title: Benznidazole and Posaconazole in Eliminating Parasites in Asymptomatic T. Cruzi Carriers: The STOP-CHAGAS Trial.
abstract: BACKGROUND
  Benznidazole is recommended for treatment of Chagas infection. Effects of combination therapy with benznidazole and posaconazole have not been tested in Trypanosoma cruzi carriers.
  
  
  OBJECTIVE
  The purpose of this study was to determine whether posaconazole alone or combined with benznidazole were superior to benznidazole monotherapy in eliminating T. cruzi parasites measured by real time polymerase chain reaction (RT-PCR) in asymptomatic Chagas carriers.
  
  
  METHODS
  A prospective, multicenter randomized placebo-controlled study was conducted in 120 subjects from Latin America and Spain who were randomized to 4 groups: posaconazole 400 mg twice a day (b.i.d.); benznidazole 200 mg + placebo b.i.d.; benznidazole 200 mg b.i.d. + posaconazole 400 mg b.i.d.; or placebo 10 mg b.i.d. T. cruzi deoxyribonucleic acid was detected by RT-PCR at 30, 60, 90, 120, 150, 180, and 360 days. The primary efficacy outcome is the proportion of subjects with persistent negative RT-PCR by day 180; the secondary outcome was negative RT-PCR at 360 days.
  
  
  RESULTS
  Only 13.3% of those receiving posaconazole and 10% receiving placebo achieved the primary outcome, compared with 80% receiving benznidazole + posaconazole and 86.7% receiving benznidazole monotherapy (p < 0.0001 vs. posaconazole/placebo). Posaconazole monotherapy or posaconazole combined with benznidazole achieved high RT-PCR conversion rates during treatment (30 days; 93.3% and 88.9% and 60 days; 90%, and 92.3%) that were similar to benznidazole (89.7% and 89.3%); all were superior to placebo or posaconazole (10% and 16.7%, p < 0.0001). This was not observed at 360 days; benznidazole + posaconazole and benznidazole monotherapy (both 96%) versus placebo (17%) and posaconazole (16%, p < 0.0001). Serious adverse events were rare (6 patients) and were observed in the benznidazole-treated patients. Permanent discontinuation was reported in 19 patients (31.7%) receiving either benznidazole monotherapy or combined with posaconazole.
  
  
  CONCLUSIONS
  Posaconazole demonstrated trypanostatic activity during treatment, but it is ineffective long-term in asymptomatic T. cruzi carriers. Benznidazole monotherapy is superior to posaconazole, with high RT-PCR conversion rates sustained at 1 year. Side effects lead to therapy discontinuation in 32%. No advantages were observed with combined therapy versus benznidazole monotherapy. (A Study of the Use of Oral Posaconazole [POS] in the Treatment of Asymptomatic Chronic Chagas Disease [P05267] [STOP CHAGAS]: NCT01377480).
authors.affiliation: McMaster University, Population Health Research Institute, Hamilton, Ontario, Canada. Electronic address: carlos.morillo@ucalgary.ca.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Morillo
authors.affiliation: Merck Sharp and Dohme Corporation, Kenilworth, New Jersey.
authors.forename: Hetty
authors.initials: H
authors.lastname: Waskin
authors.affiliation: Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben"-Administración Nacional de Laboratorios e Institutos de Salud (ANLIS), Buenos Aires, Argentina.
authors.forename: Sergio
authors.initials: S
authors.lastname: Sosa-Estani
authors.affiliation: Instituto de Cardiologia de Corrientes "Juana F. Cabral," Corrientes, Argentina.
authors.forename: Maria
authors.initials: M
authors.lastname: Del Carmen Bangher
authors.affiliation: Prevención Cardiovascular, Hospital San Bernardo, Salta, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cuneo
authors.affiliation: Centro de Diagnóstico y Rehabilitación Centro de Diagnóstico y Rehabilitación (CEDIR), Rosario, Santa Fe, Argentina.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Milesi
authors.affiliation: Sanatorio Nuestra Señora del Rosario, Centro de Investigaciones Médicas, San Salvador de Jujuy, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Mallagray
authors.affiliation: Faculty of Medicine University of Chile, Basic Clinical Laboratory of Parasitology, Biomedical Science Institute, Santiago, Chile.
authors.forename: Werner
authors.initials: W
authors.lastname: Apt
authors.affiliation: Hospital Provincial del Centenario, Rosario, Argentina.
authors.forename: Juan
authors.initials: J
authors.lastname: Beloscar
authors.affiliation: ISGlobal, Barcelona Centre for International Health Research, Hospital Clinic Barcelona, Barcelona, Spain.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Gascon
authors.affiliation: Infectious Disease Department, Vall d'Hebron Teaching Hospital, Program of the Catalan Institute of Health, Universitat Autónoma de Barcelona, Barcelona, Spain.
authors.forename: Israel
authors.initials: I
authors.lastname: Molina
authors.affiliation: Fundación Cardiovascular de Colombia, Floridablanca, Colombia.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Echeverria
authors.affiliation: Clinica Privada Colombo, Cordoba, Argentina.
authors.forename: Hugo
authors.initials: H
authors.lastname: Colombo
authors.affiliation: Hospital Ramon y Cajal, National Referral Centre for Tropical Diseases, Infectious Diseases Department, Instituto Ramón y Cajal para Investigacion en Salud (IRYCIS), Madrid, Spain.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Perez-Molina
authors.affiliation: Sociedad Centroamericana de Hipertensión Arterial y Prevención Cardiovascular CARDIOCLINIK, Guatemala, Guatemala.
authors.forename: Fernando
authors.initials: F
authors.lastname: Wyss
authors.affiliation: McMaster University, Population Health Research Institute, Hamilton, Ontario, Canada.
authors.forename: Brandi
authors.initials: B
authors.lastname: Meeks
authors.affiliation: McMaster University, Population Health Research Institute, Hamilton, Ontario, Canada.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Bonilla
authors.affiliation: McMaster University, Population Health Research Institute, Hamilton, Ontario, Canada.
authors.forename: Peggy
authors.initials: P
authors.lastname: Gao
authors.affiliation: Merck Sharp and Dohme Corporation, Kenilworth, New Jersey.
authors.forename: Bo
authors.initials: B
authors.lastname: Wei
authors.affiliation: Medimmune, Gaithersburg, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: McCarthy
authors.affiliation: McMaster University, Population Health Research Institute, Hamilton, Ontario, Canada.
authors.forename: Salim
authors.initials: S
authors.lastname: Yusuf
mesh_terms: D000284:Administration, Oral; D000328:Adult; D014355:Chagas Disease / Q000188:drug therapy*; D002908:Chronic Disease; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009593:Nitroimidazoles / Q000627:therapeutic use*; D011446:Prospective Studies; D016037:Single-Blind Method; D014230:Triazoles / Q000627:therapeutic use*; D014344:Trypanocidal Agents / Q000627:therapeutic use*; D014349:Trypanosoma cruzi
chemical_list: D009593:Nitroimidazoles; D014230:Triazoles; D014344:Trypanocidal Agents; C101425:posaconazole; C009999:benzonidazole
keywords: Chagas disease; intention-to-treat analysis; parasitemia; polymerase chain reaction; treatment failure; trypanocidal agents