workers of ELWA3 hospital in Monrovia, where many patients are treated Ebola
PHOTO :. DOMINIQUE FAGET / IMAGES AFP / GETTY
On October 2, Ashoka Mukpo left his father a voice message from Monrovia, saying he had " unwelcome but not unexpected news. "Mukpo, an independent US cameraman for NBC News, had tested positive for Ebola. Mukpo's father, Mitchell Levy, a pulmonologist who directs intensive care at Rhode Island hospital in Providence, immediately helped organize the transfer of his son to the Nebraska Medical Center in Omaha, one of four specialized centers of Ebola in the United States.
the big question then was how to treat the patient .
medical team, which included Levy, designed to intensively monitor Mukpo and give him the replacement of intravenous fluids and electrolytes, antibiotics to fight secondary infections, and medications to slow diarrhea and vomiting. But there were also three non-available treatments. TKM-Ebola, which inhibits the viral RNA, worked beautifully in monkeys, the best animal model. Kent Brantly, a medical missionary in Liberia who developed the Ebola virus and recovered, offered to donate plasma removed from the blood, which contained antibodies that might help. And there was brincidofovir, a drug being developed for other viral infections has been shown to stop the Ebola virus in test tubes. (The most famous drug candidate, zmapp, was not available at the time.)
After careful consideration, Mukpo and his doctors have chosen to use the serum with a proven response to and other virus-brincidofovir, which has significant safety record. But they decided to give up TKM-Ebola, despite its promise, due to concerns that it could trigger an overproduction of cytokines, a dangerous inflammatory response also caused by the Ebola virus, and limited data from human trials. "I'm not quite on my deathbed and does not need to take risks enormous," said Mukpo. Her doctor father had reached a similar conclusion. "I do not have a high degree of confidence that brincidofovir would work, but I was reluctant to try an experimental agent without data," says Levy.
Mukpo survived, but nobody has any idea whether experimental treatments have helped, did nothing, or even slowed his recovery. The same is true for Brantly and 17 other Ebola patients who received experimental interventions in the US and Europe. (Another Ebola patient was treated in Germany without experimental intervention.) Many like Mukpo, received multiple treatments at the same time, making it difficult to disentangle the impact of one of them. The fact that they were supported in modern hospitals, well-staffed can also help explain why 75% survived (see box, p. 911). "Probably the best we can say is that experimental treatments are not killing anyone," said Michael Kurilla, who heads the Office of Biodefense Research Resources and translational research at the National Institute of Allergies and infectious diseases (NIAID) in Rockville, Maryland.
now it's about to change. from next month, researchers will begin testing in West Africa to find an answer solid to the key question: are treatments work Carried out in makeshift emergency hospitals by researchers wearing full protective equipment in the middle of a deadly epidemic, it will be some of the drug trials most unusual ever done. and they also raise important ethical and practical questions, some of which were intensely debated at a meeting of the World health Organization (WHO) in Geneva, Switzerland, on 11 and 12 November .
Recovered patients Ebola Ashoka Mukpo with his father Mitchell Levy, a pulmonologist who helped guide treatment of Mukpo.
PHOTO: TAYLOR WILSON / Nebraska Medical Center
Perhaps most importantly, is it right to do randomized controlled trials (ECR), in which some people do not get the novel procedure? Médecins Sans Frontières (MSF), which led the medical response to the epidemic, not not say with such a deadly disease Ebola. Instead, on November 13th MSF said it will take part in three tests that will use another design in which all those who registered receives untested treatment. But others argue that these configurations can not give clear answers and wasting valuable scientific opportunity.
