Nirmatrelvir-ritonavir reduces mortality in hospitalized COVID-19 adults

Treatment with nirmatrelvir-ritonavir significantly reduced mortality risk among hospitalized COVID-19 patients compared with the combined molnupiravir and nirmatrelvir-ritonavir regimen, based on a target trial emulation study presented at IDWeek 2025.

Although molnupiravir and nirmatrelvir-ritonavir have demonstrated efficacy in reducing hospitalization and mortality among unvaccinated, high-risk COVID-19 outpatients, preclinical studies suggest that combining these antivirals may further decrease viral shedding and increase survival, according to Dr Ming Hong Choi from Queen Mary Hospital in Hong Kong, SAR, China.

However, the impact of this combination therapy on hospitalized adults remains unclear, he noted.

To address this, the researchers used data from the Hong Kong electronic health records database and identified 28,355 hospitalized COVID-19 adults (aged ≥18 years) treated within 5 days of hospital admission between March 2022 and 2024 to evaluate the efficacy and safety of nirmatrelvir-ritonavir monotherapy vs combination therapy with molnupiravir and nirmatrelvir-ritonavir.

Results showed that patients treated with nirmatrelvir-ritonavir monotherapy demonstrated a significantly lower mortality risk (hazard ratio [HR], 0.62; p<0.0001), with an absolute risk reduction of 3.16 percent, compared with those receiving combined molnupiravir and nirmatrelvir-ritonavir therapy. [IDWeek 2025, abstract P-1636]

There was no significant difference in the risk of ICU admission or the need for ventilatory support between the two groups.

Furthermore, nirmatrelvir-ritonavir monotherapy was associated with a reduced risk of acute liver injury (HR, 0.62), kidney injury (HR, 0.61), and hyperglycaemia (HR, 0.73) compared with combination therapy.

Choi suggested that “one possible reason for the reduced mortality benefits of combination therapy might be the B-lymphocyte depletion caused by molnupiravir, leading to immunomodulation or immunosuppression.”

He further noted that their study was conducted when the Omicron variant was the dominant variant of concern (VOC), whereas the Rhesus macaque model tested antiviral activities against Delta VOC. This difference could explain why there was no mortality benefit from the combination treatment compared with nirmatrelvir-ritonavir monotherapy.

Key takeaways

This is the first real-world study comparing the combination of molnupiravir and nirmatrelvir-ritonavir vs nirmatrelvir-ritonavir monotherapy in hospitalized COVID-19 adults.

“Our study identified a significant mortality benefit associated with nirmatrelvir-ritonavir monotherapy in comparison with combination therapies involving nirmatrelvir-ritonavir with molnupiravir or molnupiravir alone among hospitalized COVID-19 adults,” Choi said. “These findings were consistent across patients with varying SARS-CoV-2 vaccination status.”

“Despite the current lack of endorsement for nirmatrelvir-ritonavir monotherapy in international and local guidelines for hospitalized COVID-19 adults, our finding provides compelling preliminary evidence supporting its consideration, especially for patients who do not respond optimally to standard treatment,” Choi said.

“Further randomized controlled trials are needed to confirm these results,” he noted.