. To delineate and correlate the functional and bioenergetic status of lymphocytes in patients with VL and PKDL. In Peripheral blood of patients with VL (n = 11) or PKDL (n = 18), along with healthy controls (n = 10), the T lymphocyte subsets (CD4+ and CD8+), their activation (CD69) and exhaustion (CD279) status were determined by flow cytometry. Oxidative phosphorylation (OXPHOS) and glycolysis were measured concomitantly in an extracellular flux analyser, whilst the status of mitochondrial respiration and glycolysis related genes was measured by qPCR. In comparison to healthy controls, the activation status remained unchanged in VL and PKDL cases but the frequency of exhausted T cells was significantly raised. These exhausted T cells showed an increased expression of OXPHOS in terms of signalling markers (SMAD3 and CPT1A) and oxygen consumption rate (OCR), along with an increased expression of mitochondrial respiration genes, which correlated positively with CD279+ T cells, whereas glycolysis remained unchanged. Patients with VL and PKDL demonstrated increased expression of CD279/Programmed cell death protein 1 (PD-1). This PD-1 signalling possibly activated SMAD3 and mitochondrial CPT1A, which led to increased mitochondrial respiration. This metabolic adaptation possibly facilitated sustenance of the exhausted T cell phenotype and contributed to disease progression. Targeting immunometabolism could well be a therapeutic approach worthy of future pharmacological consideration.

Treatment regimens and clinical outcomes for post-kala-azar dermal leishmaniasis (PKDL) vary across South Asia and Eastern Africa. We evaluated the skin target site pharmacokinetics (PK) of miltefosine, liposomal amphotericin B (LAmB) and paromomycin and associated pharmacodynamics (PD) on skin parasite reduction and lesion healing, to determine PK/PD factors driving regional differences in clinical outcomes. In South Asia, participants (n = 126) received LAmB alone or with miltefosine. In Eastern Africa, participants (n = 110) received LAmB or paromomycin with miltefosine. Skin drug concentrations were compared to the in vitro EC50 of Leishmania donovani to assess PK target attainment, then correlated with skin parasite load and lesion score to evaluate pharmacokinetic-pharmacodynamic (PK-PD) relationships. Antileishmanial drug distribution varied in skin. Miltefosine showed the highest skin-to-plasma ratio, with medians of 1.19 (IQR: 0.78-1.88) in South Asia vs. 1.58 (1.1-2.08) in Eastern Africa (P < 0.05). Combining paromomycin or LAmB with miltefosine improved PK target attainment and reduced variability. In South Asia, macular or mixed (macular and papular/nodular) lesions predominated (93%) and were associated with ≥6-fold higher baseline parasite load and lesion score versus Eastern Africa, where papular and maculopapular lesions were more common (97%). By treatment end, parasite loads dropped ≥99% in both regions, with ≤7% above the transmission threshold. Lesion scores decreased by 11% in South Asia and 93% in Eastern Africa. Similar skin PK target attainment and relative parasite reduction were achieved for all regimens. Regional differences in parasite load and lesion score at baseline and lesion healing rates, suggest disease presentation is the primary factor affecting clinical outcomes.

Post-kala-azar dermal leishmaniasis (PKDL) occurs mainly in Eastern Africa (EA) and the Southeast Asia region (SEAR), but with important differences. In EA PKDL occurs in young children shortly after treatment of VL (within 1-13 months) when the immune response to leishmania is developing. In contrast, in the SEAR VL and PKDL occur in adolescents and young adults with an interval of 1-4 years or more after successful VL treatment with possible downgrading of the immune response. The risk factors for PKDL in both regions are poorly understood. From a literature search, data was extracted with regard to risk factors, epidemiology, genetics, pathophysiology, immune responses, or co-infections in PKDL. Among host factors, young age and male gender are risk factors in EA, and in both EA and the SEAR decreased expression of the IFNGR1 was found in PKDL but not VL. Parasite-related factors included differences in strains of VL and PKDL as well as co-infection with symbionts such as Leptomonas seymouri. Previous treatment of VL was a major risk factor in Sudan, India, and Bangladesh. PK and PD of drugs used in VL and PKDL may differ. Environmental factors include naturally occurring arsenic and exposure to UV light. Lastly, co-infection with other microbes is not uncommon and may result in downgrading of the immune response after successful VL treatment in the SEAR. A better understanding of the pathophysiology in PKDL is needed to describe factors that influence (excessive) upgrading or downgrading of the immune response. For control efforts, optimalization of VL treatment (multidrug approach, immune modifiers) may result a stronger immune response and therefore lower PKDL rates. Lastly, the approach to PKDL should be integrated in a joint skin disease approach to look for risk factors such as co-infection with a strategy for combined management and control.

