key: cord-0983830-yrmdjy4p
authors: Zhang, Zhicheng; Wang, Shumei; Tu, Xianglin; Peng, Xuping; Huang, Yanxia; Wang, Li; Ju, Weihua; Rao, Jianfeng; Li, Xue; Zhu, Donghong; Sun, Huabao; Chen, Hongyi
title: A comparative study on the time to achieve negative nucleic acid testing and hospital stays between Danoprevir and Lopinavir/Ritonavir in the treatment of patients with COVID‐19
date: 2020-06-05
journal: J Med Virol
DOI: 10.1002/jmv.26141
sha: 20053c8daf8e81c105b1e02a84d7714f77ba0e79
doc_id: 983830
cord_uid: yrmdjy4p

BACKGROUND: In late December 2019, the coronavirus disease 2019 (COVID‐19) first outbroke in Wuhan city, China, and has now become a global pandemic. However, there is no specific antiviral treatment for COVID‐19. METHODS: This study enrolled 33 COVID‐19 patients in the nineth hospital of Nanchang from January 27(th) to February 24(th), 2020. Clinical indexes of patients upon admission/discharge were examined. Patients were divided into two groups according to different treatment plans (Danoprevir; Lopinavir/Ritonavir). The days to achieve negative nucleic acid testing and the days of hospital stays were counted and statistically analyzed. RESULTS: COVID‐19 patients treated with Danoprevir or Lopinavir/Ritonavir were all improved and discharged. Indexes like blood routine, inflammation and immune‐related indexes were significantly recovered after treatment. Additionally, under the circumstance that there was no significant difference in patients’ general information between the two groups, we found that the mean time to achieve negative nucleic acid testing and hospital stays of patients treated with Danoprevir both were significantly shorter than those of patients with Lopinavir/Ritonavir. CONCLUSION: Collectively, applying Danoprevir is a good treatment plan for COVID‐19 patients. This article is protected by copyright. All rights reserved.

Coronavirus disease 2019 (COVID-19) is caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), a causative agent of a potentially fatal disease, and it has become a great global public health concern 1 . Form late 2019 to early 2020, the novel coronavirus SARS-CoV-2 suddenly broke out among ordinary people in Wuhan city, China, and rapidly spread in a short period of time. According to the data released by the World Health Organization (WHO), more than 2,540,000 cases were reported worldwide by April 23, 2020, among which 175,000 patients died. The massive outbreak of COVID-19 has caused numerous casualties and huge economic loss. Therefore, it is vital to make effective treatment plans as soon as possible and speed up the coordination of prevention and treatment, so as to protect people's health and reduce economic loss.

The symptoms of COVID-19 infections occur after an average incubation period of approximately 5.2 days 2 . The most common clinical symptoms include fever, dry cough, myalgia, fatigue, dyspnea, and diarrhea 3 , which are generally similar to the symptoms caused by β-coronavirus 4 . Studies have indicated that clinical indexes such as patients' blood indexes are important indicators essential for the diagnosis and treatment of COVID-19. In patients with COVID-19, there is an increase in white blood cell (WBC) count and plasma proinflammatory cytokine level. For example, a prior study showed that the C-reactive protein This article is protected by copyright. All rights reserved.

(CRP) of a COVID-19 patient was 16.16 mg/L, which was above the normal range (0-10 mg/L), with a high erythrocyte sedimentation rate (ESR) and D-dimer level 5 . Besides, studies found that the lymphocyte count and its percentage were significantly decreased in severe COVID-19 patients relative to those in mild patients 4, 6 . Moreover, the levels of cytokines and chemokines in the blood of COVID-19 patients were significantly elevated, while some severe COVID-19 patients showed high levels of pro-inflammatory cytokines, such as IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1α and TNFα 4 . Collectively, screening out the indicators with significant differences is of great reference value for the diagnosis and treatment of COVID-19 patients.

