Real-world study favours ritonavir-based regimens for hospitalized COVID-19 patients

In a real-world analysis evaluating four oral antiviral agents for the treatment of COVID-19, two ritonavir-based regimens fared better than molnupiravir and azvudine in reducing hospital stay among patients hospitalized for mild or moderate disease.

“[T]here have been no head-to-head real-world studies conducted on these four drugs to date,” said the researchers. “In this retrospective study, nirmatrelvir/ritonavir and simnotrelvir/ritonavir exert stronger potency in reducing the duration of hospital stays in hospitalized patients with COVID-19 [during the Omicron wave], suggesting a better choice for antiviral therapy.”

Data were collected from 195 patients admitted to the Second People’s Hospital of Wuxi. They were treated with either nirmatrelvir 150 mg/ritonavir 100 mg (group N; n=42), simnotrelvir/ritonavir 0.375 g/0.1 g (group S; n=81), molnupiravir 0.8 g (group M; n=33), or azvudine 5 mg (group A; n=39). The first three regimens were administered Q12H for 5 days while azvudine was given QD for up to 14 days. [Infect Drug Resist 2024:17:3967-3978]

Median length of stay (LOS) differed across treatment arms (8, 9, 10, and 12 for groups N, S, M, and A, respectively; p=0.0113). Compared with group A, the LOS was significantly shorter in groups N (p_adjusted=0.013) and S (p_adjusted=0.039).

This trend favouring groups N and S over group A was also seen among patients with comorbidities (p<0.05 for groups N & S) and those who were >65 years (p=0.0420 and p=0.0232, respectively).

Advanced age has been consistently recognized as a significant risk factor for COVID-19. [Clin Rev Allergy Immunol 2023;64:90-107] “[O]lder patients often experience more severe illnesses, poorer prognosis, and higher mortality rates … Therefore, evaluating the efficacy and safety of oral small-molecule antiviral therapy in elderly patients is crucial,” the researchers said.

No significant difference was observed in LOS between those initiating antiviral therapy within or more than 5 days after symptom onset (p=0.1109). This implies that antiviral treatment may still render therapeutic benefits despite treatment delays, the researchers noted.

“Instead of ruling out the potential benefits of early treatment, our findings suggest that patients who missed the optimal treatment window should still receive antiviral therapy promptly after symptom onset to reduce viral load and mitigate the risk of developing long COVID, [which affects up to 70 percent of hospitalized patients],” they said.

Stratified analysis revealed age (p=0.0002) and type of antiviral drug received (p=0.004) as factors that influence LOS.

The incidence of adverse events (AEs) was higher in groups N and S (16.7 percent and 19.8 percent) than in groups M and A (6.1 percent and 5.1 percent). The most common AE tied to both ritonavir-based regimens was hepatic dysfunction (n=7 and 12 for groups N and S, respectively).

“[Nonetheless,] the severity of AEs across all four groups ranged from grade 1 to 2, and no serious drug-related AEs were reported during the study,” the researchers noted.

3CLpro may have better potential

Taken together, the findings show that 3-chymotrypsin-like protease (3CLpro) inhibitors (ritonavir-based regimens) outdid RNA-dependent RNA polymerase inhibitors (molnupiravir and azvudine) in cutting LOS. “This suggests that 3CLpro inhibitors may have better potential for the treatment of hospitalized COVID-19 patients,” said the researchers.

Of note, this trial is the first to compare the efficacy and safety of simnotrelvir/ritonavir, the first Chinese-developed 3CLpro inhibitor acting on the same target as nirmatrelvir, against three widely used agents for the treatment of COVID-19. [Clin Infect Dis 2023;76:e342-e349; ACS Pharmacol Transl Sci 2023;6:1306-1309; N Engl J Med 2024;390:230-241]

However, the study may have been limited by the lack of randomization and prospective design. Data from a single institution may also have limited external validity and generalizability of the findings.

Nonetheless, these real-world data on major oral antivirals may influence clinical decision-making and optimization of COVID-19 treatment strategies in hospitalized patients, the researchers concluded. Additional well-designed real-world trials with larger cohorts are warranted to ascertain the findings.