CLINICAL EVALUATION OF EMERGING ANTIVIRAL THERAPIES FOR THE TREATMENT OF SEVERE RESPIRATORY VIRAL INFECTIONS

Abstract

The constant threat of severe respiratory viral diseases, which can be triggered by different agents, e.g., influenza viruses, respiratory syncytial virus and SARS-CoV-2 also results in the need to develop more advanced treatment plans that will reduce the resistance and increase the clinical outcome. The researchers have reviewed a systematic review of efficacy of combination antiviral therapy at various stages of viral replication cycle predominantly, influenza A polymerase basic protein 2 blocker, pimodivir and neuraminidase blocker, oseltamivir. Multi-phase program which has in vitro mechanistic studies, serial passage resistance selection studies, in vivo testing in lethal model of murine influenza and phase II randomized clinical trial of combination therapy have revealed that the combination therapy is more antiviral and resistance inhibitory compared to monotherapy. The combination index analysis showed that the A/H1N1/A/H3N2 is well combined  and the combination is highly 6.12 log 0-fold reduced of the viral yield after 48 hours which is very high, as compared to additivity. Serial passage (15 generations) revealed both partial resistance mutations  which were suppressed in combination in arm, but was easily overcome by resistant mutants in monotherapies. It has a good survival(86.7) and a pulmonary viral titer of 1.89 log -1 and lung injury score of 1.4 which is very high as compared to monotherapy. The results of the used clinical trial show that the combination had a 2.5-day shorter median time to clinical symptoms and a loss of 45.8 percent of the area under the viral load curve as compared to the use of the oseltamivir alone. A combination of these results suggests that combination of antivirals that are strategically intended to be synergetic to each other do better to overcome complementary viral effects, it is highly genetic barrier to resistance and has better clinical outcomes. The paradigm plays a significant role in the treatment of acute respiratory infections that are caused by viruses and it justifies the relevance of the combination-based strategy in development of antiviral medications and preparedness to pandemics.