The resurgence of Visceral Leishmaniasis (VL) is a natural cyclical phenomenon with an inter-epidemic period of 10-15 years. It might be due to the persistence of a silent parasite pool amongst post kala-azar dermal leishmaniasis (PKDL) and asymptomatic leishmanial infection (ALI). The present study targeted to find out the obstacles for unearthing and proper management of the hidden parasite pool for prevention of the resurgence of VL in erstwhile endemic districts of West Bengal, India. Two strategies were employed to identify the latent parasite reservoirs: follow-up of individuals having a previous history of VL and/or PKDL and limited mass sero-surveillance within a 500-m radius of recently treated VL and PKDL. Diagnosed PKDL and VL cases were treated and ALI were followed up. A total of 95 new PKDL and 70 relapse PKDL were diagnosed during the entire study period; those remained undiagnosed in spite of ongoing case searching methods recommended by the national VL elimination programme. 'Relapse PKDL'-a new challenge for VL elimination has been identified. The incidence of PKDL declined steadily during successive study years. Limited mass survey revealed 17 VL, 2 PKDL and 124 ALI. Most of the ALI sero-reverted during the follow up period and 2 of them converted to disease VL. The present work revealed three major obstacles. First, identification of the occult parasite pool may be resolved by applying the searching methods used in this study. Second, case confirmation of 'relapse PKDL' may be achieved by examining slit skin samples at the local level by existing staff with proper training. Alternative short duration treatment strategy for the treatment of new and relapse PKDL is needed. Third, considering the long inter-epidemic period and observed declining trend of incident PKDL, such surveillance should be continued for 10-15 years for the prolonged post-elimination phase and finally to achieve eradication.

Post-kala-azar dermal leishmaniasis (PKDL) is a chronic dermal sequela in apparently cured patients with visceral leishmaniasis (VL). It presents with either macular or polymorphic forms, and poses a major epidemiological challenge in South Asia, particularly in India, Bangladesh and Nepal. Although nonfatal, PKDL acts as a reservoir for Leishmania donovani, thereby sustaining transmission in the postelimination phase of VL. Potential risk factors for PKDL include a history of VL, immunosuppression, host genetics and malnutrition. The disease burden is further complicated by poor health-seeking behaviour and stigma associated with dermal lesions, leading to diagnostic delays and under-reporting. PKDL is associated with a mixed T helper 1/2 profile, translating into a mixed anti-inflammatory/regulatory and proinflammatory milieu. This is coupled with prominent infiltration of immune cells into lesional sites, including macrophages, lymphocytes and neutrophils, which cause localized immune alteration. The diagnosis of PKDL is challenging in macular cases due to their low parasite burden and overlapping symptoms with other hypopigmentary disorders, but molecular tools now offer improved sensitivity and even have field-level applicability. In terms of therapeutics, the management of PKDL is hindered by the need for prolonged treatment, chances of relapse, emerging drug resistance and noncompliance. Overall, the integration of molecular diagnostics, immunological insights and community-based treatment strategiesare essential to eliminate PKDL and sustain efforts to eliminate kala-azar.

Dermal leishmaniasis, particularly postkala-azar dermal leishmaniasis (PKDL), is an uncommon entity that may closely mimic lepromatous leprosy in endemic regions. Both conditions present with chronic, symmetric nodular or plaque-like lesions, leading to frequent diagnostic confusion, especially when peripheral nerve thickening is absent. We report a 71-year-old male with a 15-year history of diffuse erythematous nodules and scaly plaques over the palms and dorsum of the feet, repeatedly managed as lepromatous leprosy without clinical improvement. The absence of peripheral nerve thickening and a negative slit-skin smear prompted further evaluation. Skin biopsy demonstrated macrophages packed with Leishmania donovani (LD) bodies, and polymerase chain reaction (PCR) targeting the ITS-1 gene confirmed LD. The patient was initiated on miltefosine 50 mg twice daily for 12 weeks (standard regimen). At 4-week follow-up, lesions showed approximately 30% flattening, and at 12 weeks, more than 60% regression was noted, without adverse effects. This rare case of a 71-year-old male with >15 years of misdiagnosis highlights that chronic diffuse nodular dermatosis without nerve involvement should prompt consideration of PKDL even in the absence of documented prior visceral leishmaniasis. Accurate diagnosis using histopathology and PCR prevents prolonged inappropriate therapy and reduces the risk of community transmission.

