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1.
Diagn Microbiol Infect Dis ; 109(3): 116266, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38643677

ABSTRACT

The aim of this study was to describe a case of a patient with ocular toxoplasmosis, which has resulted in Kyrieleis plaques formation (segmental periarteritis associated with severe inflammation) and later follow-up and alternative treatment due to documented allergy to sulfonamide. A 33-year-old Brazilian woman diagnosed with acute toxoplasmosis, initially treated with sulfonamide, developed a critical cutaneous rash. Cotrimoxazole was changed to clindamycin and pyrimethamine, and prednisone was started. The medication was maintained for 45 days. Four months later, she developed retinal lesions suggestive of toxoplasmosis with Kyrieleis plaques in the upper temporal vessels. Pyrimethamine, clindamycin, and prednisone were initiated until healing. She presented reactivation months later, and a suppressive treatment with pyrimethamine was instituted for one year. This is the first report to use the combination of clindamycin with pyrimethamine in the treatment and recurrence prophylaxis for OT in a documented allergy to sulfonamide.


Subject(s)
Clindamycin , Pyrimethamine , Sulfonamides , Toxoplasmosis, Ocular , Humans , Female , Adult , Pyrimethamine/therapeutic use , Pyrimethamine/adverse effects , Toxoplasmosis, Ocular/drug therapy , Sulfonamides/therapeutic use , Sulfonamides/adverse effects , Clindamycin/therapeutic use , Recurrence , Trimethoprim, Sulfamethoxazole Drug Combination/therapeutic use , Trimethoprim, Sulfamethoxazole Drug Combination/adverse effects , Drug Hypersensitivity/etiology , Brazil , Antiprotozoal Agents/therapeutic use , Antiprotozoal Agents/adverse effects , Treatment Outcome , Prednisone/therapeutic use
2.
Acta Derm Venereol ; 104: adv35089, 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38682801

ABSTRACT

Israel is endemic for Old-World cutaneous leishmaniasis. The most common species is Leishmania major. However, the available treatment options are limited. This study's objective was to compare the authors' experience with different antimony intralesional treatments of Leishmania major cutaneous leishmaniasis. A retrospective evaluation was undertaken for cases of Leishmania major cutaneous leishmaniasis treated by pentavalent antimony in a university-affiliated medical centre in Israel. The previous treatment of intralesional sodium stibogluconate (Pentostam®) was compared with the current treatment of meglumine antimoniate (Glucantime®). One hundred cases of cutaneous leishmaniasis were treated during the study period, of whom 33 were treated with intralesional sodium stibogluconate and 67 were treated with intralesional meglumine antimoniate. The patients were 78 males and 22 females, mean age 24 (range 10-67) and there was a total of 354 skin lesions. Within 3 months from treatment, 91% (30/33) of the intralesional sodium stibogluconate group and 88% (59/67) of the intralesional meglumine antimoniate group had complete healing of the cutaneous lesions after an average of 3 treatment cycles (non-statistically significant). In conclusion, the 2 different medications have the same efficacy and safety for treating cutaneous leishmaniasis. Pentavalent antimoniate intralesional infiltration treatment is safe, effective, and well tolerated with minimal side effects for Old-World cutaneous leishmaniasis.


Subject(s)
Antimony Sodium Gluconate , Antiprotozoal Agents , Injections, Intralesional , Leishmania major , Leishmaniasis, Cutaneous , Meglumine Antimoniate , Humans , Meglumine Antimoniate/administration & dosage , Leishmaniasis, Cutaneous/drug therapy , Leishmaniasis, Cutaneous/parasitology , Leishmaniasis, Cutaneous/diagnosis , Female , Male , Antimony Sodium Gluconate/administration & dosage , Retrospective Studies , Adult , Antiprotozoal Agents/administration & dosage , Antiprotozoal Agents/adverse effects , Middle Aged , Leishmania major/drug effects , Aged , Young Adult , Adolescent , Treatment Outcome , Child , Time Factors , Israel , Meglumine/administration & dosage , Organometallic Compounds/administration & dosage
3.
J Coll Physicians Surg Pak ; 33(12): 1367-1371, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38062590

