Antifungal drug shows little long-term effectiveness against Chagas' disease

By Gene Emery

NEW YORK (Reuters Health) - The Merck antifungal drug posaconazole, also known as Noxafil, showed short-term benefit against chronic Chagas' disease but the effect of the drug fades after treatment stops, according to a new study.

"Unfortunately, posaconazole did not show efficacy for this purpose," said the researchers, whose findings were published in the May 15 New England Journal of Medicine.

Chagas disease is believed to afflict 7 million to 8 million people, primarily in Latin America, according to the World Health Organization. It kills an estimated 20,000 people per year.

The disease typically comes from the bite of an insect carrying the parasite Trypanosoma cruzi. If not treated successfully, it can lead to cardiac, digestive and neurological problems. The disease, which may have contributed to the death of Charles Darwin, has been showing up in the U.S., Canada and Europe.

"Due to the migratory flows, it is estimated the more than 300,000 persons with Chagas' disease are living in the States, although only a few cases have been reported," chief author Dr. Israel Molina at Vall d'Hebron Teaching Hospital in Barcelona told Reuters Health in an email. "Clinicians in North America should be aware of such disease."

Standard therapy with benznidazole or nifurtimox -- the only drugs approved for Chagas -- works best during the acute phase of the disease, which typically lasts two months, but not as well during the chronic phase, where estimates of cure range from 15% to 35% because the parasite can hide in the body. Treatment causes adverse reactions in 20% to 40% of cases.

Attempts to find a vaccine have been thwarted by the genetic variability of the parasite, said Dr. Andrew Thompson of the School of Veterinary and Health Sciences at Murdoch University in Australia, who was not connected with the research.

"The search for an effective vaccine that can protect against infection with a number of strains in an endemic region is a huge challenge. Thus there was optimism that posaconazole would offer hope in attempts to limit the morbidity and suffering caused by chronic Chagas' disease in endemic regions," he told Reuters Health by email.

"The results reported in this paper are therefore very disappointing," Dr. Thompson added, especially after mouse studies suggested that posaconazole should be effective.

Dr. Molina and his colleagues randomly assigned 78 patients from Bolivia, Brazil and Paraguay to posaconazole treatment at a dose of either 100 mg twice daily or four times higher, or to treatment with 150 mg of benznidazole twice daily. Treatment lasted 60 days.

All but two patients, both in the low-dose posaconazole group, tested negative for parasite DNA during the treatment period.

When they were followed up 10 months after the end of treatment, however, 38% of the benznidazole recipients still tested positive for parasite DNA.

The parasite was present in 92% of the low-dose posaconazole recipients and 81% of those getting the higher posaconazole dose (p<0.01 for comparison of benznidazole with either posaconazole group).

Posaconazole produced sided effects -- high aminotransferase levels in four volunteers -- but nothing severe enough to prompt discontinuance of treatment. Five people were pulled from the benznidazole group because of severe cutaneous side effects.

Dr. Molina said despite the failure of posaconazole, "very valuable information has been obtained regarding parasite kinetics under treatment condition. Such information will be very helpful in order to design new clinical trials."

In an editorial in the Journal, Drs. Pedro Albajar-Vinas and Joao Carlos Dias of the World Health Organization in Geneva cautioned that the response to any treatment may vary in different parts of the world and "therefore, the same regimen needs to be tested in diverse regions."

They also noted that "it is difficult to document the clinical benefits of antiparasitic treatment in the short term because of the slow progression of the disease and the limitations of the available serologic markers; currently, only surrogate biologic markers can be used to detect early therapeutic response."

Although posaconazole did not work over the long term, it did suppress the parasite while the drug is being given. That means "it is possible that ergosterol inhibitors could be useful as a partner drug in future combination therapies," the researchers said.

"Combined therapy appears to be a very attractive therapeutic option" and Merck is currently testing a combination of posaconazole and benznidazole, Dr. Molina said.

He and his colleagues are also involved in a large study "with the aim to achieve a more effective, cheaper and safer treatment based on a new drug delivery of benznidazol."

SOURCE: http://bit.ly/ROhyQ1

N Engl J Med 2014;370:1899-908.

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