SEATTLE, WASHINGTON When French scientists presented the results of a drug test at a conference Ebola release Monday, they did it with a lot of warnings, but their message was hopeful: the drug favipiravir seemed to reduce mortality in people with low and medium-high levels of virus in the blood the researchers told reporters at the Conference on retroviruses and opportunistic infections (CROI) here.
But when the head of Denis Malvy study from the University of Bordeaux in France has presented more details on the results CROI, many colleagues have cooled. Many scientists have criticized the evidence and the design of the trial, which is underway at four clinics in Guinea. "It tells us nothing," said epidemiologist Scott Hammer of Columbia University, who chaired the meeting.
In her presentation, Malvy focused on a group of 40 patients who started the trial with viral loads lower than 29 others who obviously do not enjoy favipiravir. As he said on Monday, only six of the 40 patients died than half what was expected on the basis of similar patients treated in the same clinics during the last 3 months. In addition, after 4 days of starting treatment on favipiravir, a drug against influenza, 51% of these patients had low levels of virus in their blood than the standard test could not detect it. "There was a signal that monotherapy favipiravir can reduce the viral load," said Malvy.
Malvy was careful to note the limitations of what he called a "non-comparative proofing" concept study. "the purpose of this test is to provide evidence that will better designed trials," said Malvy. "This type of test does not provide a high level of proof and does not definitively answer a question." Studies are underway in France with blood samples from the same patients will analyze more closely the evolution of Ebola virus levels every day they received treatment. The researchers will also for the first time to determine if the drug has an effect in monkeys, an animal model widely used for Ebola. And the current study may provide more data.
But Hammer said the trial was "a lot of flaws in it, from study design to data interpretation." The immune system naturally drives down viral levels, making it difficult to separate the effects of the drug, he noted. Because the study did not compare treated with untreated people who sought care at the same time he used what is called a "historical" control-Hammer said he could not determine whether these drops in viral levels or providing putative survival are related to favipiravir.
Since the beginning exploded in August, researchers have vigorously debated how to set up studies of drugs and vaccines for Ebola, some randomized controlled studies advocating, in which a group of patients do not receive the drug as the fastest way to get results. Clifford Lane, deputy director at the National Institute of Allergy and Infectious Diseases of the United States, made this point in his presentation at the meeting, but did not single favipiravir the critical study. "As uncontrolled, supposedly compassionate studies fail to clear conclusions, they blur the water to the point that it becomes increasingly difficult to carry out appropriate studies," warned Lane.
Together with Liberian officials, Lane is about to launch a randomized study of an antibody cocktail called ;. zmapp this study does not include a control group in which patients will receive standard care, but not the drug Lane says Guinea and Sierra Leone have so far refused to participate in the study because of ethical concerns not giving the treatment to all participants. (Sierra Leone has shown some support for the design, however, and discussions are continuing.)
Jean-François Delfraissy, which coordinates the response of France Ebola and also heads the HIV / AIDS research program of the country, said he disagreed with Lane and contrasts the argument zmapp tests as planned. "I'm a principal investigator for a long time with randomized controlled trials, and early combination therapy for HIV, they are not required to show the drugs are useful," said Delfraissy, who co-signed an editorial the Lancet which opposed this design for Ebola treatments. "It's hard to have a randomized trial when mortality is 50% or 60%."
Delfraissy does not rule out supporting the official with zmapp modification. "It is an open question," he said, noting that he had discussions with Lane here. Specifically, Delfraissy said if the studies on monkeys and finer analysis of patient samples were positive, perhaps the standard of care should include favipiravir in the control arm in the studies and zmapp other experimental treatments.
Hammer said he understands the perspective of Delfraissy but said, randomized controlled trials have played an important role in the history of the development of drugs against HIV. It highlights a controversial study in 1997, a year after the so-called "triple therapy" has proven itself found that three antiretroviral drugs were better than two. "We proved," said Hammer. "And there was no BS about it later."
A new report on the ethics of Ebola, released today by the US presidential Commission for the study of bioethical issues, takes a nuanced view of questions about the design of the study, the committee does not comment on placebo-controlled studies, but leaves room for other models too well. "test designs should be methodologically rigorous and capable of generating results that are clearly interpretable acceptable to host communities and, wherever possible, to minimize delays to the completion of the research" the report said. "The well-designed controlled trials placebo can meet these conditions, and innovative designs, such as adaptive randomization, should be considered as a way to answer these research objectives."
* Ebola files: science and Science Translational Medicine made a collection of research articles and news about the Ebola virus and the current epidemic available for researchers and the general public.
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