Triple-Combination Antiviral Drug for Pandemic H1N1 Influenza Virus Infection in Critically Ill Patients on Mechanical Ventilation

Abstract

A recent in vitro study showed that the three compounds of antiviral drugs with different mechanisms of action (amantadine, ribavirin, and oseltamivir) could result in synergistic antiviral activity against influenza virus. However, no clinical studies have evaluated the efficacy and safety of combination antiviral therapy in patients with severe influenza illness. A total of 245 adult patients who were critically ill with confirmed pandemic influenza A/H1N1 2009 (pH1N1) virus infection and were admitted to one of the intensive care units of 28 hospitals in Korea were reviewed. Patients who required ventilator support and received either triple-combination antiviral drug (TCAD) therapy or oseltamivir monotherapy were analyzed. A total of 127 patients were included in our analysis. Among them, 24 patients received TCAD therapy, and 103 patients received oseltamivir monotherapy. The 14-day mortality was 17% in the TCAD group and 35% in the oseltamivir group (P ‫؍‬ 0.08), and the 90-day mortality was 46% in the TCAD group and 59% in the oseltamivir group (P ‫؍‬ 0.23). None of the toxicities attributable to antiviral drugs occurred in either group of our study, including hemolytic anemia and hepatic toxicities related to the use of ribavirin. Logistic regression analysis indicated that the odds ratio for the association of TCAD with 90-day mortality was 0.58 (95% confidence interval, 0.24 to 1.42; P ‫؍‬ 0.24). Although this study was retrospective and did not provide virologic outcomes, our results suggest that the treatment outcome of the triple combination of amantadine, ribavirin, and oseltamivir was comparable to that of oseltamivir monotherapy.

Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis

“…In anecdotal studies, ribavirin served as a last resort to treat (multi)drug-resistant influenza infections in immunocompromised patients (20,21). The known hematological toxicity of ribavirin seems not to occur during shortterm influenza treatment (22).…”

Virological Clearance Rate of High-Dose Oseltamivir or Triple-Combination Antiviral Therapy in Complicated 2009 Pandemic Influenza A (H1N1) Infection

“…Regarding TCAD, Kim et al (11) reported lower 14-and 90-day mortalities in a TCAD group than in an oseltamivir monotherapy group (17z versus 35z and 46z versus 59z, respectively). However, the virological clearance in each group was not evaluated, and the differences in mortality were not statistically significant.…”

“…In a recent study, TCAD impeded the selection of drug-resistant influenza A in vitro (9). However, clinical data on the efficacy of TCAD remain scarce (10,11). , which shows similar sensitivity to conventional PCR (13), and Seeplex Influenza A/B OneStep Typing (Seegene, Seoul, Korea).…”

Severe Influenza Treatment Guideline

“…A recent report showed that a triple therapy with oseltamivir, amantadine, and ribavirin, having different active sites, provided not only an in vivo synergic effect on a seasonal influenza virus but also a synergic effect on a seasonal influenza virus presenting resistance to one drug [17]. With regard to the clinical usefulness of such a triple combination therapy, a retrospective study that compared the treatment result of oseltamivir monotherapy with that of oseltamivir, amantadine, and ribavirin combination therapy in severe influenza patients admitted to an intensive care unit during the epidemic period of the pandemic H1N1 in 2009 showed that the 14-day mortality and 90-day mortality were lower in the case of the combination therapy compared to the case of the monotherapy, but the difference was not significant [18]. In another study conducted with H1N1 infected patients who were admitted to an intensive care unit in 2009, a combination of antiviral agents did not show a better survival rate than that of a monotherapy [19,20].…”