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*For medical professionals only
Which patients can benefit significantly from using the new crown "special drug"? Scientific data from existing clinical studies can inform you
.
Antiviral treatment drugs are prescription drugs, should be used strictly according to the instructions under the guidance of a doctor, and special attention should be paid to the interaction
between drugs when using.
As the number of people infected with the new crown virus continues to rise, antipyretic drugs such as acetaminophen and ibuprofen are extremely sought-after, and demand exceeds supply
.
In addition to symptomatic treatment drugs such as fever reducers and cold medicines, the increase in severe patients has made the new crown "special medicine" more and more concerned and
demanded.
"Is it necessary for the masses to use the new crown 'special medicine'? Can I take it on my own? In
response to this problem, Professor Wang Guiqiang, director of the Department of Infectious Diseases of Peking University First Hospital, said at the press conference of the State Council Joint Prevention and Control Mechanism on December 20 that most people are currently mild or asymptomatic after being infected with the new coronavirus, but a small number of people are manifested as pneumonia, especially elderly patients with underlying diseases or unvaccinated, who are at high risk of severe disease
.
For people at high risk of severe disease, early intervention
is required.
The so-called new crown "special drug", that is, anti-new crown virus treatment drugs
.
Antiviral therapies recommended in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (9th Edition) include: paxlovid (nematevir/ritonavir), azvudine, and monoclonal antibodies [1].
Wang Guiqiang believes that the early use of these drugs may reduce the occurrence of severe disease, shorten the course of the disease, and shorten the detoxification time of the virus, but he also stressed that these antiviral drugs should be used
in medical institutions and under the guidance of doctors.
How effective is the new crown "special drug"? Which patients benefit significantly from these drugs? The "medical community" takes stock of relevant clinical research and tries to provide you with reference
through scientific data.
Paxlovid: The treatment of elderly patients is effective
Paxlovid (nirmatevir/ritonavir tablets) developed by Pfizer is the first oral small molecule drug authorized by the US Food and Drug Administration (FDA) for the treatment of new coronary pneumonia, and was conditionally approved for import registration by the State Food and Drug Administration in China in February this year, and its indication is: adult patients with mild to moderate novel coronavirus pneumonia (COVID-19) with
risk factors for progression to severe disease.
According to public reports, Paxlovid can significantly reduce the risk of hospitalization or death in new crown patients by up to 88
%.
This "amazing" data comes from a phase 2/3 clinical trial - EPIC-HR study [2].
As the name suggests, this is a randomized, double-blind, placebo-controlled clinical trial in a high-risk population (HR) that included 2246 adult patients, none of whom had been vaccinated, and who had ≥ 1 risk factor
for progressing to severe disease 。 The primary endpoint of the study was the proportion of patients hospitalised for coronavirus infection or death from any cause when treated within 28 days of treatment in the modified intention-to-treat (mITT) population (i.
e
.
participants who started treatment within 3 days of symptom onset and had not/did not intend to be treated with monoclonal antibodies at baseline).
The efficacy results showed:
- An interim analysis of the mITT population showed that the proportion of patients hospitalized or from any cause of death due to COVID infection was significantly lower in the Paxlovid group compared with placebo (7.
01% vs 0.
77%, P<0.
001) and a relative risk reduction of 89.
1%. - The final analysis of the mITT population showed that at day 28 of treatment, the proportion of hospitalizations or deaths from any cause due to COVID-19 infection in the Paxlovid treatment group and placebo group was 0.
72% and 6.
45%, respectively, and the difference in the data between the two groups was statistically significant (P<0.
001).
The relative risk was reduced by 88.
9%
in the Paxlovid treatment group.
A total of nine deaths were reported in the placebo group, compared with 0 deaths in the Paxlovid treatment group
. - In the patient population treated within 5 days of symptom onset, the results of the analysis showed that at 28 days of treatment, there was still a significant difference between the proportion of patients hospitalized or dying from any cause between the Paxlovid treatment group and the placebo group (0.
77% vs 6.
31%, P < 0.
001), and the relative risk reduction of 87.
8%<b10> in the Paxlovid group.
Among patients treated within 5 days of symptom onset, at 28 days of treatment, there was a significant difference
in the proportion of patients hospitalized or killed from any cause between the Paxlovid treatment group and the placebo group due to new crown infection, and it is worth noting that the EPIC-HR study was carried out during the epidemic period of the Delta strain, and the current epidemic is mainly the Omicron strain, which is less virulent and toxic
。 Moreover, after the outbreak of the epidemic, the coverage rate of the new crown vaccine has continued to expand, such as in China, the number of people covered by the new crown vaccine has accounted for more than
ninety percent of the total population of the country.
