Presatovir-resistant substitutions occurred during treatment for respiratory syncytial virus (RSV) but did not significantly affect clinical efficacy, according to a study recently published in The Journal of Infectious Diseases.
Presatovir is an oral RSV fusion inhibitor that targets the RSV F protein, which mediates RSV infection of the respiratory epithelial cells. A previous study in healthy adults experimentally infected with RSV (RSV strain Memphis-37b) showed that presatovir significantly reduced viral load and clinical disease severity in a dose-dependent manner.
However, resistance-associated amino acid substitutions have previously been identified in the cysteine-rich region of the RSV F protein and the fusion peptide. This study aimed to identify and characterize presatovir treatment-emergent amino acid substitutions in F protein and assessed their effects on in-vitro susceptibility to presatovir, viral fitness in cell-based virus replication assays, and clinical outcome.
Viral RNA was obtained from nasal wash samples and amplified to sequence the F gene to monitor for presatovir resistance. Of the 28 treatment-emergent F substitutions identified in 39 patients, 26 were tested in vitro, and 2 were not tested in vitro due to a lack of recombinant virus recovery.
Results showed that phenotypic resistance substitutions occurred at a higher frequency with regimens that contained a lower presatovir dose and a shorter duration of treatment but did not affect clinical efficacy. Of the 26 treatment-emergent F substitutions tested in vitro, 16 reduced RSV susceptibility to presatovir. Of these, 13 had high levels of resistance (38 to 410-fold or more), and 3 had moderate levels of resistance (2.9 to to 5-fold). None of the substitutions identified altered RSV susceptibility to ribavirin or palivizumab.
Resistance-associated amino acid substitutions were present in 15 of 87 (17.2%) participants across all treatment regimens. These substitutions occurred at the lowest rate of 7.7% (n=3/39) in participants treated with the highest dose of presatovir (50/25 mg once daily) for the longest duration (5 days), and occurred at the highest rate of 35.3% (n=6/17) in those who received the same dose for 3 days.
Viral load area under the curve (AUC) values were significantly higher in those with resistance-associated substitutions when compared to those without (P ≤.001). Lower symptom score AUC values and total mucus weights were lower in presatovir-treated participants compared to placebo, regardless of the presence of treatment-emergent amino acid substitutions and with or without presatovir susceptibility. This suggests the substitutions may not impact the clinical efficacy of presatovir.
Overall, the study authors concluded that, “Emergence of presatovir-resistant RSV occurred during therapy but did not significant affect clinical efficacy in participants with experimental RSV infection.”
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Stray K, Perron M, Porter DP, et al. Drug resistance assessment following administration of respiratory syncytial virus (RSV) fusion inhibitor presatovir to participants experimentally infected with RSV. J Infect Dis. 2020;222(9):1468-77. doi:10.1093/infdis/jiaa028