ABSTRACT

OBJECTIVE: To compare the efficacy and safety of meglumine antimoniate and miltefosine in the treatment of cutaneous leishmaniasis in Pakistan. STUDY DESIGN: Randomised-controlled trial. Place and Duration of the Study: Department of Dermatology, Combined Military Hospital, Lahore and Peshawar, from January to December 2021. METHODOLOGY: Smear positive and/or skin biopsy-confirmed cases of cutaneous leishmaniasis in adult males aged between 18-60 years were enrolled after receiving informed consent. Patients were randomly divided into Group A and Group B by lottery method. Group A received intramuscular meglumine antimoniate 15-20mg/kg/day, and Group B received oral miltefosine 50 mg thrice a day for a duration of 28 days. Data were analysed by SPSS 22. Effectiveness and safety of therapeutic agents were calculated by Independent t-test and p-value of 0.05 or less was taken as significant. RESULTS: Sixty-six patients, 33 in each group, participated in the study. Total number of cutaneous leishmaniasis lesions were 77 in Group A and 76 in Group B. The duration of lesions was 3.5 months in Group A and 3.2 months in Group B. Treatment response, in terms of complete or near complete resolution of lesions, was significantly higher in Group A as compared to Group B (p = 0.011). Both therapeutic agents had considerable side-effects with more patients withdrawn from Group A as compared to Group B (p = 0.010). CONCLUSION: Intra-muscular meglumine antimoniate was more effective in comparison to oral miltefosine in the treatment of cutaneous leishmaniasis. However, efficacy of meglumine antimoniate is mired by its side-effect profile. KEY WORDS: Cutaneous leishmaniasis, Meglumine antimoniate, Miltefosine, Efficacy, Side-effects, Adverse effects, Safety, Treatment, Old world cutaneous leishmaniasis.


Subject(s)
Antiprotozoal Agents , Leishmaniasis, Cutaneous , Organometallic Compounds , Adult , Male , Humans , Adolescent , Young Adult , Middle Aged , Meglumine Antimoniate/therapeutic use , Antiprotozoal Agents/adverse effects , Meglumine/adverse effects , Organometallic Compounds/adverse effects , Injections, Intramuscular , Leishmaniasis, Cutaneous/drug therapy , Treatment Outcome
4.
PLoS Negl Trop Dis ; 17(11): e0011780, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37988402

ABSTRACT

BACKGROUND: Treatment for post-kala-azar dermal leishmaniasis (PKDL) in Sudan is currently recommended only for patients with persistent or severe disease, mainly because of the limitations of current therapies, namely toxicity and long hospitalization. We assessed the safety and efficacy of miltefosine combined with paromomycin and liposomal amphotericin B (LAmB) for the treatment of PKDL in Sudan. METHODOLOGY/PRINCIPAL FINDINGS: An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with persistent (stable or progressive disease for ≥ 6 months) or grade 3 PKDL, aged 6 to ≤ 60 years in Sudan. The median age was 9.0 years (IQR 7.0-10.0y) and 87% of patients were ≤12 years old. Patients were randomly assigned to either daily intra-muscular paromomycin (20mg/kg, 14 days) plus oral miltefosine (allometric dose, 42 days)-PM/MF-or LAmB (total dose of 20mg/kg, administered in four injections in week one) and oral miltefosine (allometric dose, 28 days)-LAmB/MF. The primary endpoint was a definitive cure at 12 months after treatment onset, defined as clinical cure (100% lesion resolution) and no additional PKDL treatment between end of therapy and 12-month follow-up assessment. 104/110 patients completed the trial. Definitive cure at 12 months was achieved in 54/55 (98.2%, 95% CI 90.3-100) and 44/55 (80.0%, 95% CI 70.2-91.9) of patients in the PM/MF and AmB/MF arms, respectively, in the mITT set (all randomized patients receiving at least one dose of treatment; in case of error of treatment allocation, the actual treatment received was used in the analysis). No SAEs or deaths were reported, and most AEs were mild or moderate. At least one adverse drug reaction (ADR) was reported in 13/55 (23.6%) patients in PM/MF arm and 28/55 (50.9%) in LAmB/MF arm, the most frequent being miltefosine-related vomiting and nausea, and LAmB-related hypokalaemia; no ocular or auditory ADRs were reported. CONCLUSIONS/SIGNIFICANCE: The PM/MF regimen requires shorter hospitalization than the currently recommended 60-90-day treatment, and is safe and highly efficacious, even for patients with moderate and severe PKDL. It can be administered at primary health care facilities, with LAmB/MF as a good alternative. For future VL elimination, we need new, safe oral therapies for all patients with PKDL. TRIAL REGISTRATION: ClinicalTrials.gov NCT03399955, https://clinicaltrials.gov/study/NCT03399955 ClinicalTrials.gov ClinicalTrials.gov.