Is Paxlovid treatment effective in people infected with the Omicron strain who have been vaccinated? In response, Pfizer conducted another clinical study for standard risk (SR) patients, the EPIC-SR study [3].
Again, this is a randomized, double-blind, placebo-controlled Phase 2/3 clinical trial with inclusion criteria including: (1) ≥ 18 years of age; (2) Confirmation of new coronavirus infection within 5 days prior to enrollment; (3) Symptoms developed within 5 days after enrollment; (4) At least 1 characteristic or underlying condition is associated with an increased risk of severe illness caused by new coronary pneumonia, and the patient has been vaccinated against the new crown; or have no features associated with the risk of severe COVID, but the patient has not been vaccinated or was last vaccinated more than 12 months ago
.
The EPIC-SR study included a total of 1153 patients who were randomized 1:1 into two groups to receive either Paxlovid or placebo
.
However, the EPIC-SR study failed to meet the primary endpoint (patient-reported symptom reduction for 4 consecutive days).
For key secondary endpoints (hospitalisation or death), the relative risk was reduced by 51% in the Paxlovid group compared with the placebo group (Paxlovid group: 5/576; placebo group: 10/569), but no significant difference was
achieved.
Among vaccinated infected people, the relative risk of hospitalization or death was reduced by 57% in the Paxlovid group, but the difference was again not statistically significant
.
On June 14, 2022, Pfizer announced that it had terminated the EPIC-SR study due to very low hospitalization and mortality rates observed in the standard-risk patient population [3].
In addition to EPIC-HR and EPIC-SR, Pfizer has conducted a Phase 2/3 clinical trial EPIC-PEP study [4] designed to evaluate whether Paxlovid is effective in reducing the risk of
COVID infection after exposure.
The study included data from 2,957 adults who had a negative rapid COVID antigen test and had been exposed to symptomatic individuals who had recently tested positive for COVID within 96 hours
.
Subjects were randomly divided into three groups in a 1:1:1 ratio, namely: (1) treatment with Paxlovid for 5 days, followed by placebo treatment for 5 days; (2) treatment with Paxlovid for 10 days; (3) Treatment with placebo for 10 days
.
The results showed that patients treated with Paxlovid for 5 and 10 days had a 32% and 37%
lower risk of infection compared to the placebo group.
However, these results were not statistically significant and failed to meet the primary endpoint, suggesting that Paxlovid did not have a post-exposure
prophylaxis.
Randomised controlled trials (RCTs) are the gold standard of clinical evidence, but they also have limitations
.
Relatively speaking, real-world studies (RWS) have the characteristics of diverse source populations, relaxed entry criteria, long follow-up time, and comprehensive outcome measures, and their findings can be used as a supplement
to RCTs.
In September 2022, the New England Journal of Medicine published the results of real-world research conducted by Paxlovid in the Israeli patient population [5].
This was an observational, retrospective cohort study with a sample size of up to 109254 patients, of whom 3902 (4%) patients were treated
with Paxlovid during the study period.
At the time of the study, the dominant strain circulating in Israel was the Omicron strain
.
The results showed that patients aged 65 years and older who received Paxlovid had a 14.
7/100,000-day hospitalization due to new crown infection, and a total of 2 deaths due to new crown, and their risk of hospitalization was reduced by 73% compared with patients who did not receive Paxlovid treatment (adjusted HR: 0.
27; 95%) CI: 0.
15 to 0.
49), with a 79% reduction in the risk of death (adjusted HR: 0.
21; 95% CI: 0.
05 to 0.
82).
However, in the patient group aged 40~64 years, there was no significant difference
in the risk of hospitalization and death due to new crown infection, regardless of whether the patient was treated with Paxlovid.
In real-world studies, patients aged 65 and older (Figure A) and patients aged 40~64 (Figure B) had a cumulative risk of hospitalization compared with
October, and the top journal The Lancet published a real-world study of molnupiravir and Paxlovid in the treatment of Omicron infected patients in Hong Kong, China [6] (See: The Lancet launches Hong Kong real-world study: New crown oral drugs significantly reduce infection mortality in the elderly).
The subjects were mainly Omicron-infected people
over 60 years of age who had not been fully vaccinated.
The results show that early use of Paxlovid can effectively reduce the hospitalization and mortality rate of elderly patients, and reduce the risk of
disease progression and death after hospitalization.
In December, the team published another real-world study in The Lancet Infectious Diseases of hospitalized patients infected with the Omicron BA.
2 strain, also focusing primarily on elderly (≥65-year-old) patients
who had not been fully vaccinated.
