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PLoS Neglected Tropical Diseases Apr 2024Post-kala-azar dermal leishmaniasis (PKDL) is a dermatosis which can occur after successful treatment of visceral leishmaniasis (VL) and is a public health problem in VL...
Post-kala-azar dermal leishmaniasis (PKDL) drug efficacy study landscape: A systematic scoping review of clinical trials and observational studies to assess the feasibility of establishing an individual participant-level data (IPD) platform.
BACKGROUND
Post-kala-azar dermal leishmaniasis (PKDL) is a dermatosis which can occur after successful treatment of visceral leishmaniasis (VL) and is a public health problem in VL endemic areas. We conducted a systematic scoping review to assess the characteristics of published PKDL clinical studies, understand the scope of research and explore the feasibility and value of developing a PKDL individual patient data (IPD) platform.
METHODS
A systematic review of published literature was conducted to identify PKDL clinical studies by searching the following databases: PubMed, Scopus, Ovid Embase, Web of Science Core Collection, WHO Global Index Medicus, PASCAL, Clinicaltrials.gov, Ovid Global Health, Cochrane Database and CENTRAL, and the WHO International Clinical Trials Registry Platform. Only prospective studies in humans with PKDL diagnosis, treatment, and follow-up measurements between January 1973 and March 2023 were included. Extracted data includes variables on patient characteristics, treatment regimens, diagnostic methods, geographical locations, efficacy endpoints, adverse events and statistical methodology.
RESULTS
A total of 3,418 records were screened, of which 56 unique studies (n = 2,486 patients) were included in this review. Out of the 56 studies, 36 (64.3%) were from India (1983-2022), 12 (21.4%) from Sudan (1992-2021), 6 (10.7%) were from Bangladesh (1991-2019), and 2 (3.6%) from Nepal (2001-2007). Five (8.9%) studies were published between 1981-1990 (n = 193 patients), 10 (17.9%) between 1991-2000 (n = 230 patients), 10 (17.9%) between 2001-2010 (n = 198 patients), and 31 (55.4%) from 2011 onwards (n = 1,865 patients). Eight (14.3%) were randomised clinical trials, and 48 (85.7%) were non-randomised studies. The median post-treatment follow-up duration was 365 days (range: 90-540 days) in 8 RCTs and 360 days (range: 28-2,373 days) in 48 non-randomised studies. Disease diagnosis was based on clinical criterion in 3 (5.4%) studies, a mixture of clinical and parasitological methods in 47 (83.9%) and was unclear in 6 (10.7%) studies. Major drugs used for treatment were miltefosine (n = 636 patients), liposomal amphotericin B (L-AmB) (n = 508 patients), and antinomy regimens (n = 454 patients). Ten other drug regimens were tested in 270 patients with less than 60 patients per regimen.
CONCLUSIONS
Our review identified studies with very limited sample size for the three major drugs (miltefosine, L-AmB, and pentavalent antimony), while the number of patients combined across studies suggest that the IPD platform would be valuable. With the support of relevant stakeholders, the global PKDL community and sufficient financing, a PKDL IPD platform can be realised. This will allow for exploration of different aspects of treatment safety and efficacy, which can potentially guide future healthcare decisions and clinical practices.
Topics: Humans; Leishmaniasis, Visceral; Leishmaniasis, Cutaneous; Antiprotozoal Agents; Observational Studies as Topic; Clinical Trials as Topic; Feasibility Studies; Treatment Outcome; India; Bangladesh
PubMed: 38626228
DOI: 10.1371/journal.pntd.0011635 -
PLoS Neglected Tropical Diseases Apr 2024Cutaneous leishmaniasis (CL) is characterized by potentially disfiguring skin ulcers carrying significant social stigma. To mitigate systemic drug exposure and reduce...
BACKGROUND
Cutaneous leishmaniasis (CL) is characterized by potentially disfiguring skin ulcers carrying significant social stigma. To mitigate systemic drug exposure and reduce the toxicity from available treatments, studies addressing new local therapeutic strategies using available medications are coming up. This review systematically compiles preclinical and clinical data on the efficacy of amphotericin B (AmB) administered locally for cutaneous leishmaniasis.
