# P-1636. Comparative Effectiveness of Combination Therapy with Nirmatrelvir-Ritonavir and Molnupiravir versus Monotherapy with Molnupiravir or Nirmatrelvir-Ritonavir in Hospitalised COVID-19 Patients: A Target Trial Emulation Study

## TL;DR

A study compared combining two antiviral drugs with using them alone in hospitalized COVID-19 patients and found no benefit from the combination.

## Contribution

The study is the first to evaluate combination therapy of nirmatrelvir-ritonavir and molnupiravir versus monotherapy in hospitalized adults using real-world data.

## Key findings

- Nirmatrelvir-ritonavir monotherapy was linked to lower mortality compared to combination therapy.
- Combination therapy did not reduce ICU admissions or ventilatory support needs.
- Monotherapy also reduced risks of liver and kidney injuries compared to combination treatment.

## Abstract

While molnupiravir and nirmatrelvir-ritonavir have demonstrated efficacy in reducing hospitalisation and mortality among unvaccinated, high-risk COVID-19 patients in outpatient settings, their impact on hospitalised adults remains unclear. Preclinical studies and case reports suggest combining these antivirals may reduce viral shedding and enhance survival.Baseline characteristics of eligible COVID-19 patients after the inverse probability of treatment weighting (IPTW)SMD=Standardised mean difference; SD=Standard deviation; IQR = interquartile range; CCI=Charlson Comorbidity Index; ICU=Intensivecare units;†SMD<0.1 indicates balance between groups·†† Level 1: Hospitalised patients with no oxygen therapy; Level 2: Hospitalised patients with oxygen by mask, nasal prongs, non-invasiveventilation or high flow; Level 3: Hospitalised patients with intubation and mechanical ventilation, vasopressors, dialysis, or extracorporealmembrane oxygenationRisk of outcomes for COVID-19 patients receiving combined use of molnupiravir and nirmatrelvir ritonavir compared with patients receiving molnupiravir alone and patients receiving nirmatrelvir-ritonavir alone after weighting

Baseline characteristics of eligible COVID-19 patients after the inverse probability of treatment weighting (IPTW)

SMD=Standardised mean difference; SD=Standard deviation; IQR = interquartile range; CCI=Charlson Comorbidity Index; ICU=Intensive

care units;

†SMD<0.1 indicates balance between groups·

†† Level 1: Hospitalised patients with no oxygen therapy; Level 2: Hospitalised patients with oxygen by mask, nasal prongs, non-invasive

ventilation or high flow; Level 3: Hospitalised patients with intubation and mechanical ventilation, vasopressors, dialysis, or extracorporeal

membrane oxygenation

Risk of outcomes for COVID-19 patients receiving combined use of molnupiravir and nirmatrelvir ritonavir compared with patients receiving molnupiravir alone and patients receiving nirmatrelvir-ritonavir alone after weighting

This target trial emulation study evaluated the safety and efficacy of combined molnupiravir and nirmatrelvir-ritonavir versus monotherapy in hospitalised COVID-19 adults in Hong Kong. Data were extracted from electronic health records of patients aged 18 and older treated within five days of hospital admission between March 16, 2022, and March 31, 2024. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics. Outcomes, including all-cause mortality, Intensive Care Unit (ICU) admission, and ventilatory support, were assessed using Cox proportional hazards models.Study flow diagram90-day cumulative incidence of outcomes in recipients of combination treatment with nirmatrelvir-ritonavir and molnupiravir compared to recipients of molnupiravir monotherapy and recipients of nirmatrelvir-ritonavirShared area refers to the 95% confidence interval for the cumulative incidence. The P values indicate the overall P values of the Log-rank test comparing the three treatment groups for each outcome

Study flow diagram

90-day cumulative incidence of outcomes in recipients of combination treatment with nirmatrelvir-ritonavir and molnupiravir compared to recipients of molnupiravir monotherapy and recipients of nirmatrelvir-ritonavir

Shared area refers to the 95% confidence interval for the cumulative incidence. The P values indicate the overall P values of the Log-rank test comparing the three treatment groups for each outcome

Among 28,355 patients (combination: 1,081; molnupiravir: 8,416; nirmatrelvir-ritonavir: 18,858), IPTW-adjusted analyses showed that nirmatrelvir-ritonavir monotherapy was associated with a significantly lower risk of mortality (HR: 0.62; 95% CI 0.50-0.77; ARR: -3.16%) compared to combination therapy. Risks of ICU admission and ventilatory support were similar across all groups. Patients receiving nirmatrelvir-ritonavir monotherapy also showed lower risks of acute liver injury (HR: 0.53 [95% CI 0.32-0.88]), acute kidney injury (HR: 0.61 [95% CI 0.51-0.74]), and hyperglycaemia (HR 0·73 [95% CI 0.57- 0.93]).

Combining nirmatrelvir-ritonavir and molnupiravir does not significantly reduce mortality, ICU admissions, or ventilatory support needs in hospitalised COVID-19 adults. Further randomised controlled trials are needed to confirm these findings.

All Authors: No reported disclosures