The results suggest that early treatment with Paxlovid in these patients is effective in reducing all-cause mortality, composite disease progression outcomes, and the risk of requiring oxygen therapy [7].
Azvudine: More research results to be published
Azvudine is called China's "first oral small molecule new coronavirus treatment with completely independent intellectual property rights"
。 In July 2022, Henan Real Biotechnology Co.
, Ltd.
announced that the results of the phase III clinical trial registration of azvudine tablets for the treatment of new coronavirus pneumonia indications met expectations, and officially submitted a marketing application to the National Medical Products Administration [8].
On July 25, the State Food and Drug Administration conditionally approved the new indication of azvudine tablets for the treatment of adult patients
with common COVID-19.
At the 17th National Conference of Infectious Diseases of the Chinese Medical Association and the 14th Conference of Infectious Physicians of the Chinese Medical Doctor Association, Professor Zhang Fujie of Beijing Ditan Hospital affiliated to Capital Medical University introduced the results of the clinical research of azvudine at home and abroad [9,10].
Professor Zhang Fujie said that at present, Azvudine has carried out global clinical trials
against the new crown virus in China, Russia and Brazil.
The phase III study in China, led by Beijing Ditan Hospital affiliated to Capital Medical University, is a multi-center, randomized, double-blind, placebo-controlled clinical trial involving 11 centers across the country, including a total of 348 patients aged 18~75 years with mild and common COVID-19, according to 1:1 randomized administration of azvudine 5mg, once a day + basic treatment and placebo + basic treatment, the trial protocol treatment for up to 14 days
.
The results of the study showed that the viral load decreased significantly higher than in the control group on day 5 after azvudine treatment
.
In the phase III clinical study of azvudine, the analysis results of the change of viral load from baseline were included in the clinical study in Brazil, and the results
showed that the proportion of final clinical state improvement in the experimental group was significantly higher than that of the control group, and the nucleic acid negative time and hospital stay were significantly lower than those in the control group
。
The phase III clinical study in Russia included a total of 314 patients and observed the proportion and time
of symptom improvement on day 7.
The results showed that the proportion of clinical condition improvement in the experimental group was significantly higher than that in the control group (40.
43% and 10.
87%), achieving clinically effective results and improving clinical statusIt was lower than that of the control group (10 days vs 13 days, p< 0.
001).
<b21>
At present, the phase III clinical study of azvudine has not been officially published in academic journals, and more details are still to be disclosed
.
Neutralizing antibodies: Can the virus maintain efficacy if it continues to mutate?
Ambavirumab injection is a combination therapy drug of new coronavirus neutralizing antibody jointly developed by Tsinghua University, Shenzhen Third People's Hospital and Tengsheng Huachuang Pharmaceutical Technology (Beijing) Co.
, Ltd.
In December 2021, the combination therapy of ambavirumab and romisivimab was approved by the NMPA for the treatment of adult and adolescent patients with novel coronavirus infection with mild and ordinary forms with high-risk factors for progression to severe disease
.
Among them, adolescents (12-17 years old, weight ≥40kg) indications are conditionally approved
.
This marketing approval is based primarily on the interim and final results of the Phase 3 ACTIV-2 trial supported by the National Institutes of Health (NIH) [11,12].
According to Tengsheng Biopharma, the study was conducted at multiple clinical trial centers around the world, including the United States, Brazil, South Africa, Mexico, Argentina and the Philippines, and included a total of 837 outpatient COVID-19 patients
.
The interim results released in October 2021 showed:
Ambavirumab/romisivimab combination therapy reduced the composite endpoint of hospitalization and death in outpatients at high risk of clinical progression for COVID-19 by 78% compared with placebo (unadjusted, unilateral test P < 0.
00001).
- Of participants treated with ambavirumab/romisivimab combination therapy within 5 days of symptom onset, 2% progressed to hospitalisation or death, compared with 11% (21/197)
in the placebo group.
- Two percent (5/222) of participants treated with ambavirumab/romisivimab combination therapy 6 to 10 days after symptom onset progressed to hospitalisation or death, compared with 11% (24/222)
in the placebo group.
The analysis also showed no deaths in the treatment group within 28 days, compared with eight deaths
in the placebo group.
The final results of the trial showed that ambavirumab/romisivimab combination therapy reduced the composite endpoint of hospitalization and death in outpatients with COVID-19 at high risk of clinical progression by 80% compared with placebo
.
As of the 28-day clinical endpoint, there were 0 deaths in the treatment group compared to 9 deaths
in the placebo group.
The ACTIV-2 trial has shown that ambavirumab/romisivimab combination therapy is effective in reducing the risk of hospitalization and death in outpatients with COVID-19.