METHODOLOGY
Structured searches were conducted in major databases. Clinical studies reporting cure rates and preclinical studies presenting any efficacy outcome were included. Exclusion criteria comprised nonoriginal studies, in vitro investigations, studies with fewer than 10 treated patients, and those evaluating AmB in combination with other antileishmanial drug components.
PRINCIPAL FINDINGS
A total of 21 studies were identified, encompassing 16 preclinical and five clinical studies. Preclinical assessments generally involved the topical use of commercial AmB formulations, often in conjunction with carriers or controlled release systems. However, the variation in the treatment schedules hindered direct comparisons. In clinical studies, topical AmB achieved a pooled cure rate of 45.6% [CI: 27.5-64.8%; I2 = 79.7; p = 0.002), while intralesional (IL) administration resulted in a 69.8% cure rate [CI: 52.3-82.9%; I2 = 63.9; p = 0.06). In the direct comparison available, no significant difference was noted between AmB-IL and meglumine antimoniate-IL administration (OR:1.7; CI:0.34-9.15, I2 = 79.1; p = 0.00), however a very low certainty of evidence was verified.
CONCLUSIONS
Different AmB formulations and administration routes have been explored in preclinical and clinical studies. Developing therapeutic technologies is evident. Current findings might be interpreted as a favorable proof of concept for the local AmB administration which makes this intervention eligible to be explored in future well-designed studies towards less toxic treatments for leishmaniasis.
Topics: Leishmaniasis, Cutaneous; Amphotericin B; Humans; Antiprotozoal Agents; Administration, Topical; Treatment Outcome
PubMed: 38626196
DOI: 10.1371/journal.pntd.0012127 -
The Lancet Regional Health. Southeast... Mar 2024Occurrences of relapse after 6-months post-treatment has been reported in recent Visceral Leishmaniasis (VL) efficacy studies. A meta-analysis was carried out to...
BACKGROUND
Occurrences of relapse after 6-months post-treatment has been reported in recent Visceral Leishmaniasis (VL) efficacy studies. A meta-analysis was carried out to quantify the proportion of relapses observed at and beyond 6-months using the Infectious Diseases Data Observatory (IDDO) systematic review (SR) database.
METHODS
Studies in the IDDO SR database (1983-2021; 160 studies) were eligible for inclusion if follow-up was at least 6-months, relapse was clearly reported, and patients with HIV coinfections were excluded. Meta-analysis of single proportion was undertaken and the estimates were reported with 95% confidence intervals (CI).
FINDINGS
Overall, 131 studies enrolling 27,687 patients were included; 1193 patients relapsed. In the Indian sub-continent (ISC), relapse estimates at 6-months was 4.5% [95% CI: 2.6%-7.5%; = 66.2%] following single dose liposomal amphotericin B (L-AmB) and 1.5% [95% CI: 0.7%-3.3%; = 0%] for L-AmB in a combination therapy. In East Africa (EA), corresponding estimates were 3.8% [95% CI: 1.3%-10.9%; = 75.8%] following pentavalent antimony (PA), and 13.0% [95% CI: 4.3%-33.6%; = 0%] for PA + paromomycin. From 21 studies with follow-up longer than 6-months, 0.6% [95% CI: 0.2%-1.8%; = 0%] of patients relapsed after 6-months and estimated 27.6% [95% CI: 11.2%-53.4%; = 12%] of relapses would have been missed by a 6-month follow-up.
INTERPRETATION
The estimated relapse proportion ranged from 0.5% to 4.5% in ISC and 3.8%-13.0% in EA with the currently recommended drugs. Over one-quarter of relapses would be missed with 6-months follow-up suggesting a longer follow-up may be warranted.
FUNDING
Wellcome Trust (ref: 208378/Z/17/Z).
