Evaluating the safety, tolerability, pharmacokinetics and efficacy of clofazimine in cryptosporidiosis (CRYPTOFAZ): study protocol for a randomized controlled trial.

BACKGROUND: Cryptosporidium infection and diarrhea (cryptosporidiosis) is a life-threatening infection in persons with HIV and also in children of 6-18 months of age in the developing world. To date, only nitazoxanide is licensed for treatment of cryptosporidiosis, and only in persons after the first year of life and with healthy immune systems. Clofazimine (CFZ: Lamprene®), an established drug that has been used for leprosy for more than 50 years, recently has been described as effective against Cryptosporidium in vitro and in mouse infections. The efficacy and pharmacokinetics of CFZ in vivo, in HIV-infected patients with cryptosporidial diarrhea are not known. METHODS: CRYPTOFAZ includes a randomized, double-blind, placebo-controlled study of the safety, tolerability and Cryptosporidium inhibitory activity of orally administered CFZ in subjects with HIV infection and chronic diarrhea with Cryptosporidium. An additional open label aspect of the study will compare the pharmacokinetics (PK) of orally administered CFZ in HIV-infected individuals with and without Cryptosporidium-associated diarrhea. The study will recruit a total of 66 subjects. Study participants will be given either CFZ or a placebo for 5 days while in hospital and will be followed up after discharge. Cryptosporidium will be diagnosed by quantitative PCR as the definitive test and by stool ELISA, which will also be used to quantify the shedding of Cryptosporidium in stool. PK will be studied on plasma and stool samples. Primary endpoints include reduction in the number of Cryptosporidium shed in stools over a 5-day period and compared to placebo recipients and the PK of CFZ in plasma assessed by area under the curve, peak plasma concentration, and half-life (T ½) determined after the last dose. DISCUSSION: This study provides an opportunity to explore a possible treatment option for HIV-infected patients with cryptosporidial diarrhea, who, as of now in Malawi and most of sub-Saharan Africa, do not have a definitive treatment apart from supportive care. The strength of this study lies in it being a randomized, double-blind, placebo-controlled trial. If shown to be effective and safe, the findings will also lay a foundation for a future study of the use of CFZ in children 6-18 months of age. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03341767 . Registered on 14 November 2017.

[Infection due to Strongyloides stercoralis: epidemiological, clinical, diagnosis findings and outcome in 30 patients]. / Infección por Strongyloides stercoralis: estudio epidemiológico, clínico, diagnóstico y terapéutico en 30 pacientes.

BACKGROUND: Strongyloides stercoralis is a nematode parasite, which is endemic in tropical and subtropical regions. Infection usually remains asymptomatic, but in immunocompromised hosts severe and life-threatening manifestations such as hyperinfection syndrome and disseminated disease might occur. METHODS: We retrospectively analyzed the epidemiological and clinical characteristics, including HIV co-infection, microbiological findings, and outcome in 30 patients with strongyloidiasis, who attended in the Infectious Diseases F. J. Muñiz Hospital in Buenos Aires from January 2004 to December 2008. RESULTS: The study included 20 men and 10 women with an average age of 33 years. HIV co-infection was present in 21 patients (70%) with a median CD4 T cell count of 50 cells/mm³ (range 7-355) (average 56 cells/mm³). Among HIV negative patients the following comorbidities were detected: tuberculosis (n = 3) and chronic alcoholism, leprosy treated with corticosteroids, immunosuppressive treatment for psoriasis, and diabetes mellitus (each in one patient). Two patients did not have any predisposing diseases or immunosuppressive treatments. Seventeen patients presented with diarrhea and were classified as chronic intestinal strongyloidiasis (57%), asymptomatic infection with peripheral eosinophilia was diagnosed in 7 (23%), and 6 patients (20%) developed hyperinfection syndrome. Seventeen patients (57%) presented peripheral eosinophilia. Diagnosis was achieved by direct visualization of larvae in feces by Baermann technique (n = 20), by multiple stool smears examinations (n = 2), by combination of both (n = 1), by visualization of the filariform larvae in duodenal fluid and stool (n = 1), and in fecal and bronchoalveolar lavage specimens (n = 6). Overall mortality in this series was 20% (6/30). There was no significant correlation between age and mortality. A significant inverse correlation between the survival rate and CD4 T-cell count as well as eosinophilia was observed. There was also a significant correlation between HIV co-infection and mortality. Twenty-two patients responded favorably to treatment with ivermectin.