There is a debate uncomfortable and complex held under the pressure of extreme weather. "Everybody stepped outside their comfort zone in a big way," said Peter Horby of the University of Oxford in the UK, who heads one of upcoming trials and attended the meeting WHO
tO cURRENT ePIDEMIC dE started, Ebola treatment development was painfully slow. Since the first recognized outbreak in 1976, the virus has resurfaced two dozen times, but until 2014, it was less sickened 2,500 people in total. This was not done for an attractive market for private companies, leaving most of the research to be funded by the Government of the United States, which worries that hostile nations or bioterrorist can launch horrific attacks with the virus. and because traditional containment efforts have ceased epidemic to date in a few months, researchers have had little opportunity to test new treatments.
Among the candidates, the two leaders are TKM-Ebola, an inhibitor of RNA virus packaged in a lipid nanoparticle and zmapp, a cocktail of three antibodies that Ebola rose to fame in August, when it was given to laboratory Brantly did. (A CNN report breathlessly called a "secret serum which probably saved his life.") These drugs worked better than any other in monkey studies, which puts the "light years" other treatment, said Thomas Geisbert of the University of Texas Medical Branch at Galveston, who led many key experiences. "If I were exposed to the virus that I would take zmapp Tekmira or drugs and I do not worry," dit- he.
"Everyone keeps talking zmapp," said Annick Antierens, who heads the experimental on work Ebola drug to MSF in Geneva. But both zmapp and TKM-Ebola are relatively difficult to make, and despite vigorous efforts to accelerate their production less than a thousand of each of doses may be ready by the end of the year. both are difficult to test in affected countries because they require intravenous infusions.
other candidates are more easily manufactured and administered, but data supporting their use are lower. brincidofovir was designed to interfere with the replication of viral DNA, and it is now Phase III in progress against cytomegalovirus and adenovirus; about 1,000 people received this spring Chimerix, the manufacturer, had two laboratories outside test the drug against Ebola virus. they found that the drug effectively inhibited the virus in TestTube studies. Brincidofovir can not be tested in monkeys, because an enzyme in animals rapidly inactivate the drug, but Chimerix says studies in guinea pigs and mice are in progress.
Another option is favipiravir, a flu drug approved in Japan that has protected mice from Ebola when administered 6 days after exposure to the virus. But unlike monkeys, mice do develop a mild disease from Ebola strains, so that the experiment using a mouse genetically modified to lack the immune system against viruses. This makes the results difficult to interpret.
whole blood or plasma component-containing antibodies could theoretically be harvested from thousands of recovered Ebola patients, but "convalescent serum" has not worked well in monkey experiments. A published report shows that seven out of eight who received whole blood of survivors during a 1995 epidemic Ebola in the Democratic Republic of Congo have survived, but they were treated late in the course of the disease, and some researchers believe they might have recovered without serum. A horse serum that contains antibodies Ebola is being developed, too.
The drugs that target only the symptoms of Ebola, rather than the virus itself, could also help. Doctors in Germany, for example, two patients treated with an experimental treatment called FX06 which aims to stop the leakage of fluid from blood vessels, a major problem in patients with advanced infections Ebola virus. One patient recovered, the other died.
Many other ideas were. Kurilla sets up a WHO database publish negative results to discourage researchers from pursuing compounds that do not pass muster in screening assays or animal experiments. "We are flooded with people who suggest the same thing again and again," he said. A doctor in Liberia in particular, has received considerable attention for touting HIV drugs lamivudine, but there is zero evidence from laboratory tests that it has an anti-Ebola activity.
The researchers now unprecedented chance to test candidate therapies systematically. At the WHO meeting in Geneva last week, researchers who wish to conduct clinical trials for treatment of Ebola met with regulators, pharmacologists and representatives of the three most affected countries to work on how to spend anecdotes on the disks of evidence and test drugs. More than 0 products have been put forward as possible treatments, but far too few clinics are qualified to participate in trials, participants were informed. And given the lack of supply, and zmapp TKM-Ebola are not on the table yet. Instead, the least promising treatments go forward first.
