Study: Impact of the Use of Oral Antiviral Agents on the Risk of Hospitalisation in Community COVID-19 Patients. Image Credit: Cryptographer/Shutterstock

The effectiveness of molnupiravir and nirmatrelvir/ritonavir in reducing hospitalization and death in unhospitalized COVID-19 patients

In a recent study posted on Preprints with The Lancet*, researchers assessed the effectiveness of two orally administered antiviral drugs, nirmatrelvir/ritonavir and molnupiravir, in reducing hospitalizations and deaths among truly unhospitalized patients with coronavirus disease 2019 (COVID-19) in Hong Kong.

Study: Impact of oral antiviral drug use on the risk of hospitalization in community COVID-19 patients† Image Credit: Cryptographer/Shutterstock


Preventive and therapeutic strategies for COVID-19 have evolved rapidly since the COVID-19 pandemic began in 2020. Initial studies have focused on treating severe COVID-19 in hospitalized patients; however, the most recent COVID-19 therapies are aimed at reducing the incidence of COVID-19 and preventing the development of serious consequences (hospitalizations and deaths) in non-hospitalized patients.

Two orally administered antiviral drugs, nirmatrelvir/ritonavir and molnupiravir, are approved for the treatment of mild to moderate COVID-19 in adult patients at high risk of disease progression based on the findings of the MOVe-OUT clinical trial. However, there is a lack of knowledge about whether the antiviral drugs would demonstrate comparable effectiveness in the real world.

About the study

In the current retrospective cohort study, researchers compared the true effectiveness of nirmatrelvir/ritonavir and molnupiravir in preventing COVID-19 progression (hospitalizations and deaths) in non-hospitalized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients .

The study participants consisted of non-hospitalized SARS-CoV-2 positive individuals who attended designated outpatient clinics between February 16 and March 31, 2021. Patients who were hospitalized at the first appointment or those who received both orally administered antiviral medications were excluded from the analysis.

Data were obtained from the Clinical Data Analysis and Reporting System (CDARS) database managed by the Hospital Authority (HA) of Hong Kong. The primary endpoint was hospitalization related to COVID-19 and the secondary endpoint was a composite endpoint that included invasive mechanical ventilation (IMV) use, intensive care unit (ICU) admissions, and death. The clinical features of the participants were weighed by propensity score (PS) weighting.

Comorbidities such as diabetes mellitus (DM) and hypertension were identified based on laboratory tests, drugs and ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes. Complete SARS-CoV-2 vaccination was described as double BNT162b2 messenger ribonucleic acid (mRNA) vaccination or triple CoronaVac-inactivated SARS-CoV-2 vaccination with whole virion.

In addition, high-risk non-hospitalized COVID-19 patients ≥60 years without comorbidities or <60 years with comorbidities were considered for subgroup analysis. Cox models together with the weighted hazard ratio (HR) were used for the analysis.


Initially, 94,167 SARS-CoV-2 positive participants were identified who were assigned to the designated outpatient clinics during the study period, from which the researchers excluded participants who were hospitalized at the first outpatient appointment (n = 271) and who received both nirmatrelvir/ritonavir and molnupiravir drugs (n=13). As a result, 93,883 participants were considered for the analysis, of which 83,154 (89%), 4,921 (5%) and 5,808 (6%) and participants were oral antiviral non-users, nirmatrelvir/ritonavir drug users and molnupiravir drug users, respectively.

Compared with non-users of oral antivirals, those taking antivirals were older with more comorbid conditions, fewer complete vaccinations, and a higher number of hospitalizations in the previous year. Compared to nirmatrelvir/ritonavir users, drug abusers of molnupiravir were older with more comorbidities, fewer complete vaccinations and more hospitalizations in the previous year.

After PS weighting, the use of molnupiravir was not associated with a lower risk of hospitalization than the oral antiviral non-users (weighted HR 1.2). On the other hand, nirmatrelvir/ritonavir use was associated with a lower risk of hospitalization than oral antiviral non-users (weighted HR 0.8) and molnupiravir users (weighted HR 0.7). The cumulative incidence of the primary endpoint (hospitalization) for the 30-day follow-up period was 5%, 5%, and 4% among antiviral non-users, molnupiravir, and nirmatrelvir/ritonavir, respectively.

Nirmatrelvir/ritonavir use (weighted HR 0.8) or molnupiravir use (weighted HR 1.1) were not associated with a lower risk of IMV use/admissions/death in ICU compared to non-users of oral antiviral drugs. resources. Nirmatrelvir/ritonavir use was also not associated with a reduced risk of developing secondary endpoints compared to molnupiravir users (weighted HR 0.7). The cumulative incidence of the secondary endpoint (IMV use/ICU admissions/deaths) for the 30-day follow-up period was 0.5%, 0.4%, and 0.6% in oral antiviral non-users, nirmatrelvir/ritonavir drugs and molnupiravir drug users respectively.

After PS weighting, use of nirmatrelvir/ritonavir (weighted HR 0.8) but not molnupiravir (weighted HR 1.2) was associated with lower risks of hospitalization than non-users of oral antiviral agents. However, the use of molnupiravir or nirmatrelvir/ritonavir reduced the risk of the secondary endpoint compared to non-users. In the subgroup analysis, the use of nirmatrelvir/ritonavir, but not the use of molnupiravir, was associated with lower risks of hospitalization than nonusers.


Overall, the study results showed that the use of nirmatrelvir/ritonavir was associated with a lower risk of hospitalization, but not with the use of molnupiravir in non-hospitalized SARS-CoV-2 positive patients in the real world. However, both antiviral drugs did not reduce the risk of COVID-19-associated IMV use, ICU admissions and deaths.

*Important announcement

Preprints with The Lancet publishes preliminary scientific reports that are not peer reviewed and therefore should not be considered conclusive, which should guide clinical practice/health related behavior or be treated as established information.

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