PubMed: 38482151
DOI: 10.1016/j.lansea.2023.100317 -
PloS One 2023Leishmania aethiopica is a unique species that causes cutaneous leishmaniasis (CL), and studies evaluating treatment outcomes for this condition reported inconsistent... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Leishmania aethiopica is a unique species that causes cutaneous leishmaniasis (CL), and studies evaluating treatment outcomes for this condition reported inconsistent findings. This study aimed to summarize the evidence on treatment outcomes of CL caused by L. aethiopica to support decisions or propose further study.
METHODS
We searched PubMed, Scopus, and ScienceDirect. In addition, we searched grey literature on Google Scholar and performed manual searching on the reference list of articles. Two authors did the screening, selection, critical appraisal, and data extraction. With the narrative synthesis of evidence, we performed a random effects model meta-analysis using the metaprop package in Stata 17. We did sensitivity and subgroup analyses after assessing heterogeneity using the I-squared test and forest plots. The funnel plot and Egger's test were used to assess publication bias.
RESULTS
The review included 22 studies with 808 participants, and the meta-analysis included seven studies with 677 participants. Most studies documented treatment outcomes with antimonial monotherapy, and only one study reported outcomes with combination therapy. The overall pooled proportion of cure was 63% (95% CI: 38-86%). In the subgroup analysis, systemic antimonial monotherapy showed a cure rate of 61%, and the proportion of cure was 87% with topical therapy. Topical therapy showed a better cure for the localized clinical phenotype. A cohort study documented a cure rate of 94.8% with combination therapy for the localized, mucocutaneous, and diffuse clinical phenotypes. The pooled proportion of unfavourable outcomes was partial response (19%), relapse (17%), discontinuation (19%), and unresponsiveness (6%).
CONCLUSIONS
The pooled proportion of cure is low with antimonial monotherapy. Despite limited evidence, combination therapies are a promising treatment option for all clinical phenotypes of CL caused by L. aethiopica. Future high-quality randomized control trials are needed to identify effective monotherapies and evaluate the effectiveness of combination therapies.
Topics: Humans; Leishmania; Cohort Studies; Leishmaniasis, Cutaneous; Treatment Outcome; Combined Modality Therapy
PubMed: 37917604
DOI: 10.1371/journal.pone.0293529 -
PLoS Neglected Tropical Diseases Nov 2022Mucosal or mucocutaneous leishmaniasis is the most severe form of tegumentary leishmaniasis due to its destructive character and potential damage to respiratory and...
BACKGROUND
Mucosal or mucocutaneous leishmaniasis is the most severe form of tegumentary leishmaniasis due to its destructive character and potential damage to respiratory and digestive tracts. The current treatment recommendations are based on low or very low-quality evidence, and pentavalent antimonial derivatives remain strongly recommended. The aim of this review was to update the evidence and estimate the cure rate and safety profile of the therapeutic options available for mucosal leishmaniasis (ML) in the Americas.
METHODOLOGY
A systematic review was conducted in four different databases and by different reviewers, independently, to evaluate the therapeutic efficacy and toxicity associated with different treatments for ML. All original studies reporting cure rates in more than 10 patients from American regions were included, without restriction of design, language, or publication date. The risk of bias was assessed by two reviewers, using different tools according to the study design. The pooled cure rate based on the latest cure assessment reported in the original studies was calculated grouping all study arms addressing the same intervention. The protocol for this review was registered at the International Prospective Register of Systematic Reviews, PROSPERO: CRD42019130708.
PRINCIPAL FINDINGS
Twenty-seven original studies from four databases fulfilled the selection criteria. A total of 1,666 patients with ML were treated predominantly with pentavalent antimonials in Brazil. Other interventions, such as pentamidine, miltefosine, imidazoles, aminosidine sulfate, deoxycholate and lipidic formulations of amphotericin B (liposomal, lipid complex, colloidal dispersion), in addition to combinations with pentoxifylline, allopurinol or sulfa were also considered. In general, at least one domain with a high risk of bias was identified in the included studies, suggesting low methodological quality. The pooled cure rate based on the latest cure assessment reported in the original studies was calculated grouping all study arms addressing the same intervention. It was confirmed that antimony is still the most used treatment for ML, with only moderate efficacy (possibly increased by combining with pentoxifylline). There is already evidence for the use of miltefosine for ML, with a cure rate similar to antimony, as observed in the only direct meta-analysis including 57 patients (OR: 1.2; 0.43-3.49, I2 = 0). It was possible to gather all descriptions available about adverse events reported during ML treatment, and the toxicity reflected the pattern informed in the manufacturers' technical information.