An international consortium led by Johan van Griensven the Institute of tropical Medicine in Antwerp, Belgium, plans to test the convalescent serum in Conakry, the Guinean capital. The biomedical research INSERM French agency will conduct a trial to favipiravir Gueckedou, Guinea. Brincidofovir and will be tested in a study by Oxford or in Sierra Leone or Liberia. The three clinical trials will share a simple form to collect more data base; anything recording is extremely heavy when healthcare workers wear bulky protective gear.
patients in the processing unit Ebola spare in Kenema, Sierra Leone, in August
PHOTO :. WHO Ebola INTERVENTION TEAM
the ethical issues surrounding the tests have troubled the scientific community and humanitarian community and have been "vigorously debated" at the meeting, according to WHO. MSF said that for now it will not participate in trials that randomly decide who would receive treatment. "If an epidemic like this with such a high mortality rate would occur in Europe, I do not think that would be acceptable randomization patients," said MSF Antierens. "I certainly would not get the level of care if there is a promising drug available. "an editorial discussed many published online October 10 in the Lancet , signed by prominent ethicists and scientists from 11 countries, made the same point. Some fear RCTs can even trigger protests and violent reactions of the families of patients and their communities.
But others say that testing without an untreated control group raise ethical problems of their own. " I do not know if these agents could be harmful, and given a disease with a mortality rate as high as this one, you might not be able to detect this injury "without a control arm, said Clifford Lane, clinical director NIAID in Bethesda, Maryland. ECR also reduce the confusion introduced by variables such as how sick people are at the beginning of treatment and whether patients in a trial also receive better care. Randomization, Lane said, is the only effective way to "make sense of anything."
The three studies that will begin first, all MSF centers, will not have a design randomized instead, all patients will receive the treatment. survival rate 14 days later will be compared to survival in previous patients who did not receive treatment (the convalescent serum trial will also have an arm. " competitor "of control that escapes the ethical problems. Some patients will not be treated because there is no donor with a matching blood type)
Antierens agrees that these tests may not detect small effects of a drug, but says the goal is to determine whether an intervention is worthless or working well. "We are not interested in whether certain liver enzymes are a little higher," she said . "We are looking for a significant change in survival." Brincidofovir for testing, for example, researchers have agreed to define the survival less than 50% as "failure" and above 80% "success." If the data is ambiguous, an RCT could be considered, she said.
the horrific nature of the epidemic led to others rarely observed in clinical studies arrangements. The researchers responsible for the study favipiravir initially wanted to target adults in the first 2 days of illness. MSF called for the design to be changed so that no one can be denied to the people of drugs, including who were sick longer and children. "People on the ground said:" What we will do when a family arrives? We treat the parents and not the child? "Xavier said Lamballerie of Aix-Marseille University in France, who is leading the study. The study brincidofovir recruit up to 140 people, and at the request of MSF will continue to provide the drug while the test data are being analyzed to ensure that no patient misses a potentially effective treatment.
PROMOTERS dE RCTS are aggressively pushing ahead with test plans, too. Luciana Borio of the US Food and Drug Administration in Silver Spring, Maryland, who attended the WHO meeting; NIAID Lane; and others have developed a protocol that would test multiple interventions, including zmapp and TKM-Ebola in one large RCT, using sophisticated Bayesian statistics to get an answer as quickly as possible. Lane is currently negotiating with the Liberian government about the implementation of many of these studies. Liberia is not opposed to ECR, said Stephen Kennedy, a researcher at the University of Liberia Pacific Institute for Research and Evaluation African Centre in Monrovia, which advises the Ministry of Health of the countries on its control of research Ebola clinic. "We must use the gold standard," said Kennedy. "We understand the problems and we know what is appropriate for Liberia."
Borio understands the concerns about randomization, but said that do not get a clear answer would be worse. non-randomized trials were announced last week a "significant risk of not generating interpretable data," said Borio. "It is so important to get this right. It is important for patients who become affected in this outbreak, and for generations to come, given that future outbreaks will surely occur. "
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