Subject(s)
Antiprotozoal Agents , Leishmaniasis, Cutaneous , Leishmaniasis, Visceral , Humans , Child , Paromomycin/adverse effects , Leishmaniasis, Visceral/drug therapy , Antiprotozoal Agents/adverse effects , Leishmaniasis, Cutaneous/drug therapy , Phosphorylcholine/adverse effects , Treatment Outcome
7.
Clin Infect Dis ; 77(4): 574-582, 2023 08 22.
Article in English | MEDLINE | ID: mdl-37100061

ABSTRACT

BACKGROUND: Meglumine antimoniate (MA) remains the main treatment for cutaneous leishmaniasis (CL). Uncontrolled studies suggest that intralesional MA (IL-MA) may be noninferior and safer than systemic MA (S-MA). METHODS: Multicenter, randomized, controlled, open-label, phase 3 clinical trial to evaluate the efficacy and toxicity of IL-MA in 3 infiltrations at 14-day intervals compared with S-MA (10-20 mg Sb5+/kg/day, 20 days) for CL, with noninferiority margin of 20%. Primary and secondary outcomes were definitive cure at day 180 and epithelialization rate at day 90 of treatment, respectively. A 2-year follow-up was performed to assess relapses and emergence of mucosal lesions. Adverse events (AEs) were monitored according to the Division of AIDS AE grading system. RESULTS: We evaluated 135 patients. The cure rates (95% confidence interval) for IL-MA and S-MA treatment were, respectively, 82.8% (70.5-91.4) and 67.8% (53.3-78.3) per protocol (PP) and 70.6% (58.3-81.0) and 59.7% (47.0-71.5) per intention to treat (ITT). The epithelialization rates of the IL-MA and S-MA treatment were, respectively, 79.3% (66.6-88 + 8) and 71.2% (57.9-82.2) PP and 69.1% (55.2-78.5) and 64.2% (50.0-74.2) ITT. AEs in the IL-MA and S-MA groups were, respectively, clinical, 45.6% and 80.6%; laboratory, 26.5% and 73.1%; and electrocardiogram, 8.8% and 25.4%. Ten participants in the S-MA group and 1 in the IL-MA group were discontinued due to severe or persistent AEs. CONCLUSIONS: IL-MA provides a similar cure rate and results in less toxicity compared with S-MA and may be used as first-line therapy for CL patients. CLINICAL TRIALS REGISTRATION: REBEC: RBR-6mk5n4.


