Influenza causes excessive hospitalizations and deaths. Single agent treatment with oseltamivir in severe influenza might be insufficient. The study assessed the efficacy and safety of oseltamivir-clarithromycin-naproxen combination for treatment of serious influenza.
From February to April 2015, we conducted a prospective open-label randomized-controlled trial. Adult patients hospitalized for A(H3N2) influenza were randomly assigned to a 2-day combination of clarithromycin 500mg, naproxen 200mg and oseltamivir 75mg twice daily, followed by 3 days of oseltamivir; or oseltamivir 75mg twice daily without placebos for 5 days as control (1:1). The primary end-point was 30-day mortality. The secondary end-points were 90-day mortality, serial nasopharyngeal-aspirate (NPA) virus titer, percentage of neuraminidase inhibitor resistant A(H3N2) virus (NIRV) quasispecies by pyrosequencing, pneumonia-severity-index (PSI), and duration of hospital-stay.
Among the 217 influenza A(H3N2) patients enrolled, 107 were randomly assigned to the combination treatment. The median age was 80 years and 56% were men. Adverse events were uncommon. Ten patients succumbed during the 30-day follow-up. The combination treatment was associated with lower 30-day mortality (P=0.01), less frequent ICU/HDU admission (P<0.001), and shorter hospital-stay (P<0.0001). The virus titer, PSI (day 1-3;P<0.01), and NPA specimens with NIRV quasispecies ≥5% (day 1-2;P<0.01) were significantly lower in the combination treatment group. Multivariate analysis showed that combination treatment was the only independent factor associated with lower 30-day mortality (odds-ratio:0.06; 95%,confidence-interval, 0.004-0.94;P=0.04).
Combination treatment reduced both 30- and 90-day mortality and length of hospital-stay. Further study on the antiviral and immunomodulatory effects of this combination treatment for severe influenza is warranted.