CONCLUSIONS
This study provides an overview of the clinical experience in the Americas related to ML treatment and points out interventions and possible combinations that are eligible to be explored in future well-designed studies.
Topics: Humans; Antimony; Leishmaniasis, Mucocutaneous; Pentoxifylline
PubMed: 36395328
DOI: 10.1371/journal.pntd.0010931 -
Tropical Medicine and Infectious Disease Sep 2022Current knowledge on infection after kidney transplantation (KT) is limited. In order to offer a comprehensive guide for the management of post-transplant... (Review)
Review
Current knowledge on infection after kidney transplantation (KT) is limited. In order to offer a comprehensive guide for the management of post-transplant Leishmaniasis, we performed a systematic review following the latest PRISMA Checklist and using PubMed, Scopus, and Embase as databases. No time restrictions were applied, including all English-edited articles on Leishmaniasis in KT recipients. Selected items were assessed for methodological quality using a modified Newcastle-Ottawa Scale. Given the nature and quality of the studies (case reports and retrospective uncontrolled case series), data could not be meta-analyzed. A descriptive summary was therefore provided. Eventually, we selected 70 studies, describing a total of 159 cases of Leishmaniasis. Most of the patients were adult, male, and Caucasian. Furthermore, they were frequently living or travelling to endemic regions. The onset of the disease was variable, but more often in the late transplant course. The clinical features were basically similar to those reported in the general population. However, a generalized delay in diagnosis and treatment could be detected. Bone marrow aspiration was the preferred diagnostic modality. The main treatment options included pentavalent antimonial and liposomal amphotericin B, both showing mixed results. Overall, the outcomes appeared as concerning, with several patients dying or losing their transplant.
PubMed: 36287999
DOI: 10.3390/tropicalmed7100258 -
PLoS Neglected Tropical Diseases Aug 2021Reports on the occurrence and outcome of Visceral Leishmaniasis (VL) in pregnant women is rare in published literature. The occurrence of VL in pregnancy is not...
BACKGROUND
Reports on the occurrence and outcome of Visceral Leishmaniasis (VL) in pregnant women is rare in published literature. The occurrence of VL in pregnancy is not systematically captured and cases are rarely followed-up to detect consequences of infection and treatment on the pregnant women and foetus.
METHODS
A review of all published literature was undertaken to identify cases of VL infections among pregnant women by searching the following database: Ovid MEDLINE; Ovid Embase; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials; World Health Organization Global Index Medicus: LILACS (Americas); IMSEAR (South-East Asia); IMEMR (Eastern Mediterranean); WPRIM (Western Pacific); ClinicalTrials.gov; and the WHO International Clinical Trials Registry Platform. Selection criteria included any clinical reports describing the disease in pregnancy or vertical transmission of the disease in humans. Articles meeting pre-specified inclusion criteria and non-primary research articles such as textbook, chapters, letters, retrospective case description, or reports of accidental inclusion in trials were also considered.
RESULTS
The systematic literature search identified 272 unique articles of which 54 records were included in this review; a further 18 records were identified from additional search of the references of the included studies or from personal communication leading to a total of 72 records (71 case reports/case series; 1 retrospective cohort study; 1926-2020) describing 451 cases of VL in pregnant women. The disease was detected during pregnancy in 398 (88.2%), retrospectively confirmed after giving birth in 52 (11.5%), and the time of identification was not clear in 1 (0.2%). Of the 398 pregnant women whose infection was identified during pregnancy, 346 (86.9%) received a treatment, 3 (0.8%) were untreated, and the treatment status was not clear in the remaining 49 (12.3%). Of 346 pregnant women, Liposomal amphotericin B (L-AmB) was administered in 202 (58.4%) and pentavalent antimony (PA) in 93 (26.9%). Outcomes were reported in 176 pregnant women treated with L-AmB with 4 (2.3%) reports of maternal deaths, 5 (2.8%) miscarriages, and 2 (1.1%) foetal death/stillbirth. For PA, outcomes were reported in 88 of whom 4 (4.5%) died, 24 (27.3%) had spontaneous abortion, 2 (2.3%) had miscarriages. A total of 26 cases of confirmed, probable or suspected cases of vertical transmission were identified with a median detection time of 6 months (range: 0-18 months).