Subject(s)
Antiprotozoal Agents , Leishmaniasis, Cutaneous , Organometallic Compounds , Humans , Meglumine Antimoniate/therapeutic use , Meglumine Antimoniate/adverse effects , Antiprotozoal Agents/adverse effects , Meglumine/adverse effects , Brazil , Treatment Outcome , Organometallic Compounds/adverse effects , Leishmaniasis, Cutaneous/drug therapy
8.
Expert Opin Ther Pat ; 33(3): 179-192, 2023 Mar.
Article in English | MEDLINE | ID: mdl-37078205

ABSTRACT

INTRODUCTION: There are 12 protozoan genera that provoke zoonotic disease in humans and animals. We discuss the most common ones with a highlight on Babesia spp and Entamoeba histolytica, also mentioning Toxoplasma gondii, Trypanosoma cruzi, and Leishmania spp. AREAS COVERED: The complex life cycle of pathogenic protozoans is deeply understood but this did not contribute to the discovery of new drugs. The clinical armamentarium is poor and includes antiinfectives originally proposed as antibacterial (azithromycin, clindamycin, paromomycin, sulfadrugs), antifungals (amphotericin B), or they are outdated compounds with poor efficacy and many side effects (nitroazoles, antimonials, etc.). Few patents and innovative ideas are available. EXPERT OPINION: Protozoan diseases are not restricted to tropical countries and are difficult or impossible to treat with currently available drugs, which are limited and restricted to a low number of clinical classes. The antiprotozoal drug targets are also limited, and this had deleterious effects on translational studies for designing efficient antiprotozoal drugs. There is a stringent need for innovative approaches to tackle these problems.


Subject(s)
Amoeba , Antiprotozoal Agents , Babesia , Animals , Humans , Patents as Topic , Antiprotozoal Agents/adverse effects , Zoonoses/drug therapy
9.
Clin Exp Dermatol ; 48(8): 913-915, 2023 Jul 21.
Article in English | MEDLINE | ID: mdl-37075241

ABSTRACT

There are little data on pentamidine as a treatment for paediatric cutaneous leishmaniasis (CL). The objective of this study was to describe the effectiveness and safety of pentamidine over a 10-year period. Every child seen in French Guiana between 2010 and 2020 with proven CL and treated with pentamidine was included. In total, 55 children met the inclusion criteria - 23 girls and 32 boys. There were 38 patients (38/55, 69%) with a > 50% improvement at 1 month after pentamidine treatment and a complete cure at 3 months; 16 children had a < 50% improvement at 1 month and were given a second dose. Of these 16, 8 showed a complete cure at 3 months, 5 were lost to follow-up and 3 showed therapeutic failure at 3 months. The overall cure rate was 84% (46/55) after one or two doses. In terms of the safety of pentamidine, no severe adverse events (grade ≥ 3) were reported.


Subject(s)
Antiprotozoal Agents , Leishmaniasis, Cutaneous , Male , Female , Humans , Child , Pentamidine/adverse effects , Antiprotozoal Agents/adverse effects , French Guiana/epidemiology , Leishmaniasis, Cutaneous/drug therapy , Injections, Intramuscular
10.
Rev Soc Bras Med Trop ; 56: e0253, 2023.
Article in English | MEDLINE | ID: mdl-36820654

ABSTRACT

BACKGROUND: This cross-sectional study compared the general impact of cutaneous leishmaniasis (CL) and patient satisfaction with treatment and health services as perceived by those undergoing different therapeutic regimens in an endemic region in South-Eastern Brazil. We also investigated the factors associated with both outcomes (general impact and satisfaction). METHODS: We included 84 patients with CL treated between 2018 and 2019 with intravenous meglumine antimoniate, liposomal amphotericin B, or intralesional meglumine antimoniate therapy. Data were collected through interviews that assessed sociodemographic characteristics, comorbidity status, access and use of health services for CL diagnosis and treatment, and the items of the Cutaneous Leishmaniasis Impact Questionnaire (CLIQ). The CLIQ is a psychometric questionnaire previously validated to assess the general impact of CL on patient satisfaction with treatment and health services. Multivariate logistic regression analysis was used to identify the factors associated with high CL impact and low patient satisfaction. RESULTS: The general impact of CL and patient satisfaction with treatment and health services were not significantly associated with the therapeutic regimen. High CL impact was associated with low family income (odds ratio [OR]:3.3; 95% confidence interval [CI]:1.0-10.3), occurrence of complications/adverse effects during treatment (OR:7.7; 95%CI:2.4-25.6), and additional costs during diagnosis and/or treatment (OR:12.1; 95% CI:2.8-52.4). Low satisfaction was associated with high disease impact (OR: 9.5; 95% CI:2.7-33.9), occurrence of complications/adverse effects (OR:4.2; 95% CI:1.3-13.0), and high family income (OR:7.1; 95%CI:1.7-28.2). CONCLUSIONS: Our data support public health policies aimed at reducing the impact of CL and its treatment as well as the use of therapy with fewer adverse effects.


