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Analyses support antivirals, rapid tests for flu.


The two most commonly used antiviral drugs for treating influenza infections, oseltamivir and zanamivir, each provide a net benefit to patients compared with no treatment, concluded the authors of a meta-analysis of 74 influenza antiviral observational studies.

And in a separate report published in the same journal, another group of researchers found in a meta-analysis of 159 studies that evaluated rapid influenza diagnostic tests (RIDTs) that these tests have high specificity for positively identifying a patient infected with influenza but low sensitivity, which means that a negative test result cannot reliably rule out influenza infection (Ann. Intern. Med. 2012;156 [Epub ahead of print Feb. 28]).

Both findings support existing U.S. recommendations from the Centers for Disease Control and Prevention (CDC) for the use of neuraminidase-inhibitor anti-influenza drugs and the use of RIDTs.

The antivirals meta-analysis, which was commissioned by the World Health Organization, included 51 observational studies that compared treatment with oral oseltamivir to no antiviral therapy. However, not every study looked at the same types of patients or the same outcomes, or had similar methods. For example, three studies assessed mortality rates in hospitalized patients and adjusted for age and comorbidities.

This pooled analysis showed a statistically significant, 77% reduction in mortality compared with no antiviral therapy, suggesting that oral oseltamivir may reduce deaths, although the overall grade for the quality of the evidence was deemed low (Ann. Intern. Med. 2012;156 [Epub ahead of print Feb. 28]).

A second analysis included nine studies that also looked at the effect of oseltamivir on mortality in hospitalized patients, but these studies did not make any adjustments for possible confounders. The meta-analysis showed a more modest, 49% reduction in mortality.

Other parts of the oseltamivir analysis showed that its use reduced the rate of hospitalization among outpatients by 25%, and the duration of fever by approximately 33 hours. Oseltamivir use also reduced the incidence of neuropsychiatric events, as well as other signs and symptoms of influenza infection.

"Our findings indicate that the use of oral oseltamivir for treatment of influenza may provide net benefit by reducing mortality, the duration of symptoms, and complications of influenza. We observed a large, precise effect of oseltamivir on hospitalization" that was "compatible with the imprecise estimate from randomized controlled trials," wrote Dr. Holger J. Schunemann, chairman of the department of clinical epidemiology and biostatistics at McMaster University, Hamilton, Ont., and his associates.

The meta-analysis also included five observational studies and two surveys that compared the second marketed neuraminidase inhibitor, inhaled zanamivir, with no antiviral therapy in patients treated as outpatients. Two studies addressed hospitalization, and showed that patients with confirmed influenza or influenza-like illness who received zanamivir may be less likely to be hospitalized than patients who received no antiviral, a 34% reduction that was not statistically significant. Pooled results from three studies that reported on symptom duration showed an approximately 23-hour reduced duration of symptoms with zanamivir.

"Inhaled zanamivir reduces signs and symptoms, but we judged the overall confidence in the estimates of effect as very low, owing to imprecise and possibly biased data on mortality and hospitalization," the authors said. "A direct comparison between oral oseltamivir and inhaled zanamivir in eight studies showed that zanamivir may have a slight advantage in shortening the duration of signs and symptoms."

The meta-analysis also found that the evidence on the use of oral amantadine is "sparse, but may suggest a benefit from using this agent for treatment of drug-sensitive influenza A infection."

The analysis also suggested that earlier treatment with antivirals, within 48 hours, "may be of greater benefit" than later treatment.

"The potential positive effect of earlier rather than later administration of oseltamivir on death in hospitalized patients, and suggestions that pregnant women, children, and patients who are immunocompromised may also benefit from treatment, are among the key contributions of our study," the authors concluded. In addition, "we found moderate-quality evidence for the reduction in signs and symptoms from treatment with inhaled zanamivir compared with no treatment. The data suggest that oral oseltamivir could provide a net benefit in the treatment of patients with influenza, including a sizable reduction in hospitalized patients, although our confidence in these effects is low."

"Evidence that treatment with a neuraminidase inhibitor offers significant benefit in people with influenza is growing," commented Dr. Timothy R. Peters, a pediatric infectious diseases physician at Wake Forest University, Winston-Salem, N.C. As expected, those benefits are likely greatest in patients at highest risk for severe influenza disease, including pregnant women, young children, and immunocompromised patients. The findings of the meta-analysis generally support the recommendations of the CDC that encourage clinicians to aggressively protect influenza-infected patients at high risk for severe disease by using a neuraminidase inhibitor (MMWR 2011;60:1-24). Once the 2009 HIN1 pandemic ended, "it may be that clinicians do not prescribe neuraminidase inhibitors as aggressively as the CDC recommendations would support," he said.

The meta-analysis of RIDTs included 159 studies that assessed the accuracy of 26 commercially marketed RIDTs; 119 of the studies compared 1 or more RIDTs against either of the two reference standards for influenza infection, viral culture, or reverse transcriptase-polymerase chain reaction. The analysis showed that specificity rates ranged from 51% to 100%, and that sensitivity rates ranged from 4% to 100%. The pooled sensitivity was 62%, and the pooled specificity was 98%, reported Dr. Caroline Chartrand, a pediatrician at CHU Sainte-Justine in Montreal, and her associates.