Infección por Strongyloides stercoralis: estudio epidemiológico, clínico, diagnóstico y terapéutico en 30 pacientes / Infection due to Strongyloides stercoralis: epidemiological, clinical, diagnosis findings and outcome in 30 patients

Background: Strongyloides stercoralis is a nematode parasite, which is endemic in tropical and subtropical regions. Infection usually remains asymptomatic, but in immunocompromised hosts severe and life-threatening manifestations such as hyperinfection syndrome and disseminated disease might occur. Methods: We retrospectively analyzed the epidemiological and clinical characteristics, including HIV co-infection, microbiological findings, and outcome in 30 patients with strongyloidiasis, who attended in the Infectious Diseases F. J. Muñiz Hospital in Buenos Aires from January 2004 to December 2008. Results: The study included 20 men and 10 women with an average age of 33 years. HIV co-infection was present in 21 patients (70 percent) with a median CD4 T cell count of 50 cells/mm³ (range 7-355) (average 56 cells/mm³). Among HIV negative patients the following comorbidities were detected: tuberculosis (n = 3) and chronic alcoholism, leprosy treated with corticosteroids, immunosuppressive treatment for psoriasis, and diabetes mellitus (each in one patient). Two patients did not have any predisposing diseases or immunosuppressive treatments. Seventeen patients presented with diarrhea and were classified as chronic intestinal strongyloidiasis (57 percent), asymptomatic infection with peripheral eosinophilia was diagnosed in 7 (23 percent), and 6 patients (20 percent) developed hyperinfection syndrome. Seventeen patients (57 percent) presented peripheral eosinophilia. Diagnosis was achieved by direct visualization of larvae in feces by Baermann technique (n = 20), by multiple stool smears examinations (n = 2), by combination of both (n = 1), by visualization of the filariform larvae in duodenal fluid and stool (n = 1), and in fecal and bronchoalveolar lavage specimens (n = 6). Overall mortality in this series was 20 percent (6/30). There was no significant correlation between age and mortality. A significant inverse correlation between the survival rate and CD4 T-cell count as well as eosinophilia was observed. There was also a significant correlation between HIV co-infection and mortality. Twenty-two patients responded favorably to treatment with ivermectin.

Antecedentes: Strongyloides stercoralis, parásito endémico de áreas tropicales y subtropicales del planeta, en sujetos inmunodeprimidos puede cursar con formas graves y aun mortales como el síndrome de hiperinfestación y la enfermedad diseminada. Métodos: Análisis retrospectivo de las características epidemiológicas, manifestaciones clínicas, co-infección por virus de inmunodeficiencia humana (VIH), hallazgos microbiológicos y evolución de 30 pacientes con estrongiloidiasis, atendidos en el Hospital de Enfermedades Infecciosas F. J. Muñiz de Buenos Aires, entre enero 2004 y diciembre 2008. Resultados: Se incluyeron en la evaluación 20 hombres y 10 mujeres con una mediana de edad de 33 años. Co-infección por VIH hubo en 21 pacientes (70 por ciento); la mediana de linfocitos T CD4+ en ellos al momento del diagnóstico de la parasitosis fue de 50 céls/mm³ (rango 7 a 355), (media de 56 céls/mm³). En los pacientes seronegativos para VIH, se comprobaron las siguientes co-morbilidades: tuberculosis (n: 3) y un caso de cada una de las siguientes afecciones: alcoholismo crónico, diabetes mellitus, reacción lepromatosa bajo corticotera-pia, y psoriasis en tratamiento inmunosupresor. Hubo dos pacientes sin aparentes enfermedades de base. Diecisiete pacientes presentaron enfermedad intestinal crónica con diarrea (57 por ciento), era asintomática y fue sospechada por la eosinofilia periférica (n: 7, 23 por ciento) y se clasificó como síndrome de hiperinfestación (n: 6, 20 por ciento) diagnosticado por la identificación de larvas en la materia fecal y secreciones broncopulmonares. Diecisiete pacientes (57 por ciento) presentaron eosinofilia periférica. El diagnóstico se efectuó por la visualización directa de las larvas en muestras de heces en fresco mediante la técnica de concentración de Baer-man (n: 20); por el examen copro-parasitológico seriado (n: 2) y por ambos métodos (n: 1); en líquido duodenal y materia fecal (n: 1) y por la identificación de larvas en materia fecal y secreciones respiratorias (n: 6). Letalidad global: 20 por ciento (6/30). Los pacientes con eosinofilia tuvieron una menor letalidad que aquellos sin esta respuesta (p < 0,001). No hubo correlación estadística entre la edad y la supervivencia. Sí fue significativa la correlación entre el recuento de CD4 y la letalidad, incluyendo 18 de los 21 pacientes seropositivos para VIH (p: 0,03). Finalmente, la correlación seropositividad para VIH y letalidad también fue significativa. Veintidós pacientes respondieron a la terapia antiparasitaria con ivermectina y evolucionaron favorablemente.

Diffuse cutaneous leishmaniasis in HIV.

Cutaneous leishmaniasis is caused by the intracellular protozoan parasite belonging to the genus leishmania and is characterized by a myriad of clinical lesions including papules, nodules, and ulcers. Diffuse cutaneous forms of leishmaniasis are rare. We report a rare case from South India of diffuse cutaneous leishmaniasis masquerading as lepromatous leprosy in the context of HIV infection.