Visceral leishmaniasis (VL) is a neglected vector-borne disease caused by obligate intracellular protozoa of the genus Leishmania. In immunocompromised patients, VL may present atypically, progress more aggressively, and respond less favorably to treatment. We present the case of a 62-year-old male with chronic inflammatory demyelinating polyneuropathy (CIDP) receiving long-term corticosteroids and azathioprine who developed relapsing VL complicated by post-kala-azar dermal leishmaniasis (PKDL). The patient initially presented with prolonged fever, pancytopenia, hepatosplenomegaly, and weight loss. Bone marrow aspirate revealed Leishmania amastigotes. Intravenous lyposomal amphotericin B (L-AMB) achieved temporary remission; however, PKDL and VL recurred one year later. Despite receiving sequential therapy with L-AMB and miltefosine, the patient experienced further relapses, likely due to severe T- and B-cell lymphopenia and marasmic-like malnutrition. VL should be considered in the differential diagnosis of prolonged fever and cytopenias in immunosuppressed patients in Mediterranean Europe, even in the absence of travel history. Chronic immunosuppression, secondary immunodeficiency, and malnutrition can significantly impair treatment response and favor recurrence, highlighting the need for integrated clinical, nutritional, and epidemiological management strategies.

Post-kala-azar dermal leishmaniasis (PKDL) involves a high macrophage burden in which the Leishmania parasites reside. Liposomal amphotericin B (LAmB) plays a key role in the treatment of PKDL. The mononuclear phagocyte system (MPS) is crucial in the distribution of liposomal drugs as well as the leishmaniasis pathophysiology. This study focused on characterizing the interaction between LAmB pharmacokinetics, the MPS, and parasite dynamics for optimal dosing of LAmB in PKDL. Clinical trial data from the Indian subcontinent, involving short-course LAmB administered alone or with miltefosine, were analyzed using nonlinear mixed-effects modeling. The pharmacokinetics of LAmB were best described by a two-compartment model with a saturable LAmB uptake by the MPS. The maximum MPS uptake capacity was modeled with a baseline component and an additional disease-related component relative to the parasite burden. As treatment progressed, MPS capacity decreased with declining parasite load, resulting in a median 54% increase in the systemic LAmB exposure (AUC0-24h) by the end of treatment. Simulations suggested that a similar parasite clearance could be achieved with a 50% lower total LAmB dose, supporting the potential efficacy of reduced dosing regimens. Combining LAmB and miltefosine further accelerated parasite clearance compared to LAmB alone. This study highlights the importance of understanding the bidirectional interactions between LAmB pharmacokinetics and parasite infection for interpreting systemic exposure and optimizing treatment approaches. If confirmed in clinical trials, reduced LAmB dosing strategies could enable more rational and cost-effective management of PKDL and other dermal leishmaniases.

Efficacy of liposomal amphotericin B for treating post-kala-azar dermal leishmaniasis (PKDL): A systematic review and single-arm meta-analysis.

Kala-Azar, also known as visceral leishmaniasis, is a neglected tropical illness that mostly affects populations with inadequate resources and has a significant global morbidity and mortality rate. This systematic review summarises developments in public health initiatives, treatment, and diagnosis for the management of VL. Disease identification has been improved by diagnostic advancements such as rK39 dipstick tests, ELISA, and PCR; nonetheless, regional variations in sensitivity and specificity, as well as the ongoing dependence on invasive techniques, underscore the necessity for widely available, non-invasive substitutes. New developments in medicine, including liposomal amphotericin B and combination treatments with paromomycin or miltefosine, have greatly increased therapy effectiveness while lowering toxicity and length of treatment. Cost, opposition, and restricted accessibility issues still exist, nevertheless. As a reservoir for disease transmission, post-kala-azar dermal leishmaniasis (PKDL) continues to be a major obstacle to eradication. Although they have proven successful, vector control methods like indoor residual spraying (IRS) and durable insecticidal nets are hampered by DDT resistance and environmental issues. The illness load in the Indian subcontinent has been decreased as a result of public health measures like the Kala-Azar Elimination Initiative. Socioeconomic factors including poverty, malnutrition, and a lack of proper healthcare facilities still obstruct advancement in spite of these achievements. The urgent need for economical combination treatments, cost-effective diagnostics, and long-term vector control methods is highlighted by this review. To eradicate visceral leishmaniasis worldwide, a multisectoral strategy that addresses underlying vulnerabilities is necessary.

