By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
SYNOPSIS: A study that compared nirmatrelvir-ritonavir, remdesivir, or a combination of both for hospitalized patients with COVID-19 found those who received nirmatrelvir-ritonavir monotherapy had lower mortality, reduced intensive care unit admission, and reduced need for mechanical ventilation.
SOURCE: Choi MH, Wan EYF, Wong ICK, et al. Comparative effectiveness of combination therapy with nirmatrelvir-ritonavir and remdesivir versus monotherapy with remdesivir or nirmatrelvir-ritonavir in patients hospitalised with COVID-19: A target trial emulation study. Lancet Infect Dis 2024;24:1213-1224.
The current treatment paradigm for outpatients with COVID-19 is nirmatrelvir-ritonavir (Paxlovid), while inpatients typically receive intravenous remdesivir. There is a paucity of data on the benefits of combination therapy with nirmatrelvir-ritonavir and remdesivir, particularly for hospitalized patients with COVID-19 for whom treatment is more urgent. Choi and colleagues sought to compare outcomes for hospitalized patients treated with nirmatrelvir-ritonavir, remdesivir, or a combination of both drugs.
The study was a target trial emulation from Hong Kong that included adults aged 18 years or older diagnosed with COVID-19 and treated within five days of hospital admission with remdesivir, nirmatrelvir-ritonavir, or a combination of both drugs. Patients were excluded if they started one of the therapies more than five days after a COVID-19 diagnosis, had a contraindication (i.e., severe kidney disease, severe liver disease, or receipt within 90 days of an interacting drug such as amiodarone or direct oral anticoagulants) to receiving one of the drugs, or had received tocilizumab, baricitinib, or interferon beta-1b at any time during the hospitalization. The inclusion period occurred from March 16, 2022, to Dec. 31, 2022.
The primary endpoint was all-cause mortality. Secondary endpoints were admission to the intensive care unit (ICU), need for mechanical ventilation, or the occurrence of a stroke, myocardial infarction (MI), acute kidney injury (AKI), acute liver injury (ALI), anemia, rash, gastrointestinal symptoms, hypoglycemia or hyperglycemia, or an abnormal clotting profile.
The study included 18,196 patients, of whom 4,232 received remdesivir, 13,656 received nirmatrelvir-ritonavir, and 308 received both. The mean age was 74 years in the remdesivir and combination groups and 75 years in the nirmatrelvir-ritonavir group. Baseline characteristics were well balanced between the groups. The median follow-up was 84 days (range, 45 to 90 days).
Mortality was lower for patients who received nirmatrelvir-ritonavir (hazard ratio [HR], 0.18; 95% confidence interval [CI], 0.15 to 0.20) or combination therapy (HR, 0.66; 95% CI, 0.49 to 0.89) compared to those who received remdesivir. Similar results were found for ICU admission or need for mechanical ventilation (nirmatrelvir-ritonavir: HR, 0.09 [95% CI, 0.07 to 1.11]; combination therapy: HR, 0.68 [95% CI, 0.42 to 1.12] compared to remdesivir). Notably, nirmatrelvir-ritonavir was associated with lower mortality (HR, 0.27; 95% CI, 0.20 to 0.37) and ICU admission or need for ventilator support (HR, 0.13; 95% CI, 0.08 to 0.22) compared to combination therapy. Vaccination status did not affect any of the outcomes.
There were some differences in adverse events between the groups. Patients treated with nirmatrelvir-ritonavir alone had a significantly reduced risk of MI, AKI, anemia, hyperglycemia, and clotting abnormalities compared to those treated with remdesivir. Those treated with combination therapy had a significantly lower risk of clotting abnormalities compared to those who received remdesivir alone. The risk of other adverse events (i.e., stroke, rash, gastrointestinal symptoms, and hypoglycemia) was similar among all three treatment groups.
Commentary
The study was well designed and clinically relevant. The main result was treatment with nirmatrelvir-ritonavir alone or in combination with remdesivir was superior to remdesivir alone for patients hospitalized for COVID-19. It is interesting that nirmatrelvir-ritonavir alone outperformed both remdesivir and the combination of nirmatrelvir-ritonavir and remdesivir. This finding is difficult to explain from a mechanistic standpoint. It seems improbable that drug-drug antagonism is to blame. A more likely explanation is that it is an artifact of the study design. The investigators did not take into account potential confounding variables, such as previous COVID-19 infection, immune status, or the effect of other medications, such as monoclonal antibodies. Furthermore, it is possible that the effect of excluded patients may have been greater on the combination group compared to the nirmatrelvir-ritonavir group. Further investigation is warranted, including the identification of patients for whom combination therapy may be most beneficial.
The study had some limitations. The combination group (n = 308) was much smaller than the other groups. The study was conducted in a single city (Hong Kong), so the results might not be generalizable to other geographic areas and patient populations. COVID-19 continues to mutate, so patients infected with the current variant might not respond to treatment in the same way as those in the study. The investigators did not distinguish patients admitted specifically for COVID-19 from those admitted for another diagnosis and incidentally found to have COVID-19. Finally, all deaths in the study were attributed to COVID-19, some of which likely were due to other causes.
How the study will alter current treatment guidelines remains to be determined. But nirmatrelvir-ritonavir should be regarded as an effective option for hospitalized patients. Randomized clinical trials are needed to definitively elucidate the optimal treatment for hospitalized patients, particularly those at high risk for poor outcomes.
Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC, is Professor of Medicine, Division of Infectious Diseases, Northeast Ohio Medical University, Rootstown, OH.