At present, there have been no specific antiviral drugs or vaccines available for treatment of patients with COVID-19. Therefore, it is desirable to develop appropriate and effective therapeutic drugs. A study has revealed that broad-spectrum antiviral drugs and HIV protease inhibitors could attenuate the viral infection 7 . Antiviral therapies have been applied in patients currently. For example, patients in a study were given 75 mg oseltamivir, 500 mg lopinavir, 500 mg ritonavir and 0.25 g ganciclovir twice a day for 3-14 days 8 However, the efficacy of Danoprevir and LPV/r in the treatment of COVID -19 have not been compared.

In this study, on the basis of the treatment plan and the recovery of 33 COVID-19 patients in the nineth hospital of Nanchang, we analyzed the clinical conditions of patients treated with Danoprevir and LPV/r and made a comparative study concerning the time to achieve negative nucleic acid testing (NAT) and hospital stays between the two groups, so as to determine the efficacy of the two therapeutic drugs.

A total of 33 COVID-19 patients in the nineth hospital of Nanchang from January 27 to February 24, 2020 were involved in this study, including 11 males and 22 females aged between 18-71. Nucleic acid samples were collected from the respiratory tract of patients and were confirmed to be positive by quantitative PCR. The information was detailed in Table 2 .

The severity of disease was distinguished according to the clinical features of COVID-19 patients: 1. mild type: the clinical symptoms are mild, and no signs of pneumonia are found on imaging; 2. moderate type: having fever and respiratory symptoms, and signs of pneumonia can be observed on imaging; 3. severe type:

adults who meet any of the following criteria: respiratory rate≥30 times /min, oxygen saturation in resting state≤93%; arterial partial pressure of oxygen (PaO2) This article is protected by copyright. All rights reserved.

/concentration of oxygen (FiO2) ≤300 mmHg; pulmonary imaging shows significant progression of lesion>50% within 24-48 hours.

All patients were classified into mild, moderate and severe types, and then grouped into Danoprevir group and LPV/r group according to the therapeutic regimen based on the actual situation of patients. The specific treatment regimen was designed as below: Danoprevir Sodium Tablets, 100 mg twice daily, by oral;

Ribavirin Tablets, 1000 mg (weight<75 kg) or 1200 mg (weight≥75 kg) daily, taken two times, by oral; Lopinavir/Ritonavir Oral Solution (80 mg/20 mg), adult, 5 ml (400/100 mg) twice daily or 10 ml (800/200 mg) once daily, with meal. All drugs were given until patients were discharged.

(1) Blood routine index: WBC (4-10×10 9 /L); lymphocyte count (0.8-4.0×10 9 /L); eosinophilic granulocyte count (EOC, 0.05-0.5×10 9 /L); ferritin (male: 16-220 ng/mL, female: 10-124 ng/mL); D-dimer (0-0.6 mg/L).

(2) Inflammation-related indexes: CRP (<10 mg/L); ESR (0-15 mm/h).

(3) Immune-related indexes: immunoglobulin G (IgG, 7-16 g/L); interleukin-4 (IL-4, 0-2.8 pg/mL); interleukin-6 (IL-6, 0-5.3 pg/mL); interleukin-10 (IL-10, 0-4.91 pg/mL); CD8+% (15-44); CD4+% (27-51); CD16+%CD56+% (7-40).

(4) Negative NAT detected by PCR.

(5) The hospital days of patients.

All data were processed by Graphpad Prism 6.0 software (Graphpad Prism, San Diego, CA, USA). Enumeration data of patients in the two groups were This article is protected by copyright. All rights reserved.

analyzed by Fisher exact test, while measurement data were presented as mean ± standard deviation and were analyzed by t test. P<0.05 was considered statistically significant.