Post Kala-azar Dermal Leishmaniasis (PKDL) is a complication of Visceral Leishmaniasis (VL) and acts as a reservoir for Leishmania parasites. With climatic changes and ozone depletion increasing ultraviolet radiation (UVR), we investigated the connection between UVR and PKDL development. We have measured sun-light UVR intensities by UV light meters and satellite-based methods. Our data showed a concerning increase in the UV index (> 12.0-14.5) during summer and pre-monsoon season. A cohort of 283 PKDL patients revealed a strong correlation between prolonged sun-light (UVR) exposure (4-8h/day) and worsening skin lesions, with many patients, particularly labourers and farm workers, reporting sunburn and/or irritation, skin sensitivity. Additionally, in vitro studies with human THP-1 cells showed UVB-induced cytotoxicity and immuno-suppression, that likely to be associated with PKDL development. Serum analysis showed significant alterations in key cytokines concentrations (IL-10, IL-12), IFN-γR and Vitamin-D, iron level among PKDL and VL patients versus healthy controls. Specifically, PKDL patients exhibited upregulated expressions of TLRs-2/4 and TNFR-2, but down-regulation of TNFR-1 were observed in PKDL patients than the healthy controls. In essence, our findings implicate the risk posed by increasing sunlight UVR exposure for PKDL development in vulnerable populations from VL endemic regions of Bihar.

Post-kala-azar dermal leishmaniasis (PKDL) is a neglected tropical disease that can develop after treatment of leishmaniasis. It causes significant health risks and serves as a reservoir, perpetuating transmission. Current information on PKDL characteristics is crucial for effective disease management and control. This study aimed to describe clinical and epidemiological characteristics of PKDL patients in eastern Sudan. A retrospective cross-sectional study was conducted on suspected PKDL patients (N = 37) at a tertiary hospital in eastern Sudan. Blood samples were tested for anti-rK39 antibodies to confirm the diagnosis of the disease. Demographic, clinical, and epidemiological data of the PKDL patients were gathered and analyzed. Most PKDL cases (69.4%) came from specific locations involving one ethnic group (94.6%), mainly affecting young males (54.1%). A family history of PKDL was noted in only 27.0% of cases; 51.4% developed PKDL within 1 month after visceral leishmaniasis (VL) treatment. Most cases (56.8%) were grade 1 (a low level of parasitic load), predominantly featuring macular (51.4%), papular (18.9%), and nodular (13.5%) lesions. All patients had skin rashes; 91.9% exhibited no fever, and 29.7% reported itching. Lesions appeared within a month after VL treatment, with most patients recovering spontaneously within 3-18 months. PKDL was particularly prevalent in specific regions and ethnic groups, namely the Masaleet and Dago tribes. These findings can enhance PKDL understanding and management in the region.

