Study of use of Oral Posaconazole on the Treatment of asymptomatic chronic CHAGAS disease - STOP-CHAGAS

Description:

The goal of the trial was to compare the safety and efficacy of posaconazole, benznidazole as monotherapy or in combination with each other for the serological treatment of patients with asymptomatic Trypanosoma cruzi infection.

Contribution to the Literature: The STOP-CHAGAS study suggests that benznidazole monotherapy is superior to posaconazole either as monotherapy or as combination therapy in effecting a sustained serological response at 6 months in patients with asymptomatic T. cruzi infection.



Study Design

Patients with serological evidence of T. cruzi, but otherwise asymptomatic, were randomized in a 1:1:1:1 fashion to either posaconazole 400 mg BID (n = 30) monotherapy, benznidazole 200 mg BID monotherapy (n = 30), posaconazole 400 mg BID + benznidazole 200 mg BID (n = 30), or placebo (n = 30).

Inclusion criteria:

  • Aged 18-50 years
  • ≥2 positive serological tests for T. cruzi, duplicate positive reverse-transcription-polymerase chain reaction (RT-PCR) for T. cruzi
  • Normal electrocardiogram, 24-hour Holter, and echocardiogram
  • Total screened: 393
  • Total number of enrollees: 120
  • Duration of follow-up: 360 days
  • Mean patient age: 38 years
  • Percentage female: 45%

Other salient features/characteristics:

  • Left ventricular ejection fraction: 65%
  • QTc interval: 420 msec

Principal Findings:

Primary outcome, proportion of subjects with persistent negative RT-PCR by day 180 for posaconazole vs. benznidazole vs. posaconazole + benznidazole vs. placebo: 13.3% vs. 86.7% vs. 80% vs. 10%; p = 0.69 for posaconazole vs. placebo; p < 0.0001 for posaconazole vs. posaconazole + benznidazole.

On per-protocol analysis, 100% of patients in the benznidazole monotherapy and benznidazole + posaconazole had complete and persistent seroconversion. Interestingly, posaconazole had a very high response initially (until 60 days), but then dropped off significantly after that.

Secondary outcomes:

  • Cutaneous reactions for posaconazole vs. benznidazole vs. posaconazole + benznidazole vs. placebo: 6.3% vs. 60% vs. 42.9% vs. 10.0%, p = 0.01
  • Nervous system disorders: 12.5% vs. 33.3% vs. 32.1% vs. 10%, p = 0.04
  • Permanent discontinuation: 30-33% in both benznidazole arms

Interpretation:

The results of this trial indicate that benznidazole monotherapy is superior to posaconazole either as monotherapy or as combination therapy in effecting a sustained serological response at 6 months in patients with asymptomatic T. cruzi infection. However, dermatological and neurological side effects were higher in the benznidazole arm, with an associated high rate of drug discontinuation. Posaconazole was better tolerated and had a high initial trypanocidal action, but this action was not sustained after 2 months. It is unknown if lower doses of benznidazole would be better tolerated yet equally efficacious.

Chagas disease is an important health problem, especially in Latin America, with an approximate 20% conversion rate from asymptomatic carrier status to clinical Chagas disease. It is unclear if early treatment with benznidazole will affect progression to cardiomyopathy.

References:

Morillo CA, Waskin H, Sosa-Estani S, et al., on behalf of the STOP-CHAGAS Investigators. Benznidazole and Posaconazole in Eliminating Parasites in Asymptomatic T. Cruzi Carriers: The STOP-CHAGAS Trial. J Am Coll Cardiol 2017;69:939-47.

Presented by Dr. Carlos A. Morillo at the American College of Cardiology Annual Scientific Session, Chicago, IL, April 4, 2016.


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