In May 2022, The Lancet Infectious Diseases published a multicenter, double-blind, placebo-controlled clinical trial in hospitalized patients with COVID-19, which, unfortunately, showed that ambavirumab/romisivimab did not show efficacy in improving clinical outcomes [13].
However, as we all know, the new crown variant has a strong immune escape ability, which brings severe challenges
to the application of neutralizing antibody drugs.
In the face of doubts, Tengsheng Bo Pharmaceutical said that the results of independent laboratory studies showed that the combination therapy of ambavirumab and romisivimab maintained neutralizing activity against Omicron BA.
4/5 and BA.
2.
12.
1 subtype variants [14].
However, a recent study published in Nature by the research group of Cao Yunlong/Xie Xiaoliang of the Center for Biomedical Frontier Innovation of Peking University and the research group of Beijing Changping Laboratory and Wang Youchun's research group of the China Institute of Food and Drug Control showed that the neutralizing activity of most existing antibody drugs against Omicron was greatly reduced, including ambavirumab/romisivimab (i.
e.
, BRII.
-196+198) [15].
。
Traditional Chinese medicine treatment of Omicron subtype on the escape
of neutralizing antibody drugs: yet to be "self-certified"
The "Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia (9th Edition)" recommends a variety of TCM treatment options, among which the "explosive" drug Lianhua Qingwen capsules are sought after by many users, but how far is it scientifically from "self-certifying" the efficacy of the new crown? (See the April article this year for details: "Self-proof" of the new crown efficacy, how far is Lianhua Qingwei?) ）
。 After 8 months, the "medical community" once again searched the website of the "China Clinical Trials Registry" with the keyword "Lianhua Qingwen", and the results showed that the number of trials related to the prevention and treatment of the new crown increased by 4, but only one single-center, retrospective cohort study of asymptomatic and mild COVID-19 in children has been initiated
.
In addition, the Lianhua Qingwen International Multi-center Clinical Study, which was registered on February 11, 2022, is still displayed as "not yet started"
.
ConclusionToday
, we have "met with the new crown virus", the focus of epidemic prevention and control has shifted from infection prevention and control to medical treatment, and several anti-new crown virus drugs have also been put on the market, attracting a lot of attention and heated discussions (until crazy).
However, as Professor Wang Guiqiang emphasized at the press conference, antiviral treatment drugs are prescription drugs and should be used strictly according to the instructions under the guidance of
doctors.
For example, when using Paxlovid, special attention should be paid to the interaction between drugs, simvastatin, amiodarone and other commonly used drugs in elderly patients are drugs that are contraindicated to Paxlovid; Patients with moderate to severe liver function impairment, patients with moderate to severe renal impairment, and patients with pancreatitis should be treated with caution
.
References: [1] "Novel Coronavirus Pneumonia Prevention and Control Plan" (9th Edition).
[2]Hammond J, Leister-Tebbe H, Gardner A, et al.
Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.
N Engl J Med.
2022 Apr 14; 386(15):1397-1408.
[3] style="color: rgb(136, 136, 136);font-size: 12px;" _mstmutation="1" _istranslated="1"> [4] style="color: rgb(136, 136, 136);font-size: 12px;" _mstmutation="1" _istranslated="1"> [5] Arbel R, Wolff Sagy Y, Hoshen M,et al.
Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge.
N Engl J Med.
2022 Sep 1; 387(9):790-798.
[6]Wong CKH, Au ICH, Lau KTK,et al.
Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the omicron wave in Hong Kong: an observational study.
Lancet.
2022 Oct 8; 400(10359):1213-1222.
[7]Wong CKH, Au ICH, Lau KTK,et al.
Real-world effectiveness of early molnupiravir or nirmatrelvir-ritonavir in hospitalised patients with COVID-19 without supplemental oxygen requirement on admission during Hong Kong's omicron BA.
2 wave: a retrospective cohort study.
Lancet Infect Dis.
2022 Dec; 22(12):1681-1693.
[8]https://mp.
weixin.
qq.
com/s/LXaq4p_v0unYoFN0GaRfkw[9]https://mp.
weixin.
qq.
com/s/zIYVe6hIdph1hlt7HCGELA[10] https://mp.
weixin.
qq.
com/s/vue96LrIQJoIJYpR95rIUQ[11]https://cn.
briibio.
com/news-detail.
php?id=372#news[12] https://cn.
briibio.
com/news-detail.
php?id=1598#news [13] ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group.
Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial.
Lancet Infect Dis.
2022 May; 22(5):622-635.
[14]https://cn.
briibio.
com/news-detail.
php?id=1707#news[15]Cao Y, Jian F, Wang J, et al.
Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution.
Nature.
2022 Dec 19.
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