Abstract Post kala-azar dermal leishmaniasis (PKDL) is a well-known complication of visceral leishmaniasis (VL, kala-azar) in East Africa, with most cases reported from Sudan; the first description of PKDL dates back to 1921. Some three decades ago, increased interest (in Africa as well in other endemic regions) in PKDL was sparked through a letter published in the Lancet (1991) by the Leishmania research group of the University of Khartoum, describing PKDL in the absence of active VL. Shortly thereafter, a huge outbreak of VL was reported from the Upper Nile state and Gedaref state, which continues to date. Epidemiological studies reported PKDL incidences after VL in up to 50%–60% of VL patients, with age, poor nutrition, and inadequate drug treatment as the most important risk factors. However, the high PKDL rates were not uniformly found in all villages, where determinants such as tribal (genetic) background, socioeconomic circumstances, and exposure may differ. PKDL cases without preceding VL or with concomitant VL (para kala-azar dermal leishmaniasis) were described. Over the years, PKDL cases have been increasingly recognized with detailed clinical description, clinical staging, and combination of other post kala-azar manifestations, such as in the eye (conjunctivitis, blepharitis, and uveitis) and nasal mucosa. Diagnosis was initially done by clinically or microscopic techniques; later, the value of polymerase chain reaction (PCR) was demonstrated. Insight was gained in differential diagnosis, and, importantly, the evolving immune responses from VL (predominantly Th2) to cure (predominantly Th1) with PKDL as an intermediate condition (mixed Th2/Th1). The different immune response was also found to underlie the different most common forms: macular and papulo-nodular. Biomarkers were examined (clinical including imaging, parasitological, and serological and immunological parameters). A study about the natural history indicated that 85% of PKDL cases would self-heal, while other, more severe and persisting cases required treatment. Several studies were carried out to improve treatment outcomes of VL and PKDL with groundbreaking work in combined chemo and immunotherapy. While anthroponotic transmission of VL was assumed in PKDL patients as the reservoir, data on previous and recent entomological studies also provide evidence for zoonotic transmission. Important observations were made on sand fly biting behavior, strategies on the use of insecticide spraying, and the role of animals as zooprophylaxis and/or zoopotentation.

Abstract Leishmaniasis is a neglected tropical disease affecting the world’s poorest populations in over 90 countries, of which visceral leishmaniasis (VL)/kala-azar is the most fatal. Post kala-azar dermal leishmaniasis (PKDL) is a chronic dermal sequela that occurs in patients who have undergone treatment for VL caused by Leishmania donovani. The geographical distribution of PKDL involves East Africa, where it presents as papular or nodular lesions, and South Asia, where it presents with widespread polymorphic and macular lesions. Patients with PKDL represent an important but largely neglected reservoir of infection that perpetuates anthroponotic Leishmania transmission and can jeopardize the VL elimination program in the Indian subcontinent. Therefore, although not life-threatening, it becomes imperative to diagnose and treat PKDL cases as a part of the elimination program, which, in turn, requires the availability of robust data regarding the immunopathology of dermal lesions. However, in the absence of an animal model, understanding the immunological basis of PKDL is critical for developing effective treatment regimens, but the information remains limited. A complex interplay between dendritic cells, neutrophils, macrophages, T cells, B cells, and associated cytokines plays a significant role in disease pathogenesis. Furthermore, recent findings have indicated differential immune responses between the two clinical forms of PKDL, which may impact on the disease pathogenicity and response to chemotherapy. Collectively, this review highlights the role of immune dysregulation in South Asian PKDL, which have allowed parasite persistence, leading to disease progression. Interventions via targeted immunomodulatory therapies aiming to restore effective immune responses could provide promising therapeutic strategies for management of PKDL.

Abstract Most of the hospital-based studies in post-kala-azar dermal leishmaniasis (PKDL) have been done in the polymorphic or mixed forms where the indurated lesions comprising papules and nodules played an important part in the clinical diagnosis rather than hypopigmented macules. Limited studies have shown that the monomorphic form of macular PKDL can be localized, generalized, or at times involve the entire body. Epidemiological work in kala-azar endemic areas has disclosed that in household surveys there are many with hypopigmented macules that were proven to be PKDL. The gender bias favoring males over females was also nonexistent, and the ratio of the clinical presentation of polymorphic and predominantly macular forms was equal. Both histopathology and slit-skin smears are not helpful in diagnosis; entomological studies have conclusively shown that the macules harbor the parasite though the load as seen in quantitative polymerase chain reaction (qPCR) studies is small. Thus, the macules do play a part in the spread of kala-azar. Treatment is the same as recommended for PKDL but since the hypopigmentation takes longer to repigment, better methods of test of cure like qPCR are required. Training modules for health workers doing epidemiological work must consider this presentation more seriously, increase awareness, and discuss other confounding dermatoses like pityriasis versicolor and vitiligo.

