Nov 3, 2010 (CIDRAP News) – Combining two antiviral drugs, oseltamivir (Tamiflu) and zanamivir (Relenza), has been suggested as a way to improve treatment of influenza, but a clinical study from France suggests that oseltamivir alone works better, at least in otherwise healthy adults with uncomplicated influenza A/H3N2 infections.
In a publicly funded trial conducted in the winter of 2008-09, the French investigators found that the oseltamivir-zanamivir combination was significantly less effective overall than oseltamivir alone, according to a report published yesterday by PLoS Medicine. About 85% of the patients had H3N2 infections.
The investigators also found that, in terms of clinical results, the combination treatment was not significantly better than zanamivir alone. They also reported that oseltamivir alone appeared to work better than zanamivir alone, resulting in a shorter duration of illness.
Overall, the findings suggest that clinicians should be cautious about using the combination therapy, the authors write. They add that "oseltamivir should be the recommended primary anti-influenza treatment during influenza seasons with predominant H3N2 viruses naturally susceptible to oseltamivir."
Potential advantages of dual therapy
It has been suggested that combining oseltamivir and zanamivir—both neuraminidase inhibitors—in flu patients might reduce disease severity, the period of viral shedding, and the risk of emergence of viral resistance, while ensuring optimal treatment of all circulating flu strains, the authors write. They say these effects could be especially important for patients who shed the virus for a long time, such immunocompromised patients.
The study period ran from early January to mid March of 2009. In the study, 145 general practitioners from all over France enrolled adults who presented for treatment of flu-like illness within 36 hours of their first symptoms and who had positive rapid tests for influenza A.
The patients were randomly assigned, in double-blind fashion, to one of three treatment groups: oral oseltamivir twice daily plus inhaled zanamivir twice daily, oral oseltamivir twice a day plus an inhaled placebo, or zanamivir twice a day plus an oral placebo. Those who had been vaccinated against flu that season or had a chronic respiratory disease were excluded.
The investigators assessed the virologic results of treatment by using reverse transcriptase polymerase chain reaction (RT-PCR) to determine the percentage of patients whose viral load in nasal samples was below a certain level (200 genome equivalent copies per microliter) 2 days after treatment initiation. The clinical effectiveness of treatment was determined from the time until alleviation of illness, the percentage of patients with resolved symptoms at the end of treatment, a symptom score at the end of treatment, and the incidence of complications such as pneumonia.
The original plans called for running the trial for two flu seasons, but when the 2009 H1N1 virus emerged, the study's data-monitoring committee requested that the researchers stop the trial and analyze the results early.
A total of 541 patients were enrolled in the trial, of whom 447 tested positive for influenza A by RT-PCR. In the 447 confirmed cases, the virologic analysis showed that 45.9% of the dual therapy group, 58.9% of the oseltamivir (oseltamivir plus placebo) group, and 33.6% of the zanamivir group met the primary criterion of virologic effectiveness. The differences between dual therapy and the two single therapies were significant, as was the difference between oseltamivir and zanamivir.
As for the clinical results, in the 447 confirmed cases the median time to resolution of illness was 4.0 days for the combination treatment, 3.0 days for oseltamivir only, and 4.0 days for zanamivir only. The difference between the combination group and the oseltamivir group was significant.
In other clinical results, the median symptom scores at the end of treatment were significantly higher for the dual therapy group than for either the oseltamivir group or the zanamivir group; the latter two were the same.
"The oseltamivir-zanamivir combination seemed, both virologically and clinically, significantly less effective than the oseltamivir monotherapy," the authors write. They say this suggests that zanamivir may have a negative effect on oseltamivir. Recent in vitro research, combined with the different routes of administration for the two drugs, suggests that zanamivir may block oseltamivir by occupying the "catalytic pocket" of the neuraminidase protein first, they explain.
The investigators say the virologic findings indicate that the dual therapy was better than zanamivir alone, but the clinical results were not significantly different, "suggesting that oseltamivir adds essentially nothing to zanamivir monotherapy."
Oseltamivir alone seemed to work better than zanamivir alone both virologically and clinically, the authors write. But they say this could be the result of "a suboptimal treatment regiment in the zanamivir arm," because the dosage needed for 50% inhibition of H3N2 viruses in vitro in the 2008-09 season was two to three times higher for zanamivir than for oseltamivir.
Since most of the patients in the study had H3N2 infections, it is uncertain how well the findings apply to susceptible viruses of other subtypes, such as the pandemic H1N1, the report says.
The investigators acknowledge several limitations of their study, including that it involved only adult outpatients, which prevents extrapolating the results to children or severely ill patients.
Despite the theoretical possibility of reducing the risk of resistance, the authors conclude, "The lower efficiency of the oseltamivir-zanamivir combination found in this study calls for caution in its use in clinical practice."
Study design called sound
Frederick G. Hayden, MD, a flu expert and professor of medicine and pathology at the University of Virginia School of Medicine, who was not among the study authors, called the study design "solid," but noted the lack of a placebo control and limited virologic sampling. He said he agreed with the suggestion about a cautious approach to using the two drugs together.
"It does certainly give pause to the use of this particular combination outside the context of controlled clinical trials and until further preclinical data are provided," said Hayden, who noted that he served as a reviewer for the study after it was submitted for publication. He added that the available data for using combinations of drugs with different mechanisms of antiviral action are more encouraging.
Hayden said he didn't know to what extent oseltamivir and zanamivir have been used in combination in clinical practice, but the idea has been considered for immunocompromised patients with 2009 H1N1 infections, on grounds that it might reduce the risk that the virus would become resistant to oseltamivir.
One limitation of the study—as acknowledged by the authors—is that virologic sampling was done 2 days after the start of treatment, which is generally too soon to detect any emerging resistance, Hayden said. "This study clearly wasn't powered or designed to look at prevention of resistance emergence, which is one of the major hopes one would have for using a combination of antivirals," he commented.
Another limitation is that nasal sampling may not be the best way to measure the effect of zanamivir, which is orally inhaled, on viral load, Hayden said. On the basis of a study he was involved in some years ago, "It's not clear to what extent it affects nasal viral load, so that might not be a fair test of what zanamivir is doing virologically."
Hayden observed that at least one other aspect of the study is unique: "This is the first time I've actually seen prospective randomized data comparing these two drugs head to head for uncomplicated influenza in adults."
He concluded that the idea of using combination antiviral treatment is an important subject for further research, both preclinical and clinical. "This is a valuable contribution in terms of testing a concept, but it doesn’t really address some of the high-risk patients, those with severe illness, and especially immunocompromised patients, in whom we really want to know what would happen with combinations," he said.
Duval X, van der Werf S, Blanchon T, et al. Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a randomized placebo-controlled trial. PLoS Med 2010 Nov 2;7(11): ):e1000362 [Full text]