CONCLUSIONS
Outcomes of VL treatment during pregnancy is rarely reported and under-researched. The reported articles were mainly case reports and case series and the reported information was often incomplete. From the studies identified, it is difficult to derive a generalisable information on outcomes for pregnant women and babies, although reported data favours the usage of liposomal amphotericin B for the treatment of VL in pregnant women.
Topics: Abortion, Spontaneous; Amphotericin B; Antiprotozoal Agents; Female; Humans; Infectious Disease Transmission, Vertical; Leishmaniasis, Visceral; Maternal Death; Pregnancy; Pregnancy Complications, Parasitic; Pregnancy Outcome; Treatment Outcome
PubMed: 34375339
DOI: 10.1371/journal.pntd.0009650 -
Indian Journal of Dermatology 2021Post-kala-azar dermal Leishmaniasis (PKDL) is one of the important neglected tropical diseases, which has a tremendous epidemiological significance, being the reservoir...
Post-kala-azar dermal Leishmaniasis (PKDL) is one of the important neglected tropical diseases, which has a tremendous epidemiological significance, being the reservoir of kala-azar. Relapse and resistance to treatment along with the lack of a drug of choice and consensus treatment guideline pose a significant problem in the management of PKDL. The aim of this article was to review the available therapeutic options for PKDL, with special emphasis on their pharmaco-dynamics, pharmaco-kinetics, effectiveness, safety, tolerability, and cost factor. A comprehensive English language literature search was done for therapeutic options in PKDL across multiple databases (PubMed, EMBASE, MEDLINE, and Cochrane) for keywords (alone and in combination). MeSH as well as non-MeSH terms such as "Kala-azar," "Leishmaniasis" AND "Treatment," "Management," "Antimony Sodium Gluconate," "Meglumine Antimoniate," "Amphotericin B," "Paromomycin," "Miltefosine" were taken into consideration. Among 576 relevant articles, 15 were deemed relevant to this review. These articles were evaluated using "Oxford Centre for Evidence-Based Medicine (OCEBM)" AND "strength of recommendation taxonomy" (SORT) with respect to the level of evidence and grade of recommendation. The review includes 15 studies. The use of sodium stibogluconate is being discouraged because of multiple documented reports of treatment failure. Liposomal amphotericin B is emerging as a favorable option, owing to its superiority in terms of effectiveness and safety profile. Miltesfosine is the drug of choice in India because of the ease of oral administration and minimal risk of toxicity. Isolated Paromomycin alone is not effective in PKDL; however, combination therapy with sodium stibogluconate is found to be safe and effective. Combination of amphotericin B and miltefosine is one of the excellent options. Immunotherapy with combination of alum-precipitated autoclaved Leishmania major (Alum/ALM) vaccine + Bacille Calmette-Gu´erin (BCG) has shown promising results. Kala-azar continues to haunt the tropical countries and PKDL being its reservoir is threatening its elimination. With the availability of drugs such as liposomal amphotericin B and miltefosine, apart from the advent of immunotherapy, the future of treatment of this condition looks promising.
PubMed: 33911291
DOI: 10.4103/ijd.IJD_264_20 -
PloS One 2021Cutaneous and mucocutaneous leishmaniasis affect a million people yearly, leading to skin lesions and potentially disfiguring mucosal disease. Current treatments can...