"Overall, RIDTs have high specificity, with modest and highly variable sensitivity," the authors concluded. "This means that a positive test is unlikely to be a false positive result." In the presence of a positive RIDT result, "a clinician can confidently make the diagnosis of influenza and begin appropriate infection-control measures and antiviral therapy, if indicated, while forgoing unnecessary additional diagnostic testing and antibiotic prescription. However, a negative RIDT result has a reasonable likelihood of being a false negative and should be confirmed by other laboratory diagnostic tests if the result is likely to affect patient management."

The analysis also showed that RIDTs performed better in children than in adults, with approximately 13% higher sensitivity in children. "This is plausible because young children have higher viral loads and longer viral shedding than adults," the authors said. RIDTs also showed higher sensitivity for detecting influenza A compared with influenza B.

"Overall, no commercial brand of RIDT seemed to perform markedly better or worse than the others, but this finding should be interpreted cautiously because head-to-head comparisons were not done in most studies. Administration of the RIDT by personnel other than a trained laboratory technician does not seem to adversely influence the performance of these tests," they added.

"The most important advantage of RIDTs is their rapid turnaround time. RIDTs fill a void at the point of care that no other test is likely to fill in the near future. As long as clinicians understand the limitations of RIDTs, namely that a negative result is unreliable and should be confirmed by using culture or RT-PCR, RIDTs could enable clinicians to institute prompt infection-control measures, begin antiviral treatment in high-risk populations, and make informed decisions about further diagnostic interventions," the authors concluded.

The meta-analysis results "support the notion that a positive rapid test result is much more helpful to the clinician than a negative result," commented Dr. Peters. "Positive test results can prompt early, appropriate initiation of neuraminidase inhibitor therapy. A negative result may occur in an influenza-infected patient at high risk for severe disease, especially in adults who shed less virus [than children] when infected. Clinicians should be especially suspicious of negative test results at times when they are seeing a lot of influenza disease, and they should be prepared to initiate early neuraminidase inhibitor therapy when their clinical suspicion for influenza is high despite a negative test result," Dr. Peters said.

Dr. Schunemann and his associates, Dr. Chartrand and her associates, and Dr. Peters said that they had no disclosures.

RELATED ARTICLE: Meta-analyses help position antivirals, RIDTs.

The meta-analysis on the efficacy of oseltamivir and zanamivir for treating influenza, especially in severely infected or high-risk patients, is very important. The controlled clinical trials for these drugs excluded hospitalized patients, pregnant women, and patients at very high risk for complications. But these are precisely the patients who face the greatest risk from influenza and need effective therapy. Because it is unlikely that placebo-controlled, randomized trials of these drugs will ever be done in these populations, our only recourse is to use observational studies for guidance on whether these drugs work in these critical settings.

The observational studies reviewed in this report show the consistent finding that antiviral treatment of influenza infections in patients who need hospitalization or are pregnant prevented death and ICU admissions. The results of these studies, individually, had already led to recommendations for using antivirals in these patients from the Centers for Disease Control and Prevention and from the Infectious Diseases Society of America (Clin. Infect. Dis. 2009;48:1003-32). The new meta-analysis highlights these benefits in a more detailed way. More importantly, the new analysis provides evidence that treating high-risk patients infected with influenza with one of these drugs prevents the outcomes that we care about the most: death, hospitalization, and complications.

Observational studies are always subject to more limitations than properly controlled randomized trials, but the consistency of the evidence and the attempts to control for bias in the meta-analysis improve the quality of the evidence.

I believe that most clinicians are already aware of the CDC recommendations on antiviral use for influenza. In recent years we have seen improved rates of treatment of high-risk patients with an antiviral, but too many patients remain untreated. I worry that some clinicians have heard the message that the results from randomized trials showed modest benefits only in otherwise healthy influenza patients. These new meta-analysis results should reassure them that there is solid evidence for benefit in high-risk patients.

The meta-analysis of RIDTs involved data that, I think, were generally better known to flu experts. The meta-analysis deals with a wide range of test types and flu seasons, and that is both a strength and weakness of the analysis.

The results show that the relatively low sensitivity of the RIDTs is a consistent finding from year to year and in study to study, and that this produces a low negative predictive value. An important message from this new analysis is that RIDT sensitivity is consistently lower among adult patients. During the 2009 H1N1 pandemic, we saw that many clinicians did not appreciate that a negative test did not rule out influenza. Since then, the CDC has issued statements on how to best use RIDTs in practice, but I'm not sure how much of this misuse has changed.

It is reassuring to see that the positive predictive value of RIDTs is consistently high according to the meta-analysis. RIDTs can be very useful when positive for limiting additional testing and avoiding the use of antibiotics. Results from several studies showed that clinicians change their behavior when they get a positive RIDT result. The low negative predictive value of these tests means that a negative RIDT result should not be the reason to not use antiviral treatment. That is a major shortcoming of RIDTs. The role of RIDT on management of patients with suspected influenza would be greater if and when a more sensitive, point-of-care test becomes available.

ANDREW T. PAVIA, M.D., is a professor and chief of the division of pediatric infectious diseases at the University of Utah in Salt Lake City. He said that he has no disclosures. He made these comments in an interview.
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Author:Zoler, Mitchel L.
Publication:Pediatric News
Date:Mar 1, 2012
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