Abstract Post kala-azar dermal leishmaniasis (PKDL) that usually follows successfully treated visceral leishmaniasis (VL) can be severe and disfiguring. Treatment with sodium stibogluconate is prolonged, expensive with colossal cardiorenal toxicities. Early trials with liposomal amphotericin B (AMB) (AmBisome®) revolutionized PKDL treatment with increased safety and improved efficacy. AmBisome® pharmacokinetics and dynamics are poorly understood. This study aimed to show the efficacy of AmBisome® through its permeation within skin lesions. Following guardians’ written consent, ten PKDL patients with a history of parasitolgically confirmed VL, typical histopathological patterns, and presence of Leishmania antigens/parasites were enrolled. Blood samples were taken for DAT, hematological, and biochemical investigations. Leishmanin skin test (LST) was performed, and skin biopsies were taken for histopathology and electron microscopy. Patients received 14 daily injections of AmBisome® at 3 g/Kg/body weight. Skin biopsies revealed hyperkeratosis, loose epithelioid granulomas with dermis lymphocytic and histiocytic infiltrates, destruction of the basal layer, melanin incontinence, and loss of basal layer pigmentation. Leishmania antigens and scanty parasites were detected in the lesions. LST was non-reactive in all patients. DAT titers ranged from 6400 to 51,200. Patients responded markedly; healing continued for a few months after the stoppage of the drug. Electron micrographs showed skin lesion infiltration by T lymphocytes, macrophages loaded with parasites, and lipid droplets. Liposomal AMB was likely absorbed by circulating macrophages though their high-density lipoprotein receptors to be recruited to the skin, where the leishmanial parasites will be engulfed as well. Fusion of the phagosomes of the drug and that of the parasite leads to local release of the drug, which combined with the ergosterol of the parasite cell membrane led to its demise. Skin lesion healing continued after stoppage of the drug due to the drug persistence in macrophages. In conclusion, liposomal AMB enters the skin through recruited circulating macrophages with parasite phagocytosis and killing through binding with cell membrane ergosterol and pore formation.

Abstract The Infectious Diseases Data Observatory (IDDO) data platform was launched in 2016 with the aim of harmonizing individual participant data (IPD) from clinical trials on infectious diseases, with a specific focus on neglected tropical diseases, including visceral leishmaniasis (VL). The VL data platform hosted by IDDO was developed in collaboration with researchers at the frontline of disease combat. This platform currently hosts IPD from more than 50 studies on VL and post-kala-azar dermal leishmaniasis (PKDL). The platform remains a controlled open-access repository to the scientific community and is currently facilitating collaborative IPD meta-analyses addressing research questions regarding drug safety and efficacy. Further open-access resources maintained by IDDO include clinical case report forms (CRFs) for VL, and VL-human immunodeficiency trials, a comprehensive inventory of all published VL clinical trials (1980–to date) and PKDL trials (1973–-to date), and these are publicly available as downloadable resources to the research community. These open-access resources developed in collaboration with the scientific community can help in identifying research gaps, and facilitate the generation of new evidence, and the CRFs can help to harmonize data collection for future trials. In this study, we highlight some of the ongoing and past research activities undertaken using these open-access resources (such as predictors of relapse and the development of a clinical scoring system for detecting relapse) and how these can support generating evidence to complement the ongoing activities in the Indian subcontinent and East Africa to reach the elimination targets.

Abstract Visceral leishmaniasis (VL), a severe neglected tropical disease, presents a substantial global health burden, with an estimated 1 million new cases annually. Although cutaneous leishmaniasis (CL) is more prevalent, VL is the deadliest form, particularly in regions such as the Indian subcontinent, East Africa, and Brazil. The disease is caused by Leishmania donovani and transmitted through infected sandflies. Advances in VL management have significantly reduced the number of cases, particularly in India, Nepal, and Bangladesh. However, challenges persist due to human immunodeficiency virus-VL (HIV-VL) coinfection, which exacerbates disease severity and treatment resistance. Effective diagnostic techniques such as polymerase chain reaction and rk39 antigen tests are essential for timely identification of VL, though limitations persist in HIV-positive patients and asymptomatic carriers. Current treatment options, including liposomal amphotericin B and miltefosine, have shown high efficacy, with combination therapies offering promising results in addressing drug resistance and reducing the treatment duration. Post kala-azar dermal leishmaniasis (PKDL) poses a significant challenge to VL elimination, as it serves as a reservoir for ongoing transmission. Shorter, safer regimens are needed, particularly for endemic regions such as East Africa, where traditional treatments are less effective. Continued global collaboration is critical to achieve sustained progress in the elimination of VL and its complications, particularly for vulnerable populations affected by coinfections and drug resistance.