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The clinical and virological outcomes associated with molnupiravir or nirmatrelvir–ritonavir use in hospitalized patients with mild-to-moderate COVID-19

In a recent study published in The Lancet, researchers investigated whether early treatment with oral antivirals prevented all-cause mortality in hospitalized patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) new variant of concern (VOC) Omicron BA.2 subvariant.

Study: Real-world effectiveness of early molnupiravir or nirmatrelvir–ritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong’s omicron BA.2 wave: a retrospective cohort study. Image Credit: plo/Shutterstock


Current guidelines recommend oral antivirals, including molnupiravir and nirmatrelvir–ritonavir, for those hospitalized coronavirus disease 2019 (COVID-19) patients who do not require supplemental oxygen yet are at the highest risk of disease progression (e.g., unvaccinated elderly with multiple pre-existing comorbidities).

Even during the Delta variant wave, major clinical trials showed that oral antivirals reduced the risk of disease progression and death in such individuals. However, studies have barely evaluated the benefits of molnupiravir when given at an early stage and in less severe patients (not requiring supplemental oxygen on hospital admission) in real-world settings.

About the study

In the present retrospective study, researchers tested the efficacy of molnupiravir or nirmatrelvir–ritonavir in preventing all-cause mortality in hospitalized adult patients admitted to isolation wards at local public hospitals between February 26 and April 26, 2022. The patients who met the study eligibility criteria received drug treatment between February 26 and May 3, 2022, coinciding with the date when molnupiravir first became available. The control group, propensity-matched to the test group in a 1:1 ratio,  did not receive supplemental oxygen or oral antivirals.

The Hongkong Hospital Authority, a statutory provider of public inpatient and outpatient services in the country, provided electronic health records (EHRs) of COVID-19 patients for the study analysis. EHRs had sociodemographics, registered death details, and data on COVID-19-related hospital admissions, emergency department (ED) visits, drug dispensing, and laboratory test records.

More importantly, the Hong Kong Death Registry provided data on patient deaths outside the hospital settings. The hospital admission date was the study index date (day 0), and the researchers mandated that all the study participants had been admitted within three days of their COVID-19 diagnosis or had a confirmed COVID-19 diagnosis within three days of their hospital admission date. The team followed up with the eligible study participants from the index date until the date of registered death, the occurrence of secondary outcomes, or the end of the study period, as feasible.

While the primary outcome was all-cause mortality, the secondary outcomes were a composite of all-cause mortality, need for supplemental oxygen, invasive mechanical ventilation [IMV], or intensive care unit (ICU) admission. The team also measured disease progression outcomes, i.e., the time to attain a low SARS-CoV-2 ribonucleic acid (RNA) load, indicated by a cycle threshold [CT] value of 30 or higher on a SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) assay. Finally, the researchers presented the crude incidence rates for all COVID-19 outcomes and hazard ratios (HRs) for all COVID-19 outcomes and at least two events in each study group, except for hospital stays.

Study findings

Around 40776 patients sought hospital admission during the study duration, of which 1880 and 924 eligible participants received molnupiravir and nirmatrelvir–ritonavir, respectively, and 14,810 served as controls. All of these individuals did not need supplemental oxygen despite confirmed COVID-19 diagnosis at baseline. While 1795 (96.7%) recipients received 800 mg molnupiravir twice every day for five days, 880 (98·9%) completed a five-day regimen of 300mg nirmatrelvir and 100mg ritonavir twice per day.

Both molnupiravir and nirmatrelvir–ritonavir recipients had significantly lower risks of all-cause mortality, with crude incidence rates of 19.98 and 10.28 events per 10 000 person-days, respectively. However, the risk of IMV initiation in antiviral recipients was not significantly different from controls.

Furthermore, the current study cohort attained a lower SARS-CoV-2 burden (CT ≥30) faster with molnupiravir or nirmatrelvir–ritonavir use, evidencing its potential efficacy against Omicron sub-variant BA.2, also demonstrated in experimental studies. However, study subgroup analyses suggested that oral antivirals did not benefit younger patients aged 65 years or less and those fully vaccinated as much as the elderly.

Clearly, the older population should be prioritized when it comes to prescription use of these oral antivirals. In fact, researchers have proposed developing an evidence-based scoring system or risk prediction tools to promote optimal and equitable access to SARS-CoV-2 oral antivirals in the face of limited supplies and its distribution to those COVID-19 patients on priority who would benefit most from them.

In vitro studies have shown some long-term risks associated with molnupiravir use. For instance, its use could have carcinogenic and teratogenic effects. Moreover, molnupiravir could induce more infectious and vaccine-resistant viral variants. Amid rising concerns about developing resistance to molnupiravir and nirmatrelvir–ritonavir, active pharmacovigilance and rapid genomic sequencing of viral mutants would be needed to monitor their long-term safety and effectiveness across different types of patients and coming waves of the COVID-19 pandemic.


The current retrospective cohort study showed that early initiation of oral antivirals markedly reduced the risk of all-cause mortality and COVID-19 progression in hospitalized COVID-19 patients who did not require supplemental oxygen during a period of dominance of SARS-CoV-2 Omicron BA.2 subvariant. However, their continued use as a COVID-19 mitigation measure would require active pharmacovigilance, with future studies evaluating their safety and effectiveness across different patient populations, drug combinations, and clinical settings.

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