Subject(s)
Antiprotozoal Agents , Drug-Related Side Effects and Adverse Reactions , Leishmaniasis, Cutaneous , Organometallic Compounds , Humans , Meglumine Antimoniate , Antiprotozoal Agents/adverse effects , Cross-Sectional Studies , Patient Satisfaction , Leishmaniasis, Cutaneous/drug therapy , Social Class , Organometallic Compounds/adverse effects , Meglumine
12.
Clin Infect Dis ; 76(3): e1177-e1185, 2023 02 08.
Article in English | MEDLINE | ID: mdl-36164254

ABSTRACT

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.


Subject(s)
Antiprotozoal Agents , Leishmaniasis, Visceral , Adult , Humans , Child , Paromomycin/adverse effects , Antiprotozoal Agents/adverse effects , Antimony Sodium Gluconate/adverse effects , Leishmaniasis, Visceral/drug therapy , Treatment Outcome , Drug Therapy, Combination , Africa, Eastern , Phosphorylcholine/adverse effects
13.
Acta Trop ; 235: 106661, 2022 Nov.
Article in English | MEDLINE | ID: mdl-35998680

ABSTRACT

Visceral leishmaniasis or Kala-azar is a vector-borne disease caused by an intracellular parasite of the genus leishmania. In India, Amphotericin B (AmB) is a first-line medication for treating leishmaniasis. After a large-scale resistance to pentavalent antimony therapy developed in Bihar state, it was rediscovered as an effective treatment for Leishmania donovani infection. AmB which binds to the ergosterol of protozoan cells causes a change in membrane integrity resulting in ions leakage, and ultimately leading to cell death. The treatment effect of liposomal AmB can be seen more quickly than deoxycholate AmB because, it has some toxic effects, but liposomal AmB is significantly less toxic. Evidence from studies suggested that ABLC (Abelcet) and ABCD (Amphotec) are as effective as l-AmB but Liposomal form (Ambisome) is a more widely accepted treatment option than conventional ones. Nevertheless, the world needs some way more efficient antileishmanial drugs that are less toxic and less expensive for people living with parasitic infections caused by Leishmania. So, academics, researchers, and sponsors need to focus on finding such drugs. This review provides a summary of the chemical, pharmacokinetic, drug-target interactions, stability, dose efficacy, and many other characteristics of the AmB and their various formulations. We have also highlighted the clinically significant aspects of PKDL and VL co-infection with HIV/TB.


Subject(s)
Antiprotozoal Agents , Leishmania donovani , Leishmania , Leishmaniasis, Visceral , Amphotericin B/pharmacology , Antimony/pharmacology , Antiprotozoal Agents/adverse effects , Humans , Leishmaniasis, Visceral/drug therapy , Leishmaniasis, Visceral/parasitology , Liposomes/therapeutic use
16.
PLoS Negl Trop Dis ; 16(3): e0010238, 2022 03.
Article in English | MEDLINE | ID: mdl-35255096

