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. November 2010; 7(11): e1000362.

CONCLUSIONS: For the treatment of adults with seasonal influenza A (H3N2), oseltamivir was more effective when given as monotherapy than as combination therapy with zanamivir, and was also significantly more effective than zanamivir monotherapy. New drug trials may be needed for each new seasonal or pandemic influenza virus. It is still not clear whether combination therapy might prevent or promote the emergence of resistant strains.

ABSTRACT: The neuraminidase inhibitors oseltamivir and zanamivir reduce the duration of symptoms and of viral shedding in outpatients with uncomplicated seasonal influenza and slow the spread of virus in the community. It has been hypothesized that the widespread use of a single antiviral risked encouraging the emergence of resistant strains. Mathematical modelling showed that the combined use of 2 antivirals early in an epidemic reduced this risk. Combinations might also speed up viral clearance and clinical recovery. The combination of neuraminidase inhibitors is attractive: both are licensed for seasonal influenza, they are delivered to the respiratory tract by distinct means, and key mutations associated with resistance are different for each drug. This article describes a double-blind, randomized trial of oseltamivir and zanamivir in combination against each drug separately as monotherapy during the influenza season of 2008-2009 in France.

From January 7 though March 15, 2009, the trial enrolled adults over 18 years of age who consulted their general practitioner within 36 hours of influenza symptoms onset, with a temperature at or above 38 degrees Celsius, 1 or more respiratory symptoms, 1 or more general symptoms, and a positive nasal rapid test for influenza A performed by the practitioner.

At enrollment (day 0), a nasal swab was taken and sent to the nearest National Influenza Centre for virological analysis by real-time reverse transcription (RT)-PCR and virus isolation and subtyping. Patients were allocated by a randomization list to 1 of 3 treatment arms: oral oseltamivir 75 mg twice daily plus inhaled zanamivir 10 mg twice daily (arm OZ), oseltamivir plus inhaled placebo (arm O), and zanamivir plus oral placebo (arm Z). All treatments were given for 5 days. On day 2, a second nasal swab was taken for virological analysis; on day 7, patients returned to their general practitioner for follow-up examination; and on day 14, they were contacted by telephone.

Virological response was defined as a normalized viral load less than 200 copies genome equivalent (cgeq)/fÝl at day 2. Clinical response was assessed daily by oral temperature and 7 chosen symptoms scaled for severity. Treatment compliance was recorded by patients. The primary efficacy endpoint was the proportion of patients with RT-PCR less than 200 cgeq/microliter on day 2. Other endpoints were: decrease in viral load between days 0 and 2, the time to resolution of illness, the number of patients with alleviation of symptoms at the end of treatment (day 5), the symptom score at the end of treatment, the incidence of secondary complications, and the occurrence of adverse events.

Recruitment was ended prematurely after the enrollment of 541 of the planned 900 patients, because of the arrival of pandemic H1N1 influenza in France. Of the 541 enrolled patients, 192 were assigned to arm OZ, 176 to arm O, and 173 to arm Z. Mean age was 39 years, 49% were male, mean fever was 38.2 degrees Celsius, and mean duration of illness was 25 hours. Other characteristics, including rates of compliance (~86%), did not differ among the 3 arms.

Of the 541 enrolled patients, 447 (83%) had RT-PCR-confirmed influenza A virus infection with a mean viral load of 4.38 log10 cgeq/microliter. In the intention-to-treat analysis, the proportion of all enrolled patients with RT-CPR less than 200 cgeq/microliter on day 2 was 52.6% in the OZ arm, 62.5% in the O arm (p = 0.005 for the OZ vs. O comparison), and 40.5% in the Z arm (p = 0.02 for the OZ vs. Z comparison). In the 447 influenza RT-CPR-confirmed patients, the proportions were 45.9% in the OZ arm, 58.9% in the O arm (p = 0.025 for the OZ vs. O comparison), and 33.6% in the Z arm (p = 0.028 for the OZ vs. Z comparison). The mean decrease in viral load between day 0 and day 2 was 2.14 log10 cgeq/microliter in the OZ arm, 2.49 log10 cgeq/microliter in the O arm (p = 0.060 for the OZ vs. O comparison), and 1.68 log10 cgeq/microliter in the Z arm (p = 0.016 for the OZ vs. Z comparison).

The median time to resolution of illness in all 541 enrolled patients was 3.5 days in the OZ arm, 3.0 days in the O arm (p = 0.015 for the OZ vs. O arm), and 4 days in the Z arm (p = 0.78 for the OZ vs. Z comparison), with comparable figures among the patients who were initially RT-CPR positive. Of 4 serious adverse events, 3 were deemed to be related to treatment, 2 of them in the OZ arm. Of the non-serious adverse events, nausea and/or vomiting were 3 times more common in the OZ arm than in the O or Z arms.

COMMENTARY: This study compared the efficacy of 3 regimens for the treatment of seasonal influenza caused predominantly by H3N2 viruses in France in the winter of 2009 before the arrival of pandemic H1N1 influenza. It showed clearly that the oseltamivir-zanamivir combination was less effective than oseltamivir monotherapy and not significantly more effective than zanamivir monotherapy. Clinical and virological endpoints were in broad agreement. Without untreated controls, the actual efficacy of each treatment regimen could not be measured. Two important conclusions emerge from this study.

The first conclusion is that oseltamivir and zanamivir are not synergistic and may have an antagonistic effect against H3N2 influenza virus. When outcomes in the OZ arm were compared with those in the O arm, there were significant reductions in the rate of viral shedding, of time to resolution of illness, and of the percentage of asymptomatic patients and symptom score at the end of treatment, in both subgroups of patients (clinical influenza and laboratory-confirmed influenza). The article suggests that inhaled zanamivir may bind quickly to the neuraminidase receptor and block the attachment of the more slowly absorbed oral oseltamivir, thus reducing the efficacy of oseltamivir, which in this epidemiological setting seems to be the more powerful of the 2 drugs.

By contrast, when the OZ and Z arms were similarly compared, the combination was significantly more effective in reducing in the rate of virus shedding, but did not increase the speed of resolution of any of the clinical measurements of illness. In addition, the common adverse effects of nausea and/or vomiting were more frequent in arm OZ than in arms O or Z. In vitro studies on 2009 H1N1 pandemic influenza viruses have also noted both additive efficacy and antagonism between zanamivir and oseltamivir, according to dose. At the moment, H3N2 viruses are susceptible to both drugs.

The second conclusion is that oseltamivir was significantly more effective than zanamivir in the treatment of seasonal influenza due to 2008/2009 influenza A (H3N2) virus. This study may represent the first head-to-head prospective comparison of these 2 drugs in the treatment of H3N2 influenza. When compared with zanamivir, oseltamivir treatment resulted in a 22% greater reduction in viral shedding after 2 days, and a faster decrease in time (by 1 day) to resolution of symptoms, with 11.5% more patients symptom free at the end of treatment and with a lower symptom score. By comparison, pandemic 2009 A (H1N1) viruses were sensitive to both drugs, although seasonal H1N1 viruses circulating before 2009 were resistant to oseltamivir. Thus, the choice of treatment will vary with the type or sub-type of the currently circulating influenza virus as well as the clinical situation.

The study did not resolve the initial hypothesis that combination therapy might reduce the risk of emergence of resistant strains, and it is possible that treatment with 2 neuraminidase inhibitors might encourage rather than deter the emergence of resistance.