Nirmatrelvir/Ritonavir Reduces Post-Acute Mortality in Immunocompromised COVID-19 Patients

A recent study analyzing the impact of nirmatrelvir/ritonavir (Paxlovid) in immunocompromised patients hospitalized with COVID-19 found that the antiviral therapy was associated with a significantly reduced risk of post-acute inpatient death. Conducted using electronic health records from the Hong Kong Hospital Authority and the Hong Kong Department of Health, the study examined data from 39,923 hospitalized patients between March 2022 and November 2023.

Among the 2,217 immunocompromised patients included in the study, those who received nirmatrelvir/ritonavir had a 42% lower risk of post-acute inpatient death compared to those who did not (HR .58, 95% CI .45–.74; p<.0001). The antiviral was also linked to a reduced risk of hospitalization due to acute respiratory distress syndrome (HR .43, 95% CI .20–.90; p=0.024).

The study found that while the treatment improved survival rates, its impact on post-acute hospitalizations was less pronounced in immunocompromised patients than in immunocompetent individuals. A significant negative interaction was observed between immune status and nirmatrelvir/ritonavir on post-acute all-cause hospitalizations (relative excess risk due to interaction –.84, 95% CI –1.30 to –.37; p=.0004).

To gain further insight into these findings, in an email interview with Marc Ka-Chun Chong, PhD, assistant professor at the JC School of Public Health and Primary Care at The Chinese University of Hong Kong (CUHK), we asked about the factors contributing to the observed reduction in post-acute inpatient mortality, Chong highlighted the importance of early intervention.

“Early administration of nirmatrelvir-ritonavir is linked to lower severity in the acute phase. As severity in the acute phase is an important risk factor for post-acute complications, nirmatrelvir-ritonavir may help lower post-acute death,” he explained. “Moreover, immunocompromised patients are prone to viral persistence. It has been shown that viral persistence in tissues is associated with long-term complications. Effective in viral clearance, nirmatrelvir-ritonavir may further contribute to reducing post-acute death in this high-risk population.”

The study also compared the effects of nirmatrelvir-ritonavir in immunocompromised and immunocompetent patients. Chong noted that while the antiviral was effective in reducing mortality, it had a slightly lower impact in immunocompromised patients.

“In terms of reducing post-acute inpatient mortality, nirmatrelvir-ritonavir is slightly less effective (a 5% difference) for immunocompromised patients than for immunocompetent patients,” he said. “For hospitalization outcomes, nirmatrelvir-ritonavir is effective in reducing all-cause hospitalization as well as hospitalization due to major pulmonary, cardiovascular, and renal conditions among immunocompetent patients. However, among immunocompromised patients, we did not find significant associations between nirmatrelvir-ritonavir and hospitalization outcomes except for hospitalization due to acute respiratory distress syndrome (ARDS).”

The study also explored whether the effectiveness of nirmatrelvir-ritonavir varied across different immunocompromised groups, such as cancer patients and transplant recipients.

“We conducted a subgroup analysis stratified by recent use of immunosuppressants for cancer treatment,” Chong said. “Our results show that nirmatrelvir-ritonavir is less effective (a 17% difference) in reducing post-acute inpatient mortality among patients with recent use of such cancer treatments than among those without recent use.”

A key finding of the study was the negative interaction between immune status and nirmatrelvir–ritonavir regarding post-acute hospitalization outcomes.

“The negative interaction implies that the effectiveness of nirmatrelvir-ritonavir is significantly lower among immunocompromised patients than among immunocompetent patients,” Chong explained. “This aligns with the results from our separate analyses of patients with different immune status, which show that nirmatrelvir-ritonavir is significantly associated with reduced risk of all-cause hospitalization for immunocompetent patients but not for immunocompromised patients.”

Looking ahead, Chong emphasized the need for further research to optimize antiviral strategies for immunocompromised patients, “One of the key next steps in improving post-COVID care for immunocompromised populations is to optimize antiviral strategies,” he said. “In clinical trials for COVID-19 antivirals, typically only a few, if any, immunocompromised patients were included. Therefore, the treatment guidelines may not be optimal for immunocompromised patients.”

Chong highlighted the need for studies exploring whether extended or repeated courses of antivirals could be more effective, as well as potential combination therapies with other treatments such as monoclonal antibodies.

“Another meaningful research direction is to understand how SARS-CoV-2 persists in immunocompromised individuals,” he added. “Unlike in immunocompetent individuals, SARS-CoV-2 may persist in immunocompromised patients for extended periods. This persistence can lead to worse long-term outcomes and even potentially the emergence of variants of concern.”

He also stressed the importance of establishing specialized programs to monitor immunocompromised patients for long COVID and potential reinfections.

“These programs should provide long-term care for immunocompromised patients and may also facilitate research on the topics mentioned above,” Chong concluded.

This study underscores the potential of nirmatrelvir–ritonavir to reduce mortality in high-risk COVID-19 patients while highlighting the need for continued research to improve treatment strategies for immunocompromised individuals.

Reference

Lin G, Wei Y, Wang H, et al. Association of nirmatrelvir–ritonavir with post-acute sequelae and mortality among patients who are immunocompromised with COVID-19 in Hong Kong: a retrospective cohort study. Lancet Infect Dis. 2025;7(2):e108-e117. doi:10.1016/S2665-9913(24)00224-8