Clinical efficacy of remdesivir for COVID-19 in children: A propensity-score-matched analysis

Abstract

Clinical efficacy of remdesivir in children with COVID-19 is unclear. This propensity-score-matched retrospective cohort study of children with COVID-19 showed that the rate of patients achieving defervescence on Day 4 was higher in the remdesivir group than in the non-remdesivir group, but was not statistically different (86.7% vs 73.3%, P = 0.333).

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has accounted for many cases and deaths worldwide [1]. The COVID-19 pandemic started mainly in adult patients, but the number of pediatric COVID-19 patients increased with the spread of highly infectious mutant strains, including the Delta and Omicron variants of concern [2]. As the infection spread to children, the number of pediatric deaths due to COVID-19 increased in Japan [3], necessitating the development of treatments for children.

Remdesivir is a prodrug of adenosine nucleoside, and its analog of adenosine triphosphate (ATP), an active metabolite produced in vivo by hydrolysis, inhibits ribonucleic acid (RNA)-dependent RNA polymerase, which is necessary for RNA virus replication, including SARS-CoV-2 [4]. The efficacy of remdesivir for COVID-19 has been confirmed, particularly in adult patients [4,5], and it is used as a main treatment option for COVID-19 in many countries around the world.

In Japan, remdesivir was approved for use in May 2020 [6]. Remdesivir has been used in pediatric patients to treat moderate-to-severe COVID-19 and is also used to prevent the development of severe disease in patients with risk factors with mild COVID-19 [6]. However, reports on the use of remdesivir in pediatric patients are limited worldwide [6,7], and data on its efficacy are scarce.

Therefore, we conducted this study to evaluate the efficacy of remdesivir in children younger than 18 years using data from a COVID-19 registry in Japan.

We used the data from the COVID-19 Registry Japan (COVIREGI-JP), which is the largest COVID-19 registry in Japan. The details of the registry have been described previously [8]. Briefly, approximately 700 institutions across Japan participated and about 80,000 laboratory-confirmed, hospitalized COVID-19 cases of all ages were registered by the end of March 2023. The study data were collected and managed using REDCap (Research Electronic Data Capture) a secure, web-based data capture application hosted at Joint Center for Researchers, Associates and Clinicians (JCRAC) data center of National Center for Global Health and Medicine.

This is a retrospective, cohort study using the propensity-score-matching method. Patients under 18 years of age with COVID-19 who were enrolled in the COVIREGI-JP between January 2020 and January 2023 were included in the study. The study period was divided into three periods based on the major variant strain of concern at the time, namely, pre-Delta period (January 2020 to July 2021), Delta period (August 2021 to December 2021), and Omicron period (January 2022 to January 2023). Patients aged 18 years or older were excluded from the study. The definitions of mild, moderate, and severe COVID-19 were adopted from a previous report [9]. The primary outcome of the study was defervescence on Day 4 of hospitalization and secondary outcomes were tracheostomy/oxygenation/renal replacement therapy at discharge or death. We compared these outcomes between patients with and without remdesivir.

Categorical and continuous variables were summarized by number (%) and median (interquartile range [IQR]), respectively. Fisher's exact test for categorical values and the Mann-Whitney U test for continuous values were used to compare the two groups. Propensity-score (PS) matching was performed to adjust for confounding factors. PS was defined as the probability of receiving remdesivir and was estimated using multivariable logistic regression. Baseline variables included age, time from onset to admission, body temperature on admission, severity (mild or moderate), comorbidity, predominant variant strains, and COVID-19 vaccination history (receipt of two or more doses or 0–1 dose). Patients were matched using nearest-neighbor matching with a minimum caliper of 0.25 and a fixed ratio of 1:1 without replacement. The balance between the two groups for each covariate was assessed with a standardized mean difference less than 0.1. The matchit function in the MatchiIt package was used for PS matching. A two-tailed value of P < 0.05 was considered statistically significant. These statistical analyses were performed using R statistical software version 4.0.2.

The National Center for Global Health and Medicine ethics review committee and the National Center for Child Health and Development (NCCHD) ethics committee approved the study (NCGM-G-003494-0 and NCCHD-2022-202, respectively).

