On March 19, Beijing time, researchers from the National Respiratory Disease Clinical Research Center, China Friendship Hospital, Wuhan Jinyintan Hospital and other teams jointly published a research paper in the New England Journal of Medicine (NEJM), a leading medical journal. The results of clinical trials for the treatment of severe COVID-19 adult patients in Lopinavir-Litonavir were published.
The authors of the study were Cao Bin, Vice President of the Sino-Japanese Friendship Hospital, Director of Respiratory and Critical Lyoon Medicine, Zhang Dingyu, Director of Jinyintan Hospital in Wuhan City, Vice President of the Chinese Academy of Engineering, President of the Beijing Concord Hospital of the Chinese Academy of Medical Sciences, and Wang Chen, Director of the National Center for Clinical Medical Research for Respiratory Diseases.
On the same day, the New England Journal of Medicine published an editorial, “Covid-19 – Finding Effective Treatments.” This is a heroic effort, the editorial wrote. “Medical staff in Hubei Province are providing care to patients in this massive epidemic, and they are one of the most high-risk groups. As we saw during the 2014 Ebola outbreak, obtaining high-quality clinical trial data to guide patient care in the face of an outbreak is extremely difficult and the feasibility of randomised design syamwes into question. “
“Cao Bin et al.’s research team not only succeeded, but eventually recruited more patients (199) than originally intended,” the editorial said. “
Covid-19, a new coronary pneumonia Covid-19, currently does not have a specific drug, and an antiviral candidate is an HIV protease inhibitor, known as the Lopinavir/ritonavir combination. Lopinavir has an effect on the main protease (3CL protease) of the virus SARS coronavirus, and has some antiviral activity against the new coronavirus. Lopinavir, along with litonavir, which increases the bioavailability of the drug, was also used in clinical trials to treat Middle East Respiratory Syndrome (MERS) (Clinical.Gov, NCT02845843) in combination with the immunomodulator interferon beta-1b.
Clinically, the particular concern of Lofinave-Litonavir is either because of its wide accessibility and scale of productivity. There are also numerous case reports of the drug combination being used to treat Covid-19.
But what’s the specific effect? That’s a question mark. It was to address this problem that Cao Bin et al. conducted an emergency randomized clinical trial of the efficacy of Lopinave-Litonawe in Patients of Covid-19 in Wuhan, the center of the initial outbreak.
The clinical trial was conducted on 9 January 2020 and conducted at Jinyintan Hospital in Wuhan from January 18 to February 3, 2020 (the date of admission of the last patient). A total of 199 laboratory-confirmed and eligible new coronavirus infection patients were randomly grouped. Of these, 100 cases were assigned to the standard treatment group and 99 were assigned to the Lopinave-Litonavir group, i.e. on the basis of standard treatment, the addition of Lopinavir-Litonavir treatment (400 mg, 100 mg, twice a day, 14 days of course).
The overall conclusion of the study was that in adult hospitalized patients with severe COVID-19, the team did not observe the benefits of lopinavir-Litonavir treatment compared to standard treatment. It is worth noting that the overall mortality rate in the trial was 22.1 per cent, still significantly higher than the 11 to 14.5 per cent mortality rate in the initial descriptive study of COVID-19 hospitalized patients, indicating that the patients who were included in the trial were seriously ill.
“Unfortunately, the results of this clinical trial are disappointing,” the editorial said. No benefit was observed at the main endpoint of clinical improvement: both groups required a median time of 16 days. But the results of some secondary endpoints are interesting. The death toll in the Lopinave-Litonawe group was slightly lower, but it was difficult to explain the observation spree given the small number and the fact that the standard care group appeared to be more ill at baseline. “
One detail of the clinical trial is that if three patients who died early in the Lopinavir-Litonavir group were excluded from the statistics, the results would be relatively optimistic. The three patients died after a randomized group, but no first administration was made. However, such statistics can be controversial because the same cull did not occur in the control group.
The study’s lead researcher also noted in a review that each research team wants the interventions and drug-show effects proposed by the team, and that we, as researchers on the project, have a strong desire for the drug to be effective. However, in line with the principle that the results of the study should stand up to the challenge and test, NEJM magazine editors and we have taken a cautious attitude to choose THE ITT (Intention therapy) analysis set as the main endpoint result, as the main conclusion of this article, but did not select the mITT (improved intention therapy) analysis set of the main endpoint results.
Aside from the lack of hope in the conclusion of the main endpoint, the secondary end point is mixed. The number of deaths in the Lopinave-Litonavir treatment group was slightly lower. However, the release of the virus did not have a significant effect. “Since the drug is considered to be a direct inhibitor of viral replication, the inability to suppress viral load and the continued detection of viral nucleic acidstrongly indicate that it has no expected activity,” the editorial said. Therefore, although the drug may have some effect, it is not yet easy to observe. “
So why didn’t The Lopinave-Litonavedo have the desired effect? The editorial analyses that there may be two main factors: first, the team selected a particularly challenging group of patients who were more likely to be infected with more advanced infections and had considerable tissue damage, after previous studies showed that even highly active antimicrobials had limited efficacy for advanced bacterial pneumonia; Lopinavir is not particularly effective with the new coronavirus.
The editorial also focuses on the results of this clinical virology. It is worth noting that 35% of those who were screened positive for the new coronavirus through a nasopharyngeal swab tested negative for the first day with a mouth swab. Is this due to the difference in the detection site, the time of illness, the characteristics of the test, or the natural evolution of the disease?
In addition, 42% of patients tested positive for the virus on the 28th day, but the quantitative data at the time showed low levels that could be close to the test threshold. Since viral nucleic acids were tested, positive results do not necessarily indicate the production of an infectious virus.
These data indicate that assessing the ability to spread after the recovery of serious diseases will be a priority in helping to control transmission.
The editorial concludes that although Lorpinavir-Litonavir is not effective for Covid-19 patients, there are many important findings in this study. The researchers quickly launched the experiment and designed an experiment that could quickly arrive at an answer. “What we’ve learned from their work can help design new experiments. It is clear that fast-starting, high-quality randomized clinical trials are possible under epidemic conditions, even in difficult conditions in Wuhan. “