ABSTRACT

BACKGROUND: Systemic pentavalent antimonials, mainly meglumine antimoniate, continue to be the first-choice drugs for treatment of cutaneous leishmaniasis (CL) despite their toxicity, difficulty of administration and high cost. In the search for therapeutic alternatives, combining two treatment interventions has emerged as a potential alternative to either reduce the use of antimonials with the associated toxicities, or to increase efficacy. Here, we report the results of a recently completed trial assessing the efficacy and safety of a combination of thermotherapy (TT) plus a short course of miltefosine (MLT) for the treatment of uncomplicated CL in Colombia and Peru. METHODS: A multicenter, randomized, evaluator-blinded, phase II, controled clinical trial was conducted. Adult volunteers with a parasitologically confirmed diagnosis of uncomplicated CL were randomly allocated to receive either a single session of TT or a combination of TT plus a short course of MLT (3 weeks). Therapeutic response outcomes and safety were assessed. RESULTS: 130 subjects were included in the study, of whom 64 were randomly assigned to the TT arm and 66 to the TT + MLT arm. Cure at 3 months' follow-up was achieved in 57.8% (n = 37) and 80.3% (n = 53) in the TT and TT + MLT groups, respectively, in the intention to treat analysis. The TT + MLT regimen was better that TT alone (p = 0.0055). The presence of vesicles at the site of heat application was the most common adverse event reported associated with the use of TT; while vomiting (31.8%) and elevation of liver enzymes (28.8%) were the most frequent adverse events reported associated with the use of MLT. CONCLUSION: The combination of TT plus a short course of MLT was shown to be significantly better than TT alone for the treatment of uncomplicated CL in the New World. TRIAL REGISTRATION: Registered in clinicaltrials.gov NCT02687971.


Subject(s)
Antiprotozoal Agents , Hyperthermia, Induced , Leishmaniasis, Cutaneous , Organometallic Compounds , Adult , Antiprotozoal Agents/adverse effects , Humans , Hyperthermia, Induced/adverse effects , Leishmaniasis, Cutaneous/drug therapy , Leishmaniasis, Cutaneous/etiology , Meglumine/therapeutic use , Meglumine Antimoniate/therapeutic use , Organometallic Compounds/therapeutic use , Phosphorylcholine/analogs & derivatives , Treatment Outcome
17.
Acta Derm Venereol ; 102: adv00721, 2022 May 24.
Article in English | MEDLINE | ID: mdl-35229163

ABSTRACT

The effectiveness of systemic treatment for Leishmania tropica cutaneous leishmaniasis remains unclear. The purpose of the study is to evaluate the efficacy and safety of systemic treatments for L. tropica cutaneous leishmaniasis. This retrospective study was performed in 114 patients. Systemic treatments included liposomal amphotericin B and sodium stibogluconate. All patients underwent systemic treatment for L. tropica cutaneous leishmaniasis. Favourable treatment responses were recorded in 72.5% and 70.2% of the patients in the liposomal amphotericin B and sodium stibogluconate groups, respectively; 25.3% and 46% of those in the liposomal amphotericin B and sodium stibogluconate groups respectively, experienced at least one adverse effect. Lesions in cartilaginous areas were associated with higher treatment failure. Prior topical or systemic treatment increased the chance of future systemic treatment success. Liposomal amphotericin B was associated with a shorter intravenous treatment duration and better safety profile. Thus, liposomal amphotericin B is the treatment of choice for L. tropica cutaneous leishmaniasis.


Subject(s)
Antiprotozoal Agents , Leishmania tropica , Leishmaniasis, Cutaneous , Antimony Sodium Gluconate/adverse effects , Antiprotozoal Agents/adverse effects , Humans , Leishmaniasis, Cutaneous/diagnosis , Leishmaniasis, Cutaneous/drug therapy , Retrospective Studies
18.
Clin Infect Dis ; 75(8): 1423-1432, 2022 10 12.
Article in English | MEDLINE | ID: mdl-35147680

