introduction
At present, the mainland is still facing the epidemic of novel coronavirus infection (COVID-19), and for people at high risk of severe COVID-19, it is necessary to start small molecule antiviral therapy as soon as possible after diagnosis. Recently, the New England Journal of Medicine published the results of the EPIC-SR study, which showed that nirmatrelvir/ritonavir (Paxlovid) was not significantly different from placebo in improving symptoms in standard-risk populations1. Does this have implications for current drug choices, and how should we rationally view the results of this study?
In this article, Professor Yang Wenjie of Tianjin First Central Hospital is invited to bring us wonderful comments.
Don't forget the original intention: The primary goal of treatment for high-risk people is to reduce the risk of severe disease and death
Paxlovid is currently approved in China for the treatment of adult patients with mild to moderate COVID-19 who are at high risk of progressing to severe disease. For people at high risk for severe COVID-19, COVID-19 infection can have flu-like symptoms on the one hand, and the risk of developing severe COVID-19 on the other hand is higher than that of the general population. For antiviral therapy in this population, Chinese and foreign guidelines clearly recommend that reducing the risk of hospitalization and death in COVID-19 patients should be the primary treatment goal2,3,4 (Fig. 1).
Fig. 1 Treatment targets for people at high risk of severe COVID-19 recommended by Chinese and foreign guidelines
Science wins: 4 explorations of Paxlovid for COVID-19 prevention and treatment
To fully explore the value of small molecule antivirals in the prevention and treatment of COVID-19 infection, Paxlovid conducted four registrational Phase III studies in people at higher risk for severe disease (EPIC-H5R study), people at low risk for severe disease (EPIC-SR study), close contacts (EPIC-PEP study), and people under 18 years of age at higher risk for severe disease (EPIC-Peds study) At present, except for the EPIC-Peds study, which is still ongoing, the other three clinical trials have been completed (Figure 2)5.
Figure 2 Overview of the four phase III studies of Paxlovid
As early as 2021, Pfizer published interim data from the EPIC-SR study6, and the results of the EPIC-SR study published in the New England Journal showed that the trial enrolled nearly 1,300 vaccinated and unvaccinated people, mainly those with relatively low risk of severe disease, and the nirmatrelvir/ritonavir group and placebo group had a similar time to sustained symptom resolution (median 12 days and 13 days, respectively)1. Results from the EPIC-PEP study showed a 32% and 37% reduction in the risk of COVID-19 virus infection in adults taking nirmatrelvir/ritonavir at 5 and 10 days, respectively, compared with placebo.7
The EPIC-HR study showed an 89% and 88% reduction in the risk of hospitalization or death and a 10-fold reduction in viral load in people at high risk for severe disease who were treated within 3 and 5 days of COVID-19 symptoms compared with placebo, suggesting that nirmatrelvir/ritonavir significantly reduced the risk of hospitalization or death in high-risk populations (Figure 3). In May 2023, the U.S. FDA published a post-hoc analysis8 summarizing data from the EPIC-HR and EPIC-SR clinical trials supporting the efficacy of nirmatrelvir/ritonavir in adults with mild to moderate COVID-19 in adults at high risk for severe disease, with benefits independent of COVID-19 vaccination status or prior COVID-19 infection status.
Fig.3 Results of the EPIC-HR study
In summary, nirmatrelvir/ritonavir has limited benefit in people who are not severely ill and in close contacts, but it can significantly reduce the risk of hospitalization or death in people at high risk of severe disease. On December 22, 2021, the U.S. FDA approved Paxlovid for the emergency treatment of COVID-199, mainly based on the EPIC-HR study, which confirmed that Paxlovid can significantly reduce the risk of hospitalization and death in people at higher risk of severe disease.
Double validation: RCTs and RWE studies consistently confirmed that Paxlovid definitively reduces the risk of severe disease and death
Paxlovid has ample real-world evidence (RWE), with real-world studies conducted in China10, the United States11, and Israel12 confirming that Paxlovid reduces the risk of hospitalization and death in patients at higher risk of severe disease in vaccinated and unvaccinated populations, as well as in first-time and re-infected people.
There is also real-world evidence that Paxlovid can significantly reduce the risk of severe disease/death in different populations, from immunocompromised patients13 to older patients14. A recent real-world study15 published in BMC selected 8,803 patients with autoimmune rheumatic disease treated with Paxlovid and 8,803 untreated controls after a propensity match score, and found that Paxlovid significantly reduced the risk of hospitalization, ICU, and death, and that Paxlovid was more effective in men and older patients in a subgroup analysis (Figure 4).
