key: cord-0965683-5cfz4kug
authors: Aiswarya, Dhanapalan; Arumugam, Venkatesh; Dineshkumar, Thanigachalam; Gopalakrishnan, Natarajan; Moses Lamech, Tanuj; Nithya, Govindasamy; Sastry, Bhagavatula V.R.H.; Vathsalyan, Paulpandian; Dhanapriya, Jeyachandran; Sakthirajan, Dr. Ramanathan
title: USE OF REMDESIVIR IN PATIENTS WITH COVID-19 ON HEMODIALYSIS- A STUDY OF SAFETY AND TOLERANCE
date: 2020-12-18
journal: Kidney Int Rep
DOI: 10.1016/j.ekir.2020.12.003
sha: 6a4aeee5e738f2eb1341ae85648386e32cedad6f
doc_id: 965683
cord_uid: 5cfz4kug

BACKGROUND: There is scarce data regarding the use of Remdesivir in Severe acute respiratory distress syndrome Corona virus 2 (SARS CoV2) patients with End Stage Renal Disease (ESRD) as the Food and Drug Administration (FDA) cautions against its use in patients with estimated glomerular filtration rate(eGFR) less than 30ml/min/1.73m(2) unless the potential benefits outweigh potential risks. We intend to study the compassionate use and safety profile of remdesivir in End stage renal disease patients with moderate to severe SARS CoV2 infection. METHODS: We conducted an observational prospective study in 48 dialysis dependent patients with SARS CoV2 infection who received remdesivir as part of institutional treatment protocol. During the treatment period, 100 mg of remdesivir was given 4 hours before hemodialysis sessions. Liver function tests (LFT), Inflammatory markers such as serum C-reactive protein (CRP), ferritin, Lactate dehydrogenase (LDH) levels, oxygen requirement before and after remdesivir treatment were compared. RESULTS: There were no events of significant LFT alteration with administration of 2-6 doses of remdesivir. Significant decline in Serum CRP level (p<0.001) was noted. 68.57% of patients showed an improvement in oxygen requirement. Early administration of remdesivir within 48 hours of hospital admission shortened the duration of hospitalization by mean of 5.5 days(p=0.001) CONCLUSION: Remdesivir was well tolerated and found safe in our study. If initiated within 48 hours of hospitalisation, it reduces recovery time. It requires further randomized control trial with larger population to assess mortality benefits.

Institutional management protocol (Table S1 ):

All ESRD patients requiring renal replacement therapy were admitted. The blood investigations done on admission included complete hemogram, renal function test, liver function tests, serum C-reactive protein(CRP), ferritin and lactate dehydrogenase (LDH) levels. All patients were subjected to computerized tomography(CT) of chest and severity of lung involvement was graded as less than 25%, 25-50%, 50-75% and more than 75% (grade 1, 2, 3 and 4 respectively). These investigations were repeated as clinically indicated. According to the hospital protocol mild disease was defined as having any one of the following: Oxygen saturation in room air more than 94%, respiratory rate less than 24 per minute, neutrophil lymphocyte ratio between 3.13 and 5, serum C reactive protein level between , 10 J o u r n a l P r e -p r o o f 5 and 50mg/dl, serum ferritin between 400 and 600 ng/ml, serum LDH between 220-300 IU/ml, serum interleukin-6 between 20-100 pg/ml, CT chest showing less than 25% lung involvement. Moderate disease was defined as having any one of the following: Oxygen saturation in room air less than 94% requiring oxygen, respiratory rate more than 24-30 per minute, neutrophil lymphocyte ratio more than 5, C reactive protein 50-100 mg/dl, serum ferritin 600-1500 ng/ml in males and 500-1000 ng/ml in females, serum LDH 300-500 IU/ml, serum interleukin-6 20-100pg/ml, CT-Chest showing 25-75% lung involvement (grade 2 and3). Severe infection was defined as having any one of the following:

Oxygen saturation in room air less than 90% in room air requiring oxygen, respiratory rate more than 30 per minute, neutrophil lymphocyte ratio more than 7, C reactive protein more than 100mg/dl, serum ferritin more than 1500ng/ml in males and more than 1000ng/ml in females, serum LDH more than 500IU/ml, serum interleukin -6 more than 100pg/ml, CT-Chest showing more than 75% lung involvement (grade 4).

Remdesivir was given at a dose of 2.5 mg/kg of edema free body weight (dry weight) up to a maximum dose of 100 mg on Day 1 in patients undergoing hemodialysis 4 hours before the session. Subsequent doses up to a maximum of 6 doses were given 4 hours before each hemodialysis session. LFT was monitored daily and further doses were withheld if there was Alanine amino transferase (ALT) elevation 

At Table 4) 

The presumed toxicity in patients with decreased renal function is attributed to both Remdesivir and accumulation of its solubulising excipient Sulphabutyl-ether-beta-cyclodextrin(SBECD). 8 Among the biochemical markers, CRP correlated with the severity of the disease. Serum levels of CRP were significantly higher in patients with severe disease similar to the reports of other available studies 11, 12 . Even though there was a trend towards increased levels of serum LDH and serum Ferritin in patients with severe disease it was not found to be statistically significant. CKD and dialysis are chronic 12 inflammatory states. Serum ferritin level may not be a good marker of inflammation in patients on dialysis due to supplemental iron therapies and blood transfusions. These patients have higher serum ferritin levels than the general population. 13 The total number of doses of remdesivir administered in this study ranged from 2 to 6 over a duration of 5 to 11 days, as subsequent doses were administered depending on the clinical assessment and biochemical parameters. Following administration of Remdesivir there was a significant decline in serum CRP levels across all sub groups based on age, disease severity and timing of drug administration.

In our study population, early initiation of remdesivir within 48 hours of hospital admission was shown to decrease the mean duration of hospitalization by 5.5 days (p=0.001) compared to those who received it after 48 hours. This delay of 48 was unintentional and was mainly due to delay in obtaining consent, therapeutic decision making and logistic reasons. The time taken for the swab test to become negative was significantly lower in those who received the first dose of remdesivir within 48 hours of admission.

These results are similar to the final reports of ACTT-1 trial where the recovery time was reduced by five days in those who received remdesivir compared to those who did not. 14 . The median duration of hospitalization in our study population was 9 days (IQR 6-12 days) whereas the median recovery time in the remdesivir group of ACTT-1 trial was 10 days.. But these results could not be translated into any benefit when mortality was considered. The mortality in our cohort was 20.8% compared to 17.9 % in the entire population of ESRD patients with SARS CoV 2 infection who received dialysis in our center (unpublished data). This difference could be due to the presence of more number of asymptomatic patients as well as those with milder disease in the latter group. Compared to other studies in ESRD patients, the mortality in our study population is considerably lower [3] [4] [5] . 

Our study showed that remdesivir use in ESRD patients is safe and was not associated with any serious adverse effects. Early initiation of remdesivir appears to confer clinical benefits in terms of shorter time to recovery and discharge. Hence Remdesivir may be considered as a therapeutic option in the ESRD population with covid 19 infection.

The authors declared no competing interest 

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Supplementary table S1: Institutional protocol for categorization and management of patients with COVID-19 (pdf) Supplementary figure S2: Comparison of oxygen requirement of patients during hospitalisation (pdf) Supplementary figure S3: Survival of patients admitted with moderate and severe disease (pdf

We would like to thank the Dean and all the members of COVID care team of Madras Medical College & Rajiv Gandhi Government General Hospital, Chennai, India