ABSTRACT

BACKGROUND: Visceral leishmaniasis (VL) in patients with human immunodeficiency virus (HIV) presents an increasingly important patient cohort in areas where both infections are endemic. Evidence for treatment is sparce, with no high-quality studies from the Indian subcontinent. METHODS: This is a randomized, open-label, parallel-arm, phase 3 trial conducted within a single hospital in Patna, India. One hundred and fifty patients aged ≥18 years with serologically confirmed HIV and parasitologically confirmed VL were randomly allocated to 1 of 2 treatment arms, either a total 40 mg/kg intravenous liposomal amphotericin B (AmBisome; Gilead Pharmaceuticals) administered in 8 equal doses over 24 days or a total 30 mg/kg intravenous AmBisome administered in 6 equal doses given concomitantly with a total 1.4 g oral miltefosine administered through 2 daily doses of 50 mg over 14 days. The primary outcome was intention-to-treat relapse-free survival at day 210, defined as absence of signs and symptoms of VL or, if symptomatic, negative parasitological investigations. RESULTS: Among 243 patients assessed for eligibility, 150 were recruited between 2 January 2017 and 5 April 2018, with no loss to follow-up. Relapse-free survival at day 210 was 85% (64/75; 95% CI, 77-100%) in the monotherapy arm, and 96%, (72/75; 90-100%) in the combination arm. Nineteen percent (28/150) were infected with concurrent tuberculosis, divided equally between arms. Excluding those with concurrent tuberculosis, relapse-free survival at day 210 was 90% (55/61; 82-100%) in the monotherapy and 97% (59/61; 91-100%) in the combination therapy arm. Serious adverse events were uncommon and similar in each arm. CONCLUSIONS: Combination therapy appears to be safe, well tolerated, and effective, and halves treatment duration of current recommendations. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry India (CTRI/2015/05/005807; the protocol is available online at https://osf.io/avz7r).


Subject(s)
Antiprotozoal Agents , Coinfection , HIV Infections , Leishmaniasis, Visceral , Adolescent , Adult , Amphotericin B , Antiprotozoal Agents/adverse effects , Coinfection/drug therapy , Drug Therapy, Combination , HIV , HIV Infections/complications , HIV Infections/drug therapy , Humans , India , Leishmaniasis, Visceral/complications , Leishmaniasis, Visceral/drug therapy , Pharmaceutical Preparations , Phosphorylcholine/adverse effects , Phosphorylcholine/analogs & derivatives , Recurrence , Treatment Outcome
19.
Cochrane Database Syst Rev ; 12: CD015374, 2021 12 09.
Article in English | MEDLINE | ID: mdl-34882307

ABSTRACT

BACKGROUND: Human African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without treatment. Conventional treatments require days of intravenous infusion, but a recently developed drug, fexinidazole, can be given orally. Another oral drug candidate, acoziborole, is undergoing clinical development and will be considered in subsequent editions.   OBJECTIVES: To evaluate the effectiveness and safety of currently used drugs for treating second-stage Trypanosoma brucei gambiense trypanosomiasis (gambiense human African trypanosomiasis, g-HAT). SEARCH METHODS: On 14 May 2021, we searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, BIOSIS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We also searched reference lists of included studies, contacted researchers working in the field, and contacted relevant organizations. SELECTION CRITERIA: Eligible studies were randomized controlled trials that included adults and children with second-stage g-HAT, treated with anti-trypanosomal drugs currently in use. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed risk of bias; a third review author acted as an arbitrator if needed. The included trial only reported dichotomous outcomes, which we presented as risk ratio (RR) or risk difference (RD) with 95% confidence intervals (CI).   MAIN RESULTS: We included one trial comparing fexinidazole to nifurtimox combined with eflornithine (NECT). This trial was conducted between October 2012 and November 2016 in the Democratic Republic of the Congo and the Central African Republic, and included 394 participants. The study reported on efficacy and safety, with up to 24 months' follow-up.  We judged the study to be at low risk of bias in all domains except blinding;  as the route of administration and dosing regimens differed between treatment groups,  participants and personnel were not blinded, resulting in a high risk of performance bias.   Mortality with fexinidazole may be higher at 24 months compared to NECT. There were 9/264 deaths in the fexinidazole group and 2/130 deaths in the NECT group (RR 2.22, 95% CI 0.49 to 10.11; 394 participants; low-certainty evidence). None of the deaths were related to treatment. Fexinidazole likely results in an increase in the number of people relapsing during follow-up, with 14 participants in the fexinidazole group (14/264) and none in the NECT group (0/130) relapsing at 24 months (RD 0.05, 95% CI 0.02 to 0.08; 394 participants; moderate-certainty evidence).   We are uncertain whether there is any difference between the drugs regarding the incidence of serious adverse events at 24 months. (31/264 with fexinidazole and 13/130 with NECT group at 24 months). Adverse events were common with both drugs (247/264 with fexinidazole versus 121/130 with NECT), with no difference between groups (RR 1.01, 95% CI 0.95 to 1.06; 394 participants; moderate-certainty evidence).  AUTHORS' CONCLUSIONS: Oral treatment with fexinidazole is much easier to administer than conventional treatment, but deaths and relapse appear to be more common. However, the advantages or an oral option are considerable, in terms of convenience, avoiding hospitalisation and multiple intravenous infusions, thus increasing adherence.


