Effect of Remdesivir on COVID-19 PCR Positivity and Cycle Threshold in Kidney Transplant Recipients

Abstract

Information regarding Coronavirus disease 2019 in the transplant population is lacking. Recently it has been suggested that cycle threshold values obtained on polymerase chain reaction tests may serve as a marker of disease severity with lower values (i.e., higher viral load) being associated with higher mortality. This study was done to assess the impact of remdesivir use on the time to a negative COVID-19 PCR as well as the degree of change between two Ct’s based on treatment. A total of 30 kidney transplant patients with a new diagnosis of COVID-19 were assessed. Serial PCR results were followed from the time of diagnosis then every 2–4 weeks until negative. In patients who received remdesivir immediately after COVID-19 confirmation compared to no remdesivir, time to negative PCR was not statistically different with a median duration of 57 days in both groups (p = 0.369). The change in the Ct between the first and the second PCR test was also not statistically different between groups with a median change of 18.4 cycles in the remdesivir group and 15.7 cycles without remdesivir (p = 0.516). The results of this small single-center analysis suggest that remdesivir may not be beneficial in shortening time to a negative COVID-19 PCR.

1. Introduction

Coronavirus disease 2019 (COVID-19) has an increased incidence and risk of severe infection among immunocompromised patients [1]. Transplant patients are also known to frequently have delayed clearance or prolonged shedding of respiratory viruses [2]. With this in mind, therapy that may reduce the severity and/or duration of illness are crucial. Currently, remdesivir is the only FDA approved anti-viral drug for COVID-19 although the evidence supporting its benefit is uncertain based upon published trials [3]. Recently it has been suggested that cycle threshold values (Ct) obtained on polymerase chain reaction (PCR) tests may serve as a marker of disease severity with lower values (i.e., higher viral load) being associated with higher mortality [4]. Similarly, reduction in SARS-CoV-2 viral load with treatment is now considered a valid surrogate marker of treatment efficacy [5]. This letter describes our center’s experience with using remdesivir and/or reduced anti-metabolite dosing in an attempt to expedite clearance of the virus, as indirectly measured by serial PCR Ct testing. Patients with severe leukopenia (WBC < 3.0) were treated with elimination of anti-metabolite while the remainder received a 50% reduction in anti-metabolite dose [6].

2. Materials and Methods

This is a retrospective analysis using the electronic medical record. A total of 30 kidney transplant patients with a new diagnosis of COVID-19 as confirmed by PCR testing were included in this analysis. Patients were diagnosed between 31 March 2020—4 September 2020. Remdesivir was indicated in all patients for a (+) COVID-19 PCR and symptoms requiring presentation to receive care per clinical judgement of the transplant nephrologist. Serial PCR results were followed from the time of diagnosis and then every 2–4 weeks until becoming negative. Student’s T-testing was performed on parametric continuous data, and Wilcoxon Signed Rank testing was employed when data were not guaranteed to be parametric. The chi-square or fisher’s exact test was used for categorical data. Statistical analysis was performed using JMP PRO version 15.0.

3. Results

These data are presented in

Table 1. Baseline Variables and Outcomes.

	Remdesivir (12)	No Remdesivir (18)	p-Value
Baseline Variables
Age (years)	57.5 [50, 67.8]	56 [41.5, 66]	0.582
Time from Transplant (months)	60 [19.5, 61]	71 [10, 115.5]	0.320
LDH (units/L)	245 [213, 299]	245 [193.5, 428]	1.0
Ferritin (ng/mL)	866 [198, 2237.8]	1843 [488, 2379.5]	0.430
WBC (10 e9/L)	4.5 [1.6, 5.9]	5.5 [3.2, 7.4]	0.328
GFR (mL/min)	67 [54.5, 101.3]	53 [22, 76.5]	0.047
pO2 (%) a	97 [94, 98]	97 [95, 98.5]	0.878
CRP (mg/dL)	4.7 [2, 15.1]	0.95 [0.5, 6.1]	0.076
Anti-metabolite stopped	9 (75%)	8 (44%)	0.141
Initial Ct	19.2 ± 2.3	21.6 ± 1.9	0.568
Outcomes
Time to (-) PCR (days) c	57 [46, 127]	57 [31, 101.5]	0.369
Change in Ct from PCR 1 to PCR 2 (Cycles) b,c	18.4 [9, 22.4]	15.7 [5.6, 17.9]	0.516

All medians compared using Wilcoxon rank sums for non-parametric data; ^a Missing 9 data points in “no remdesivir” arm; ^b 7 patients in “remdesivir” arm and 5 patients in “no remdesivir” arm; ^c SARS-CoV-2 PCR testing was performed using the following assays based on which reagents were available at the time: TaqPath COVID-19 Combo Kit (ThermoFisher), cobas SARS-CoV-2 Test (Roche), Xpert Xpress SARS-CoV-2 (Cepheid), or a lab developed test adapted from the CDC SARS-CoV-2 assay.

. In patients who received remdesivir immediately after COVID-19 confirmation compared to no remdesivir, the time to negative PCR was not statistically different with a median duration of 57 days in both groups (p = 0.369). The change in the Ct between the first and the second PCR test was also not statistically different between groups with a median change of 18.4 cycles in the remdesivir group and 15.7 cycles without remdesivir (p = 0.516). The median time between two PCRs in the remdesivir group was 23 days and 27 days in the no remdesivir group.

4. Discussion

The Adaptive COVID-19 Treatment Trial (ACTT-1) demonstrated a reduced time to recovery with use of remdesivir [7]. The World Health Organization recently published their interim results of antiviral drugs for COVID-19. In this analysis, the authors describe 2750 patients who were randomized to treatment with remdesivir. They concluded that none of the drugs assessed, including remdesivir, had an effect on overall mortality, initiation of ventilation, or length of stay [3]. While these large studies utilized clinical endpoints, little is known about the effect of remdesivir on viral load. Clearance of virus with negative or high Ct PCR is often of increased importance regarding disposition and isolation requirements, immunosuppression regimens, and transplant listing [8]. The results of this small single-center analysis suggest that remdesivir may not be beneficial in shortening time to a negative COVID-19 PCR. As far as the change between two cycle thresholds after beginning remdesivir, our data suggest no difference, however our sample is small and likely underpowered. Our data are inadequate to determine drug efficacy; and is limited by a small sample size. Nevertheless, it suggests that an unnecessary admission or prolonged hospitalization for the sole purpose of remdesivir administration may not warranted.