February 27, 2012 — A novel strain of a swine influenza virus that sickened just 12 individuals in 2011 nevertheless merits continued surveillance because tests indicate that the emerging virus has "pandemic potential" among humans, according to an article published online February 21 in the Proceedings of the National Academy of Sciences.
In the tests, ferrets were inoculated with isolates of this novel virus, as well as earlier versions. The viruses efficiently replicated and spread among the ferrets, which resemble humans in terms of lung physiology and susceptibility to influenza viruses, lead author Melissa Pearce, PhD, an associate service fellow at the US Centers for Disease Control and Prevention (CDC), and coauthors write.
The swine influenza virus from 2011 is designated A(H3N2)v, with the "v" standing for variant. What accounts for the variance in this particular virus is a gene from the pandemic 2009 influenza A(H1N1) virus that codes for matrix proteins in the viral shell.
Seasonal human influenza strains now in circulation include an A(H3N2) virus, as well as the pandemic 2009 A(H1N1) virus. The current trivalent influenza vaccine guards against both of these viruses in addition to an influenza B strain. However, Dr. Pearce and colleagues write that the swine influenza variant is antigenetically distinct from the current human A(H3N2) virus, and therefore "would not be well covered by the current trivalent vaccine."
With that limitation in mind, the CDC has already embarked on developing a vaccine for the A(H3N2)v virus from 2011 in case it should begin to spread among humans on a sustained basis.
Virus Give-and-Take Between Humans and Pigs
The article by Dr. Pearce and 12 other authors traces a convoluted history of the novel virus that has rung alarm bells. The human A(H3N2) virus, they write, infected pigs in the late 1990s and spread widely through North American herds. In turn, variations of this now-swine influenza virus, all of which were designated A(H3N2)v, infected a smattering of humans, including 5 individuals in 2010. Four of the 5 people infected either had direct contact with pigs or lived close to pig farms. One of those individuals apparently passed the virus to his child. All 5 recovered, although 2 patients required hospitalization.
The CDC identified 12 individuals in 2011 who were infected with a swine-origin A(H3N2)v virus with a twist not seen in the previous cases: The 2011 version contained a matrix gene from the pandemic 2009 influenza A(H1N1) virus, which had made its way into pigs as well.
These 12 infected individuals, all but 1 of them children, were scattered across 5 states. Similar to the 5 patients in 2010, they all recovered, although 3 were hospitalized. The symptoms and severity of their influenza resembled that of the seasonal variety, according to the CDC.
What worries the CDC is that, as in 2010, some of the 12 individuals in 2011 apparently caught the A(H3N2)v virus from another person, as opposed to from a pig. Human-to-human transmission was limited, but the agency notes that influenza viruses can mutate into more easily spread forms.
Ferreting Out the Viral Truth
To delve into the question of pandemic potential, Dr. Pearce and coauthors analyzed the virulence, transmissibility, and receptor-binding preferences of 4 A(H3N2)v viruses isolated from human subjects: 1 from 2009, 2 from 2010, and 1 from 2011. After inoculating ferrets with the isolates, they found that:
•All 4 viruses replicated efficiently in a ferret's upper respiratory tract.
•Inoculated ferrets lost 8% to 10% of their weight and developed a fever. Their lymphocyte count temporarily fell by 13% to 24%. In contrast, infection with a "highly pathogenic" avian influenza virus can reduce lymphocyte counts by more than 20%.
•All 4 A(H3N2)v viruses spread efficiently among ferrets in the same cage.
•When ferrets were separated by perforated walls, the swine influenza viruses from 2010 and 2011 also spread efficiently by respiratory droplets, in contrast with the less efficient 2009 virus.
The researchers also inoculated cultures of human airway epithelial cells with the 4 A(H3N2)v viruses, along with seasonal human A(H3N2) viruses. All 4 of the swine-origin variants replicated to higher levels than their seasonal human virus counterparts. In a glycan array analysis, the viruses from 2009 and 2010 exhibited binding characteristics similar to those of seasonal human influenza A viruses, suggesting that they, too, would replicate handily in the upper respiratory tract of humans.
"These findings," the authors write, "underscore the need for continued surveillance and characterization of these viruses because they resemble viruses with pandemic potential."
The authors note that it is unclear whether the matrix gene from the pandemic A(H1N1) virus found in the swine-origin A(H3N2)v virus from 2011 improves its ability to spread in pigs and infect humans. Although some have suggested that the matrix segment of the pandemic human virus enhances respiratory-droplet transmission in a guinea pig model, the isolate viruses from 2010 without that matrix segment spread among ferrets just as easily as the 2011 version.
