Thursday, February 5, 2015

Ebola Drug Trial Has Encouraging Early Results, and Questions Follow

An Ebola treatment center run by the Alliance for International Medical Action has tested the drug favipiravir. Credit Sylvain Cherkaoui/Cosmos for ALIMA Sylvain Cherkaoui/Cosmos for ALIMA
For the first time, a drug is showing promising signs of effectiveness in Ebola patients participating in a study. The medicine, which interferes with the virus’s ability to copy itself, seems to have halved mortality — to 15 percent, from 30 percent — in patients with low to moderate levels of Ebola in their blood, researchers have found. It had no effect in patients with more virus in their blood, who are more likely to die.
The drug, approved as an influenza treatment in Japan last year, was generally well tolerated.
“The results are encouraging in a certain phase of the disease,” Dr. Sakoba Keita, director of disease control for the Guinean Ministry of Health, said in a telephone interview. The drug is being tested in Guinea, one of the three West African countries most affected by the Ebola crisis.
The early findings have not yet been announced, but they raise questions about which patients, if any, outside the study should be offered treatment with the drug, favipiravir. “These are very difficult, agonizing decisions,” said Susan Ellenberg, a professor of biostatistics at the University of Pennsylvania’s Perelman School of Medicine, who was not involved in the research. She cautioned that early results were sometimes not borne out.
Avigan, a drug approved as an anti-influenza drug in Japan, is showing promise in treating ebola. Credit Issei Kato/Reuters Issei Kato/Reuters
The drug has been provided on an emergency basis to Ebola patients in European countries, but not in Africa. The Japanese maker of the drug announced in October that it had 20,000 courses of treatment in stock. The epidemic is now ebbing but is not over. The World Health Organization on Wednesdayreported 124 new cases in Guinea, Sierra Leone and Liberia in the week that ended on Sunday, warning of an increased geographical spread in Guinea and a rise in new cases in all three countries for the first time this year.
Early reports of the interim results of the drug trial have created unanticipated complications, delaying the testing of at least one other therapy as researchers reconsidered plans and some doctors pressed to make favipiravir more widely available.
Researchers and health authorities have been quietly debating whether and when to release the preliminary results of the study. The dilemmas they face echo those from the early years of the AIDS epidemic. Because mortality was so high in a disease with no proven treatment, there was demand to provide experimental therapies to everyone.
The results for the drug favipiravir are based on an analysis of 69 patients older than 14 who have received it at two sites in Guinea since December. The survival rates of those with low to moderate levels of virus in their blood were significantly better than those of patients previously treated at a center run by Doctors Without Borders in Guéckédou, Guinea.
Caroline Guele, 31, a rice farmer who lost two children and her husband to Ebola, received the drug in January at the site run by the Alliance for International Medical Action soon after she developed symptoms. She said she believed it contributed to her survival. “When I heard I could take the medicine, I actually prayed to God it would help me,” she said in a telephone interview Wednesday.
In a typical drug study, participants would be randomly assigned to take the drug or not, and the outcomes would be compared to see if the drug made a difference. However, because Ebola is so deadly and there is no known treatment aside from supportive care, all patients in the study were provided with the treatment. Fluctuating death rates during the current epidemic have complicated researchers’ efforts to assess whether the new drug should be credited with the reduced mortality.
The drug was expected to be most effective in patients receiving it within two to three days of showing symptoms, similar to antiviral treatments for influenza. However, most study participants arrived at the Ebola treatment units later in their illnesses, a median of five days after their symptoms began, so results were analyzed instead in terms of the approximate levels of virus in the blood.
Independent boards charged with monitoring the drug trial detected the encouraging findings and recommended that they be made public. Results were submitted for review to the Conference on Retroviruses and Opportunistic Infection, which will take place in Seattle at the end of the month. A draft of an abstract of the findings was reviewed by The New York Times.
“With Ebola, there’s precious little good news,” said Dr. Susan Shepherd, who served as medical coordinator at a treatment unit run by the Alliance for International Medical Action, one of two sites where the drug was tested. (The other was a facility run by Doctors Without Borders.)
Dr. Shepherd added, “There will, I think, be an enormous pressure and desire to offer the treatment more broadly.”
A patient is treated at the ALIMA ebola treatment center in Nzerekore, Guinea. Credit Sylvain Cherkaoui/Cosmos for ALIMA Sylvain Cherkaoui/Cosmos for ALIMA
The trial is sponsored by the French public research institute Inserm, with support from the European Union, and is run by a consortium of organizations and the Guinean government. The drug, also known by the trade name Avigan, was developed by the Japanese company Toyama Chemical, part of Fujifilm Group, and approved for influenza treatment in that country last March after safety testing.
The company has said it would produce more doses of the drug in anticipation of the trial. It has also provided the tablets on an emergency basis to several Ebola patients in Europe, according to a company spokeswoman, Kana Matsumoto. She said that the drug had never been provided on that basis to patients in any African country, and that the company had no comment as to whether it would do so in the future given the new findings.
“With a medication that seems to be safe, you really don’t have a leg to stand on in terms of this person gets it and this person doesn’t,” Dr. Shepherd said. “The problem we seem to have is it doesn’t help at all for people who have high viral loads.”
Researchers hope that some patients’ lives might be saved by bolstering the immune system, including through transfusions of serum extracted from the blood of Ebola survivors, which contains virus-fighting antibodies.
However, expectations around favipiravir have contributed to a delay in a trial of serum transfusions, also known as convalescent plasma therapy, in Guinea’s capital, according to Roeland Scholtalbers, the head of communications for the Institute of Tropical Medicine in Antwerp, Belgium, the study’s sponsor.
Some doctors are urging that if favipirivir has a positive effect and seems safe, it should be given to everyone with the virus.
If patients getting the serum transfusions also get favipiravir, it would probably be more difficult to discern whether the serum had an effect. Mr. Scholtalbers said that just because early results for favipiravir came first did not mean that researchers or the public should “put more hope on that solution than any other solution.”
“There are pretty good arguments to think that plasma can give good impact,” she continued. “It will be a shame if we don’t manage as a scientific community to test it.”
Dr. Xavier Anglaret, the lead investigator of the favipiravir trial in Guinea, said that he and his colleagues agreed that the other study was important. “The plasma trial should start as early as possible,” he said.
Both trials are all the more important because of the abrupt cancellation last Friday of a study testing a third therapy, the anti-viral drug brincidofovir, after the manufacturer found an insufficient number of Ebola patients in Liberia, where the trial had been planned, to determine the effectiveness of the drug.
Dr. Anglaret said researchers had expected to have results from all three studies around the same time. Instead, one study advanced ahead of the others, with early results that are encouraging but not definitive. As of Tuesday, Dr. Anglaret said, the favipiravir trial had enrolled 101 patients in the continuing study.
The complications of managing the Ebola trials are a sign that more needs to be done to prioritize research in future outbreaks, said Dr. Bernard Lo, a bioethicist and president of the Greenwall Foundation in New York City.

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Prejeesh Sreedharan

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I am a Biotechnologist very much interested in #SciTech (Science And Technology). I closely follow the developments in medical science and life science. I am also very enthusiast in the world of electronics, information technology and robotics. I always looks for ways to make complicated things simpler. And I always believes simplest thing is the most complicated ones.

 
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