Figure 4 Paxlovid reduces the risk of severe disease in the overall population compared with no treatment
Based on randomized controlled trials (RCTs) and real-world evidence, Paxlovid has been approved by the US FDA and the European Union EMA for the treatment of patients with mild to moderate COVID-19 infection who are at high risk of progression to severe disease.
The best choice: For people at higher risk for severe disease, Paxlovid is the only one highly recommended by WHO guidelines16
There are a total of 7 small molecule COVID-19 antiviral drugs approved for marketing in mainland China, and the clinical studies of various small molecule antiviral drugs are not completely consistent in virus variants, patient baseline characteristics, efficacy endpoint settings, etc., from the instructions and published related clinical studies, 3CLpro inhibitor subnotrelvir/ritonavir tablets combination packaging, deuteromedevir hydrobromide tablets (VV116), Aretegravir tablets, atatetervir tablets/ Drugs such as ritonavir tablets in combination packaging have only evidence of improving COVID-19-related symptoms, and there is no evidence of reducing the risk of severe disease or death17-20. RdRp (RNA-dependent RNA polymerase) inhibitors, such as molnupiravir and azvudine, have been shown to reduce the risk of severe disease or death in some real-world studies10,21 but are positive in genotoxicity studies22,23. At the same time, a real-world study conducted in Hong Kong, China24 showed that Paxlovid was pharmacoeconomically superior to molnupiravir, saving US$5,502.53 (about 37,000 yuan) compared with no antiviral drugs for every one death avoided in hospitalized patients, while molnupiravir added an additional US$2,629.08 (about 18,000 yuan).
Given the therapeutic benefits, ease of administration, and low concern about the potential harms of nirmatrelvir/ritonavir, the latest WHO guidelines still strongly recommend nirmatrelvir/ritonavir (the only strongly recommended) for patients at high risk of hospitalization for non-severe disease, and nirmatrelvir for patients at intermediate risk of hospitalization without severe disease/ Ritonavir (the only recommendation)16, molnupiravir is weak or conditional for use in patients at high risk of hospitalization with non-severe disease, deuteromedevir hydrobromide tablets are only used in clinical studies, and other drugs are not recommended (Figure 5).
Fig.5 WHO COVID-19 guidelines for treatment
Review experts
Prof. Wenjie Yang
Department of Infectious Diseases, Tianjin First Central Hospital
Chief physician, professor, master's supervisor
Member of the Hospital Infection Control Standards Professional Committee of the National Health Commission
Member of the Expert Committee on Infection Prevention and Control in Medical Institutions of the National Health Commission
Since its inception, Paxlovid has received widespread attention and discussion around the world and has played an important role in the treatment of COVID-19. The clinical trial results show that Paxlovid has shown significant efficacy in reducing the risk of hospitalization and death in people at higher risk of severe disease, and Paxlovid has been approved by the US FDA and the European Union EMA, as well as the only strong recommendation by the WHO guidelines, which fully confirms Paxlovid's status in the treatment of COVID-19.
Recently, the New England Journal of Medicine published the results of the EPIC-SR study in populations at low risk for severe disease, which may be related to a variety of factors, such as the timing of treatment initiation, the characteristics of the participating patients, the way in which symptom improvement was assessed, SARS-CoV-2 mutations25, and the results of this study corroborate each other with the recommendations of the WHO guidelines, it is reasonable to use Paxlovid mainly for people at high risk of severe disease, even if the patient has been vaccinated, considering the effectiveness of the vaccine against the new variant and the duration of protection of the vaccine, the patient still lacks effective immune protection, so for patients who have been vaccinated but have high-risk factors, it is still necessary to pay attention to antiviral therapy after infection. For people at high risk of severe disease, Paxlovid remains the best choice for the goal of reducing severe disease and death.
Paxlovid, a small molecule antiviral drug, has been shown to reduce the risk of severe disease and death in COVID-19 patients in both RCTs and real-world studies, and has been highlighted and recommended in treatment guidelines in many countries and regions. In addition, a post-hoc analysis published by the U.S. FDA showed that the efficacy of Paxlovid was independent of the patient's vaccination status or previous COVID-19 infection status. This means that even after vaccination, Paxlovid can still be an important treatment option if the patient is still at higher risk of severe disease for certain reasons, such as an inadequate immune response.
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