Cutaneous and mucocutaneous leishmaniasis affect a million people yearly, leading to skin lesions and potentially disfiguring mucosal disease. Current treatments can have severe side effects. Allylamine drugs, like terbinafine, are safe, including during pregnancy. This review assesses efficacy and safety of allylamines for the treatment of cutaneous and mucocutaneous leishmaniasis. It followed the PRISMA statement for reporting and was preregistered in PROSPERO(CRD4201809068). MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Global Health Library, Web of Science, Google Scholar, and clinical trial registers were searched from their creation to May 24th, 2020. All original human, animal, and in vitro studies concerning allylamines and cutaneous or mucocutaneous leishmaniasis were eligible for inclusion. Comparators-if any-included both placebo or alternative cutaneous or mucocutaneous leishmaniasis treatments. Complete cure, growth inhibition, or adverse events served as outcomes. The search identified 312 publications, of which 22 were included in this systematic review. There were one uncontrolled and two randomised controlled trials. The only well-designed randomised controlled trial that compared the treatment efficacy of oral terbinafine versus intramuscular meglumine antimoniate in 80 Leismania tropica infected patients showed a non-significant lower cure rate for terbinafine vs meglumine antimoniate (38% vs 53%). A meta-analysis could not be performed due to the small number of studies, their heterogeneity, and low quality. This systematic review shows that there is no evidence of efficacy of allylamine monotherapy against cutaneous and mucocutaneous leishmaniasis. Further trials of allylamines should be carefully considered as the outcomes of an adequately designed trial were disappointing and in vitro studies indicate minimal effective concentrations that are not achieved in the skin during standard doses. However, the in vitro synergistic effects of allylamines combined with triazole drugs warrant further exploration.
Topics: Allylamine; Animals; Humans; Leishmania; Leishmaniasis, Cutaneous; Leishmaniasis, Mucocutaneous; Prognosis
PubMed: 33826660
DOI: 10.1371/journal.pone.0249628 -
PLoS Neglected Tropical Diseases Mar 2021Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a previous systematic review of all published clinical trials in visceral leishmaniasis (VL) from 1980 to 2019 to document any reported serious adverse events (SAEs).
METHODS
For this updated systematic review, we searched the following databases from 1st Jan 2016 through 2nd of May 2019: PUBMED, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, and the Global Index Medicus. We included randomised and non-randomised interventional studies aimed at assessing therapeutic efficacy and extracted the number of SAEs reported within the first 30 days of treatment initiation. The incidence rate of death (IRD) from individual treatment arms were combined in a meta-analysis using random effects Poisson regression.
RESULTS
We identified 157 published studies enrolling 35,376 patients in 347 treatment arms. Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal amphotericin B (L-AmB) in 52 (15.0%), amphotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), amphotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only). During the first 30 days, there were 285 (66.6%) deaths with the overall IRD estimated at 0.068 [95% confidence interval (CI): 0.041-0.114; I2 = 81.4%; 95% prediction interval (PI): 0.001-2.779] per 1,000 person-days at risk; the rate was 0.628 [95% CI: 0.368-1.021; I2 = 82.5%] in Eastern Africa, and 0.041 [95% CI: 0.021-0.081; I2 = 68.1%] in the Indian Subcontinent. In 21 study arms which clearly indicated allowing the inclusion of patients with HIV co-infections the IRD was 0.575 [95% CI: 0.244-1.355; I2 = 91.9%] compared to 0.043 [95% CI: 0.020-0.090; I2 = 62.5%] in 160 arms which excluded HIV co-infections.
CONCLUSION
Mortality within the first 30 days of VL treatment initiation was a rarely reported event in clinical trials with an overall estimated rate of 0.068 deaths per 1,000 person-days at risk, though it varied across regions and patient populations. These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared. The methodological limitations exposed by our review support the need to assemble individual patient data (IPD) to conduct robust IPD meta-analyses and generate stronger evidence from existing trials to support treatment guidelines and guide future research.
Topics: Amphotericin B; Antimony; Antiprotozoal Agents; Deoxycholic Acid; Drug Combinations; Humans; Leishmaniasis, Visceral; Phosphorylcholine
PubMed: 33780461
DOI: 10.1371/journal.pntd.0009302