The authors have disclosed no relevant financial relationships.
Missing Data Lead FDA Panel to Vote Against Rivaroxaban for ACS May 23, 2012 (Updated May 24, 2012) (Silver Spring, Maryland) — The missing data issues plaguing the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the FDA Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting, the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus clopidogrel, or ticlopidine. Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the ATLAS ACS TIMI 46 phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the risk of bleeding and intracranial hemorrhage, but the studies were hindered by early patient withdrawals and missing data. We Don't Know What We're Missing Based on the ATLAS ACS 2 results, FDA reviewer Dr Karen Hicks recommended approval of rivaroxaban for the requested indications except all-cause mortality. However, another FDA reviewer, Dr Thomas Marciniak, was adamant that the trial results are not interpretable because about 12% of the patients had incomplete follow-up, far higher than the 1% to 1.5% differences in the end-point rates between rivaroxaban and placebo. A total of 1294 subjects discontinued the trial prematurely, and the company was only able to contact 183, of which 177 were confirmed to be alive. Because of the patient dropouts, the company adopted a "modified intention-to-treat analysis," whereby patients were observed for 30 days after randomization or the global end date for the trial, instead of observing all the patients until the end of the trial as the FDA originally suggested. Marciniak criticized the sponsor's efforts to follow the patients and said that three patient deaths not counted in the modified intention-to-treat analysis may just be the "tip of the iceberg." Because the percentage of patients whose ultimate vital status remains unknown is much greater than the reported differences in mortality rates, the claimed mortality benefits are not reliable. The majority of the panel sided with Marciniak. For example, Dr Sanjay Kaul (University of California, Los Angeles) voted "no" because "there was enough uncertainty in the quality and robustness of the data that dissuaded me from voting yes. . . . The 'missingness' of the data doesn't invalidate it, but it certainly makes it hard to infer [the conclusion]." Dr Steven Nissen (Cleveland Clinic, OH) said that the decision to use the modified intention-to-treat analysis had a "profound impact" on the interpretability of the data. "It's saying we don't care what happens after 30 days, [and] that colored the trial in ways we couldn't recover from." Given the risk of major bleeding, "I want to see better evidence that this strategy of adding an Xa inhibitor or a direct thrombin inhibitor or something else to a good antiplatelet agent is robustly better for the patient," Nissen said. He recommends that the companies run a new trial of the 2.5 twice-daily dose of rivaroxaban using a strict intention-to-treat approach, but, he said, "I don't expect the death benefit to be too robust." Several panelists said they were concerned that the patients who dropped out of the trial were disproportionately likely to have a bleeding event, which led them to quit the trial, or a "protopathic" event, as statistician Dr Scott Emerson (University of Washington, Seattle) put it. "We're worried that an impending event is what is changing their behavior. We see that all the time in clinical trials--that regularly measured end points do not pick up [all of] the events," he said. He said that since the company was only able to contact 183 of the over 1200 patients who dropped out, it is possible that the dropouts skew the outcomes comparison of the trial. "Differential event rates after dropout are the number-one thing we're afraid of, so you have to explore it" in a statistical sensitivity analysis of the potential impact of these unknown outcomes. "It would not surprise me if, at the end of the day, these data did not hold up under a proper sensitivity analysis," he said. "What I want to know is, among the people who had events, how differential was the follow-up, but I can tell you by just looking at it, there was a very slightly different amount of follow-up of the people in the treatment arm. But I don't know whether everyone in the treatment arm was cured and they were trekking in the Himalayas and everyone in the placebo arm went home to die. I don't know that that's not the case." Dr Maury Krantz (University of Colorado, Denver) voted in favor of approval but said he does not know how rivaroxaban would perform in general clinical practice, especially when used with aspirin and clopidogrel. "I felt very much torn by this. This isn't a simple paradigm shift. It means going to triple therapy, which is really a three-headed monster in many ways. I think that what you're going to see in practice, if this is not done carefully with the proper labeling and secondary studies, is really dramatic magnification of bleeding and perhaps minimization of the efficacy benefit."
May 23, 2012 (Updated May 24, 2012) (Silver Spring, Maryland) — The missing data issues plaguing the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the FDA Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting , the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus clopidogrel , or ticlopidine . Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the ATLAS ACS TIMI 46 phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the ri...
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