A total of 80,623 COVID-19 patients were enrolled in the registry during the study periods. Of these, 3628 pediatric patients under 18 years of age were included into the study (Fig. 1 ). Patient characteristics are shown in Supplemental Table 1. The median age was 7 years old and 433 (11.9%) of the patients had underlying diseases. The majority of the patients had mild-to-moderate COVID-19 and only 24 (0.7%) of patients were classified as severe COVID-19. Only 86 (2.4%) of patients received remdesivir. Body temperatures on Day 1 and Day 4 are shown in Supplemental Fig. 1. Overall, 1461 (40.3%) patients had fever ≥37.5 °C on Day 1 of hospitalization. The median of body temperature on Day 1 was higher in patients with remdesivir than in those without remdesivir(38.5 °C vs 37.2 °C, P < 0.001), but was similar on Day 4 (36.8 °C vs 36.8 °C, P = 0.08). The clinical characteristics of 86 patients treated with remdesivir are shown in Table 1 . The majority of patients were older than one year and approximately half of the patients had underlying disease. Despite the receipt of remdesivir, 75 (87.2%) patients had had only mild or moderate COVID-19. For propensity-score matching, we used these patients with mild-to-moderate disease because of the difficulty of matching patients with severe disease due to the small number of these patients. Finally, we found 30 patients with and without remdesivir after the matching process. All standardized differences were within 10% (Supplemental Fig. 2) and the clinical characteristics of the matched cohorts were acceptably similar (Supplemental Table 2). The number and rate of patients with body temperature <37.5 °C on Day 4 were higher in the remdesivir group than in the non-remdesivir group, but without statistical difference (n = 26, 86.7% vs n = 22, 73.3%; P = 0.333) (Table 2 ). There were no differences between the two groups for other secondary outcomes including death, given the small numbers of patients with these outcomes.

Fig. 1.

Patient selection flowchart.

Table 1.

Clinical characteristics of patients who received remdesivir.

Variables	Number of cases	Subcategory	Median [IQR] or number (%)
Case numbers	86	Pre-delta period	8 (9.3)
		Delta period	17 (19.8)
		Omicron period	61 (70.9)
Age	86	0 to < 6 months	1 (1.2)
		6 to < 12 months	1 (1.2)
		1–4 years	24 (27.9)
		5–12 years	25 (29.1)
		≥13 years	35 (40.7)
Male sex	86		53 (61.6)
Body weight (kg)	76		32.3 [14.8–53.5]
Underlying disease, number (%)	86	Any underlying disease	47 (54.7)
		Congenital anomaly or chromosomal abnormality	12 (14.0)
		Congenital heart anomaly	10 (11.6)
		Bronchial asthma	5 (5.8)
		Obesity	4 (4.7)
		Diabetes without complications	2 (2.3)
		Hypertension	2 (2.3)
		Others	39 (45.3)
Immunosuppressive condition	86		15 (17.4)
Number of patients with two or more doses of SARS-CoV-2 vaccine	64		7 (10.9)
Severity	86	Mild	20 (23.3)
		Moderate	55 (64.0)
		Severe	11 (12.8)
Timing of admission from the onset (days)	86		1 [[1], [2], [3], [4]]
Timing of remdesivir initiation from the onset (days)	86		2.5 [[1], [2], [3], [4]]
Remdesivir duration (days)	86		5 [[3], [4], [5]]
Co-administered medication	86	Molnupiravir	0 (0.0)
		Nirmatrelvir/ritonavir	0 (0.0)
		Monoclonal antibodies	0 (0.0)
		Steroids	24 (27.9)
		Antibiotics	32 (37.2)
Duration of hospitalization	85		8 [[6], [7], [8], [9], [10], [11]]
Death	86		1 (1.2)

SARS-CoV-2, severe acute respiratory coronavirus type 2; IQR, interquartile range.

Table 2.

Comparison of outcomes between patients with remdesivir and propensity-score-matched patients without remdesivir.