Subject(s)
Antiprotozoal Agents , Pharmaceutical Preparations , Trypanosomiasis, African , Animals , Antiprotozoal Agents/adverse effects , Humans , Nifurtimox/adverse effects , Randomized Controlled Trials as Topic , Trypanosoma brucei gambiense , Trypanosomiasis, African/drug therapy
20.
PLoS Negl Trop Dis ; 15(11): e0009903, 2021 11.
Article in English | MEDLINE | ID: mdl-34748572

ABSTRACT

BACKGROUND: Nifurtimox-eflornithine combination therapy (NECT) for the treatment of second stage gambiense human African trypanosomiasis (HAT) was added to the World Health Organization's Essential Medicines List in 2009 after demonstration of its non-inferior efficacy compared to eflornithine therapy. A study of NECT use in the field showed acceptable safety and high efficacy until hospital discharge in a wide population, including children, pregnant and breastfeeding women, and patients with a HAT treatment history. We present here the effectiveness results after the 24-month follow-up visit. METHODOLOGY/PRINCIPAL FINDINGS: In a multicenter, open label, single arm phase IIIb study, second stage gambiense HAT patients were treated with NECT in the Democratic Republic of Congo. Clinical cure was defined 24 months after treatment as survival without clinical and/or parasitological signs of HAT. Of the 629 included patients, 619 (98.4%) were discharged alive after treatment and were examined for the presence of trypanosomes, white blood cell count in cerebro-spinal fluid, and disease symptoms. The clinical cure rate of 94.1% was comparable for all subpopulations analyzed at the 24-month follow-up visit. Self-reported adverse events during follow-up were few and concerned mainly nervous system disorders, infections, and gastro-intestinal disorders. Overall, 28 patients (4.3%) died during the course of the trial. The death of 16 of the 18 patients who died during the follow-up period was assessed as unlikely or not related to NECT. Within 24 months, eight patients (1.3%) relapsed and received rescue treatment. Sixteen patients were completely lost to follow-up. CONCLUSIONS/SIGNIFICANCE: NECT treatment administered under field conditions was effective and sufficiently well tolerated, no major concern arose for children or pregnant or breastfeeding women. Patients with a previous HAT treatment history had the same response as those who were naïve. In conclusion, NECT was confirmed as effective and appropriate for use in a broad population, including vulnerable subpopulations. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov, number NCT00906880.


Subject(s)
Antiprotozoal Agents/administration & dosage , Eflornithine/administration & dosage , Nifurtimox/administration & dosage , Trypanocidal Agents/administration & dosage , Trypanosomiasis, African/drug therapy , Adolescent , Adult , Aged , Antiprotozoal Agents/adverse effects , Child , Child, Preschool , Democratic Republic of the Congo , Drug Therapy, Combination , Eflornithine/adverse effects , Female , Follow-Up Studies , Humans , Infant , Male , Middle Aged , Nifurtimox/adverse effects , Pregnancy , Treatment Outcome , Trypanosoma brucei gambiense/drug effects , Trypanosoma brucei gambiense/genetics , Trypanosoma brucei gambiense/physiology , Trypanosomiasis, African/parasitology , Trypanosomiasis, African/pathology , Young Adult
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