Chagas Disease Drug Disappoints, but Offers Hope

Larry Hand

May 15, 2014

Treatment of patients with chronic Chagas disease with the ergosterol inhibitor posaconazole resulted in significantly more treatment failures than treatment of patients with the current standard of care, benznidazole, according to a randomized clinical trial report published in the May 15 issue of the New England Journal of Medicine.

Despite the results, however, enough antiparasitic activity occurred in posaconazole-treated patients to point to future possibilities that ergosterol inhibitors may be useful when used in combination with other drugs, the researchers note.

Israel Molina, MD, from the Infectious Disease Department, Catalan Institute of Health, Barcelona, Spain, and colleagues conducted a prospective, randomized trial comparing low-dose posaconazole, high-dose posaconazole, and benznidazole in 78 adult patients at 3 centers participating in the International Health Program of the Catalan Institute.

Dosages of the drugs were 100 or 400 mg twice a day for posaconazole and 150 mg twice a day for benznidazole for a period of 60 days. The researchers used real-time polymerase chain reaction (PCR) assays during the treatment period and 10 months of follow-up to test for the presence of Trypanosoma cruzi DNA.

During follow-up, 92% of patients receiving low-dose posaconazole and 81% of patients receiving high-dose posaconazole tested positive for T cruzi DNA compared with 38% of patients receiving benznidazole (P < .01) in an intent-to-treat analysis.

When the researchers restricted their analysis to patients who completed treatment and follow-up, the numbers tilted farther in favor of benznidazole: 90% of patients receiving low-dose posaconazole and 80% of patients receiving high-dose posaconazole tested positive for T cruzi compared with 6% of patients receiving benznidazole (P < .001).

Five patients receiving benznidazole had to discontinue treatment because of severe cutaneous reactions. No patients receiving posaconazole had to discontinue treatment, but 4 did experience elevated levels of aminotransferase.

The researchers also conducted a pharmacokinetic analysis, the results of which did not meet their expectations for serum concentrations on day 14 of treatment.

Neglected Disease

Chagas disease, considered a neglected disease, is a chronic parasitic infection caused by T cruzi, and no definitive tests exists today to determine a cure, the researchers write.

"[W]e did not use the PCR results as a measure of efficacy or cure but used them only as a marker of treatment failure," the researchers write. "A negative PCR result may be indicative only of the absence of circulating DNA at the moment when blood is drawn for testing."

They write that T cruzi DNA was undetectable from blood in all patients beyond the second treatment week, which indicates that posaconazole may have suppressive activity.

"Therefore, despite the unfavorable final outcome of this treatment in our study, it is possible that ergosterol inhibitors could be useful as a partner drug in future combination therapies," they conclude.

An estimated 8 million people worldwide have chronic Chagas disease, and it has been spreading from Latin American countries to the United States, Canada, Europe, and the Western Pacific, write Pedro Albajar-Viñas, MD, PhD, from the Chagas Disease Program, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland, and João Carlos P. Dias, MD, from the Strategic and Technical Advisory Group on Neglected Tropical Diseases, World Health Organization, and the René Rachou Research Center, Oswaldo Cruz Foundation, Brazilian, Ministry of Health, Belo Horizonte, Brazil, in an accompanying editorial.

The new study is the first randomized, double-blind clinical trial in decades to test a new commercial drug for the disease, they write.[It] provides relevant, timely, and extremely valuable information about antiparasitic treatment for chronic Chagas disease that should stimulate the various actors of the health system and health authorities to facilitate access to diagnosis and treatment."

This research was supported by the Spain Ministry of Health. The authors and editorialists have disclosed no relevant financial relationships.

N Engl J Med. 2014;370:1899-1908, 1942-1943. Article abstract, Editorial extract


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