In this study, we enrolled 33 COVID-19 cases in the nineth hospital of Nanchang, and nucleic acid samples were collected from the respiratory tract of patients and confirmed to be positive. We statistically analyzed the blood routine and immune-related indexes of the patients on admission/discharge for the purpose of direct comparison of therapeutic outcomes. As shown in Table 1 , the abnormal proportions (the percentage of patients with abnormal clinical indexes in total number of patients) of clinical indexes were evidently lower in patients on discharge than those in patients on admission. Besides, several indexes (WBC count, lymphocyte count, CRP, IL-6, IL-10, and CD4+%) of patients on admission and discharge showed a significant difference (P<0.05). Blood routine and some immune indexes are commonly used for disease diagnosis, as they can effectively determine the patients' physical conditions. Based on the clinical data, it turned out that most indexes of patients recovered to normal after treatment, suggesting that our treatment had favorable outcomes. Collectively, most blood routine and immune-related indexes recovered to normal in patients who could be discharged.

Five cases out of 33 COVID-19 patients were given Danoprevir, and 28 cases out of 33 COVID-19 patients were given LPV/r. Our study included demographic information, clinical features on admission, underlying medical This article is protected by copyright. All rights reserved.

disease and clinical classification on admission (Table 2 ). Most COVID-19 patients showed some clinical features upon admission, among which fever (58%) and cough (61%) were the most common symptoms. Symptoms like chest distress, dyspnoea and fatigue mainly appeared in patients over 40 years. On the basis of clinical diagnosis, patients were divided into mild type, moderate type and severe type. The moderate cases were the main subject of our study. In order to compare the efficacy of Danoprevir and LPV/r in treating COVID-19, we performed statistical analysis on the general information of the patients in the two groups. In terms of significance, there was no significant difference (P>0.05) in patients' general information between the two groups, which is conducive to the subsequent assessment of the efficacy of two drugs.

Finally, we analyzed the time to achieve negative NAT and hospital stays of patients in the two groups. All patients in the two groups were monitored until they were discharged. The time for two consecutive negative NAT of throat swab and hospital stays of COVID-19 patients were analyzed and compared. As illustrated in Table 3 This article is protected by copyright. All rights reserved.

Accessed 16 Feb 2020). SARS-CoV and MERS-CoV are both recognized to be major threat to public health. SARS-CoV-2, which is also originated from bats, manifests variable clinical features from asymptomatic status to acute respiratory distress syndrome and multiple organ dysfunction. The epidemiological and clinical features of COVID-19 suggest a higher transmissivity and a lower mortality rate compared to those of SARS 8, 15 . Despite that the overall mortality rate of COVID-19 is lower than SARS or MERS, the mortality rate of severe cases with COVID-19 is rather worrying 16 

immunodeficiency virus 1 (HIV-1) protease inhibitor, usually extends its half-life by inhibiting cytochrome P4507 in combination with RTV. Studies have indicated that LPV at a high dose (9.6 g/mL) or a low dose (5.5 g/mL) can inhibit SARS-CoV, and it also plays an inhibitory role in the replication cycle of MERS-CoV 19, 20 . Although most studies focus on the efficacy of LPV, we also need to be aware the adverse reactions like diarrhea, nausea and weakness which are common in patients. Also there was a report revealing that some patients exhibited elevated total bilirubin, triglyceride and liver enzyme levels after the treatment with LPV 21 .

In order to better compare the efficacy between Danoprevir and LPV/r in clinical practice and to provide a guidance for clinical treatment of COVID-19 and other pneumonia, we analyzed 33 COVID-19 patients and divided them into two groups (Danoprevir group and LPV/r group). Prior to that, we first analyzed the general information of patients in two groups to exclude the interference of age, gender, underlying diseases, clinical symptoms and other factors ( Table 2 

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superior efficacy to LPV/r. In conclusion, our study suggests that it is a correct choice to use Danoprevir in the treatment of patients with COVID-19.

All authors consent to submit the manuscript for publication.

The data used to support the findings of this study are included within the article.The data and materials in the current study are available from the corresponding author on reasonable request.

The authors declare no conflicts of interest.

This study was supported by the funds from Science and Technology Bureau of Nanchang City. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work. This article is protected by copyright. All rights reserved.