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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., Objectives: 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)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)