	Remdesivir (n = 30)	Non-remdesivir (n = 30)	P value
Body temperature <37.5 °C on Day 4, number (%)	26 (86.7)	22 (73.3)	0.333
SpO2 on Day 4, median [IQR]	97.5 [97–99]	97 [97–98]	0.396
Duration of hospitalizationa, median [IQR]	7 [[6], [7], [8], [9]]	7 [[5], [6], [7], [8], [9]]	0.702
Intensive care unit staya, number (%)	0 (0.0)	1 (3.3)	1
Tracheostomy at dischargea, number (%)	1 (3.4)	0 (0.0)	0.492
Oxygenation at dischargea, number (%)	2 (6.9)	0 (0.0)	0.237
Renal replacement therapy at discharge, number (%)	0 (0.0)	0 (0.0)	NA
Death, number (%)	0 (0.0)	0 (0.0)	NA

NA, not applicable; IQR, interquartile range.

^aOne patient who had no outcome documented at day 60 of hospitalization was excluded.

In our propensity-score-matching analysis, clinical efficacy of remdesivir in pediatric COVID-19 was not demonstrated. Several reports have shown clinical efficacy of remdesivir in the adult population. Beigel et al. showed a shorter time to recovery in COVID-19 patients treated with remdesivir compared to the placebo group in a randomized control trial [4]. It has also been shown that remdesivir has a prophylactic effect against severe disease in outpatients with risk factors for severe COVID-19 [10]. However, reports on the use of remdesivir in children are limited to a small number of observational studies [6,7,11,12]. These studies reported that the majority of patients who received remdesivir recovered; however, it is difficult to assess the clinical efficacy of remdesivir due to the lack of a comparator. The strength of our study is that we compared several clinical outcomes between children treated with remdesivir and the propensity-score-matched control group. As pediatric COVID-19 is generally mild, we chose defervescence as our primary endpoint. Although more patients in the remdesivir group achieved defervescence on Day 4, the difference was not statistically significant. However, it is difficult to conclude from the results of this study that remdesivir was not effective because of the insufficient statistical power due to the small number of patients. Further, our data did not include information on antipyretic use and we were unable to analyze its impact. As expected, there were very few severe cases, and we were unable to evaluate the clinical efficacy of remdesivir for death or other serious outcomes.

Adverse events of remdesivir in children are also an important topic. A case series including 20 children with COVID-19 reported no serious adverse events and few mild adverse events, including liver enzyme elevation (n = 4, 20%), leukopenia (n = 1, 5%), neutropenia (n = 1, 5%), and hypokalemia (n = 1, 5%) [6]. Another observational study including 48 children with COVID-19 reported that approximately 20% and 50% of patients experienced mild bradycardia and hypertension, respectively, but no patients required discontinuation of remdesivir. In our study, we were unable to assess the safety of remdesivir in children because the case report form (CRF) used during the study period did not include an item on adverse events related to remdesivir and we recognize this as a limitation of our study.

In conclusion, no apparent clinical efficacy of remdesivir was observed in hospitalized children with mild-to-moderate COVID-19. Further larger scale study is warranted to investigate of the clinical efficacy of remdesivir in children in more detail.

Authorship statement

KS and IM contributed to the design and conception of the study and drafted the manuscript. YA and ST contributed to data collection, statistical analysis, and revision of the manuscript. TA, NM, SS, and NI contributed to data collection and revising the manuscript.TF contributed to revising the manuscript. NO contributed to the revision of the manuscript and supervised the study. All authors meet the ICMJE criteria for authorship. All authors approved the final manuscript as submitted and agree to take responsibility for all aspects of the work.

Funding

None.

Declaration of competing interest

K. Shoji received payment for lectures from bioMérieux Japan, Nippon Becton Dickinson Company, Ltd., Viatris, Inc., Meiji Seika Pharma Co., Ltd., AstraZeneca K.K., Novartis Pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd., and Gilead Sciences, Inc. S. Tsuzuki received payment for supervising medical articles from Gilead Sciences, Inc. I. Miyairi received payment for lectures from Astellas Pharma, Sanofi K.K., Pfizer, Inc., Takeda Pharmaceutical Company, Ltd., Biken Group, Shionogi & Company, Ltd., bioMérieux Japan, and Gilead Sciences, Inc. The other authors declare that they do not have any conflicts of interests directly associated with the study.

Appendix A. Supplementary data

The following are the Supplementary data to this article: