|Year : 2021 | Volume
| Issue : 4 | Page : 244-249
Comparative therapeutic efficiency of remdesivir in COVID in a tertiary care center
Mahendra Munirathnam, R Kishore, SN Sanjana, R Archita, CN Mohan, Preethi Rajeshwari Gandhi, Manjushree Mohan, Bhahuddin Mulla
Department of Medicine, Bowring and Lady Curzon Hospital and Research Institute, Bengaluru, Karnataka, India
|Date of Submission||12-Jan-2021|
|Date of Decision||11-Feb-2021|
|Date of Acceptance||01-May-2021|
|Date of Web Publication||20-Oct-2021|
Dr. Mahendra Munirathnam
No. 44, 4th Main, 4th East Cross, Riches Garden, Kalkare Road, Rammurthy Nagar, Bengaluru - 560 016, Karnataka
Source of Support: None, Conflict of Interest: None
Introduction: The catastrophic effects of corona in 2020 identified the use of broad-spectrum antiviral remdesivir (RDV). The beneficial effects of RDV are not proven and documented in many trials in COVID. Materials and Methods: Reverse transcriptase–polymerase chain reaction (RT-PCR)-confirmed cohort cases of COVID were retrospectively analyzed for outcomes including mortality and clinical improvement with and without RDV during the period September 21, 2020–October 9, 2020. The data were analyzed statistically for outcome in COVID. The present study was carried out to evaluate the clinical benefits of RDV and its outcomes in COVID. Results: A total of 91 RT-PCR positive COVID patients were grouped into 37 RDV (41%) and 54 non-RDV (51%). The mean age was 51 and 55. Male-to-female ratio of 67:32 and 65:35 in the RDV and non-RDV groups was found, indicating male predominance in the study. The recovery time for COVID was 11 days with a cure rate of 78% in the RDV group, while it was 21 days with 98% in the non-RDV group. A statistical significant association was found between RDV and the need for oxygen support (hypoxic patients) and noninvasive ventilation (NIV). Twenty-seven percent in RDV group needed NIV (P = 0.009). Morbidity and mortality were 19% (7) and 22% (8) and 7% (4) and 2% (1) in the RDV and non-RDV groups, respectively. Conclusion: RDV use in COVID was associated with increased mortality (22% vs. 2%) but reduced duration of hospitalization by 50% as compared to non-RDV group. Early identification of hypoxia plays an important role in COVID management for initiating RDV treatment.
Keywords: COVID, hypoxia, remdesivir
|How to cite this article:|
Munirathnam M, Kishore R, Sanjana S N, Archita R, Mohan C N, Gandhi PR, Mohan M, Mulla B. Comparative therapeutic efficiency of remdesivir in COVID in a tertiary care center. APIK J Int Med 2021;9:244-9
|How to cite this URL:|
Munirathnam M, Kishore R, Sanjana S N, Archita R, Mohan C N, Gandhi PR, Mohan M, Mulla B. Comparative therapeutic efficiency of remdesivir in COVID in a tertiary care center. APIK J Int Med [serial online] 2021 [cited 2021 Nov 29];9:244-9. Available from: https://www.ajim.in/text.asp?2021/9/4/244/328673
| Introduction|| |
Remdesivir (RDV) was first described in 2016, from the stock of reserved antiviral molecules intended to use against emerging infective RNA viruses. Therapeutic benefit of RDV was proved in vivo animal models of EBOV, MERS-CoV, SARS CoV1, and SARS CoV2 infections. RDV is a broad-spectrum antiviral drug and FDA approved its use for COVID in May 2020. RDV was included in most guidelines for COVID treatment.,,,,,,,,,,,,,,,,,,,,
There were many clinical studies of remdesivir use in COVID proving efficacy
The Wuhan clinical trials
RDV was not associated with substantial clinical improvement in the treatment arm compared to the placebo (hazard ratio [HR] = 1.23, [95% confidence interval [CI], 0.87–1.75]). Furthermore, there was no statistically significant difference between groups regarding mortality and time to viral clearance. In a subset of patients who were treated early within 10 days of symptom onset, RDV was associated with a numerical median reduction of 5 days in the time to clinical improvement, but this finding was not statistically significant (HR, 1.52 [95% CI,0.95–2.43]).
The adaptive COVID treatment trial (ACTT) treatment with RDV was associated with a reduction in the time to recovery from a median of 15–11 days (recovery rate ratio [RRR], 1.32 [95% CI, 1.12–1.55] [P = 0.001]). This consequence was independent of symptom duration prior to randomization. However, subset analyses showed that patients with the need for oxygen therapy (ordinal score of 5) profit most from the treatment (RRR, 1.47 [95% CI, 1.17–1.84] [n = 421]), while no effect could be illustrated for patients on invasive ventilation and/or extracorporeal membrane oxygenation (ECMO). The mortality rate at 14 days was 7.1% (RDV) versus 11.9% (placebo), which was not statistically significant (HR, 0.7 [95% CI]), RCT trial from National Institute of Allergy and Infectious Diseases published in April 2020 showed RDV effects in COVID mortality 8% versus 11.6% in the placebo group and recovery was quicker with RDV by 31% (11 vs. 15 days, P = 0.001).Gilead trail mortality with RDV was 7% ([0.47–1.03] [P = 0.06]). The WHO Solidarity Trial showed no effect of RDV in COVID.
| Materials and Methods|| |
During the COVID pandemic days, admitted COVID patients in Charka Super Specialty Hospital (designated COVID hospital under Bowring and Lady Curzon Hospital and Research Center) meeting the inclusion and exclusion criteria were enrolled. Other asymptomatic COVID patients not meeting the criteria were excluded. The RDV treatment group was retrospective cohort of patients receiving RDV and other medications as per the national protocol and the hospital protocol depending on the severity and other supportive of treatment between September 27, 2020, and October 28, 2020; 37 patients who meet the criteria for treatment were collected and analyzed. Non-RDV who did not receive RDV due to failure to receive consent with explanation of risk–benefit ratio of RDV or nonavailability during the period September 21, 2020–October 9, 2020, were analyzed. The history, comorbidities, investigations, outcomes, and exit interview or feedback were collected and data were analyzed. The statistical analysis was done by Independent sample t-test, Chi-square test, and Fisher's exact test. The outcome of COVID in the recent study is measured in the form of cure or recovery, postdischarge oxygen requirement, NIV requirement during stay, complications, death, and duration of hospitalization. The Brixia score, a simple and bedside scoring was done using a chest x-ray to predict Severity and outcome in COVID. Scoring was done by dividing lungs into six zones and score ranging from 0 to 18. Most patients tolerated injection RDV in the treatment group and had no significant adverse drug reactions. In view of studies of RDV in COVID showing no mortality benefit and reduction in days of hospitalization, there is a need to analyze outcomes of COVID mortality, morbidity, and recovery time with and without RDV in the Indian context.
| Results|| |
The study cohort consisted of 91 patients who were admitted and included in the study group between September 2020 and October 2020. Out of 91 patients, 37 (40.7%) patients received RDV and the remaining 54 (49.3%) did not receive it (non-RDV). The median ages of patients in RDV and non-RDV groups were 51 and 55 years, respectively. There was no difference in the mean age of patients in the groups (distribution is the same in both groups). The ratio of male-to-female distribution was 25:12 (67% vs. 32%) and 35:19 (65% vs. 35%) in the RDV and non-RDV groups, respectively. The males' ratio in the study population is significantly higher in both RDV and non-RDV groups in COVID. The comorbidities observed in the study population were diabetes, hypertension, and chronic obstructive pulmonary disease (COPD). The presence of comorbidities was greater in the RDV group (56.8%) when compared to non-RDV group (42.6%) and the distribution of comorbidities was not significant. No statistically significant difference was observed between the two groups when it came to the presence of comorbidities, day of worsening, and the Brixia score as a measure of disease severity.
Comparisons of symptoms
In the RDV group and non-RDV Group, fever was the most common symptom with the average duration of 1.7 versus 2.3 days, followed by cough of 2.2 versus 1.66 average day duration. Anosmia and myalgia were present in 16.6% vs. 8% and atypical symptoms such as diarrhea were present in 5.5% versus 8%. The average respiratory rate in the RDV group was 31 (27–42) versus 30 (22–44) in the non-RDV group and average saturation was 82 (<92) versus 87 (<92). Of the comorbidities, diabetes contributed to 31.5% (17) versus 54% (20), hypertension 18.5 (10) versus 30 (11%), and COPD in 3.7% (2) versus 2.7% (one case). Blood pressure was increased in 7 versus 5 cases on admission and only normal in 3 versus 6 cases only. The average day of worsening was 1.88 days in the non-RDV group (with a maximum of day 3 in 6 cases).
The 34 cases in RDV group were diagnosed with severe acute respiratory infection (SARI) and 3 cases with influenza-like illness and all the 37 cases were administered with RDV along with steroids, low molecular-weight heparin (LMWH), and other supporting drugs as per the institutional protocol. The average Brixia score in RDV group was 10. All the 54 cases in the non-RDV group were diagnosed with SARI with an average Brixia score of 9 [Table 1]. In RDV group, the average day of worsening was 2.24 days [Table 1], and 7 patients had a day of worsening as day 3 and 4 patients had a day of worsening on day 4. In RDV group, 32 patients during hospitalization required oxygen by face mask, 20 required oxygen by high-flow nasal cannula (HFNC), and 10 patients required NIV during hospital stay and 4 patients were put on NIV immediately at time of admission [Table 2]. The most common X-ray finding in COVID is ground glass, intestinal thickening, and consolidation opacities. Following treatment, during hospitalization in RDV group, 7 cases developed complications – 6 cases acute respiratory distress syndrome (ARDS) and 1 case developed ST-elevation myocardial infarction (STEMI). The average duration of stay in the RDV group (n = 37) was 10.45 days and the total number of death was 8 [Table 3]. The average duration of hospitalization in recovered cases (n = 29) with RDV was 10.93 and the average duration of hospitalization in death cases (n = 8) with RDV was 8.12.
|Table 2: Distribution of need for supportive care based on treatment with remdesivir|
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In the non-RDV group, the average day of worsening was 1.89 days [Table 1], with day-3 worsening seen in 6 patients and day-4 worsening seen in 1 patient. At the time of admission, 2 cases required oxygen, 32 required oxygen by face mask, 20 required oxygen by HFNC, 10 required NIV, and 4 cases requiring oxygen were put on NIV at the time of admission. Following treatment, 7 cases develop complications – 6 developed ARDS and 1 non-STEMI (NSTEMI). The average duration of stay in the treatment group was 20.78 days. The total number of deaths was only 1 [Table 3].
In non-RDV group, on admission, 35 required oxygen by face mask, 15 by HFNC, 4 NIV, and 1 patient was put on NIV. Following treatment, 4 cases developed complications – ARDS. The average duration of stay in the control group was 21 days and the total number of death was 1.
A statistically significant association was found to exist (P < 0.05) between the need for face mask, HFNC, and NIV with RDV treatment [Table 2]. About 27% of patients receiving RDV required NIV as compared to 7.4% in non-RDV group. Similarly, the need for HFNC and face masks with oxygen was also greater in those patients who received RDV, 54.1% and 86.4%, respectively. However, no statistically significant association was found with the need for ventilator support and RDV (P = 0.071).
Patients who received RDV were found to have more complications [Table 1] than those who did not receive it. Duration of hospital stay was found to be significantly longer in the non-RDV group than the RDV group (P < 0.001). The mean duration of hospital stay in RDV group was 10.5 ± 3.7 days and the non-RDV group was 20.78 ± 5.4. The mean Brixia score was 10.32 in RDV group and 9.0 in non-RDV group and was not significant. In patients receiving RDV, 18.9% ended up with complications, whereas only 7.4% in non-RDV group suffered from complications (P = 0.098). The main complications observed were NSTEMI (only 1 in RDV group) and ARDS, 6 had ARDS in RDV group and 4 in non-RDV group. The proportion of patients with comorbidities who recovered or cured was greater in the non-RDV group 100% (23/23) than the RDV group 76% (16/21). The mortality and morbidity were more in the RDV group (5 vs. 0, 24% vs. 0%). The relationship of comorbidities with treatment was found to be statistically significant (P < 0.005) in the present study. The outcome measure in RDV group with comorbidities was also measured as the average duration of hospitalization in death cases (n = 8) which was 8.12 days and complications rate was 7/37 (19%).
| Discussion|| |
RDV reduced time to clinical improvement or duration of hospitalization significantly in the present study in treatment with RDV by 50% (11 vs. 21 days). This finding should be expected to confirm or refuted in further studies. Animal studies with RDV have shown decreased lung SARS-CoV-1 titers but did not decrease disease severity or mortality.,, RDV was not associated with significant clinical benefits but reduced time in clinical improvement (in subgroup analysis) as per Wang et al.
Increased mortality associated with the use of RDV was observed in the present study: 8 cases in RDV group (22%) and 1 case in non-RDV group (2%). The outcome of severe COVID is uncertain and cannot be predicted. The average LDH and C-reactive protein (CRP) biomarkers were increased in the RDV group in death and complicated cases. The markedly increased CRP and marginally increased LDH in the RDV group may explain the pathogenesis and immune response role in morbidity and mortality cases.
The mortality rate in the present study was 22% (8/37) in the RDV group and all 8 cases had moderate-to-severe COVID clinically and radiologically (Brixia score >14). All cases with mortality had oxygen requirement of 3–6 L/min at the time of admission and later changed to HFNC and NIV during hospitalization. All these cases had CRP of more than 100 mg/L and increased LDH at the time of admission. In 2 out of 8 death cases, death was around 8th day and total count was in normal limits; however in the remaining 6 death cases, it was around 12th day of admission and 2 of them had leukopenia (Total count <1200) at admission. Early death may be probably due to cytokine storm and the timing of RDV is a more important factor in COVID management. Late or inappropriate use of RDV in the inflammatory phase would have caused cytokine activation and triggered or worsened by RDV. Further studies are needed to follow-up markers of cytokine activation in COVID and role of inhibitors of cytokine activators.
The complications such as ARDS, myocarditis, STEMI, and arrhythmias are attributed to increased viral load, severe COVID disease, abnormal immune response, and late start of RDV. Degradation of cells infected with coronavirus produces inflammatory mediators which may lead to systemic complications and death. Cardiovascular manifestations influence the outcome in COVID as per the case report published. Other complications such as coagulation in COVID diseases and thrombosis are not reported due to early treatment with steroids and LMWH. Steroid use may also cause flaring of infections.
In non-RDV group, the average Brixia score was more with a marginal increase in D-dimer and ferritin, but the complication rate was 7% (4/54) and death rate was 2% (1/54).
RDV has a significant role in COVID outcome in background of nonspecific antiviral options as a treatment for the corona virus- Jomah et al. RDV showed a shorter timeto discharge (11 vs. 15 days) and risk of death by 14 days was reduced (7.1 vs. 11.9) as per Beigel et al., NEJM. A benefit of early treatment that prevents progression of severity and death is documented by Kaddoura et al. in Frontiers in Pharmacology. RDV reduces time to recovery by 31% reflected by reduction in hospitalization days as per Malin in clinical microbiology reviews. The ACTT-1 study showed no significant mortality benefits. Reduction in time to recovery is decreased from 15 to 11 days (HR: 1.32) independent of symptom duration. Subgroup analysis showed that hypoxic patients benefit more with RDV, no benefit on mechanical ventilation/ECMO and non-significant mortality rates HR 0.73 (6.7% in RDV vs. 11.9% in control group). Compassionate use experienced by Gilead sciences showed 68% clinical improvement, no efficiency statement made as no control group. In February 2020, Phase 3 clinical trials in Wuhan did not show any significant clinical improvement with RDV (HR1.23), and also no significant difference in mortality and time to viral clearance. However, subgroup analysis of Wuhan study showed non-significant decreased time to clinical improvement (HR 1.52).
As COVID patients move through the course of the disease, long-term outcomes of ARDS, thrombosis, and lung infiltrations are seen and reported. With LMWH treatment and oxygen, the vascular thrombosis and vascular complications would have altered during the course of treatment. The COVID-19 severity is measured clinically by systemic manifestations and indirectly by laboratory parameters-CRP, erythrocyte sedimentation rate, D-dimer, ferritin, and chest radiograph scoring.
In COVID patients with hypoxia, RDV treatment produces clinical improvement and in the present study, cure rate (CR) was 78% in the RDV group and 98% in the non-RDV group. The patients requiring home oxygen at the time of discharge were 11% in the RDV group and 15% in non-RDV group. Increased complications and death rates (n = 8) in the present retrospective observation study should be refuted from large randomized control studies.
Early treatment of COVID patients with RDV when hypoxia develops benefits COVID outcomes because of nonspecific mechanism of action of the drug (as refuted from other studies). Identifying hypoxia in COVID by monitoring respiratory rate, saturation pulse rate, breathlessness on exertion, 6-min walking test, and limitation of activities of daily life physically is important. CR s was 78% with RDV in the present study and recovery time was decreased. RDV improved clinical and psychological benefit as measured by analysis of the feedback and exit interview at the time of discharge and counseling.
RDV treatment has no effect on mortality or progression of the disease if started late in course of the disease due to systemic effects of the virus, as reported in Solidarity Trial. The small effect of RDV on time to recovery is also explained by Solidarity Trial which is probably due to early and timely treatment with RDV which inhibits RdRp nonspecifically before systemic effects of the virus are noticed. The comorbidities in the study constituted 56.8% and 42.6% in the RDV and non-RDV groups, respectively. In comorbidities, CR was 76% (16/23) and 100% (23/23) and mortality was 24% (5) and 0% in RDV and non-RDV groups, respectively. Comorbidities are another risk factor with RDV use in COVID because of increased angiotensin-converting enzyme 2 expression, interleukin-6, and impaired T-cell function.
Increased path physiological disturbances due to the systemic effects of corona complications cannot be prevented even with RDV treatment as increased cytokines and intracellular signaling pathways are activated as evidenced by decreased lymphocytes and cytokine storm in certain COVID patients contributing to mortality and morbidity, hence need to identify early disease and treatment.
Limitations of this study
The limitations of this study included small sample size, retrospective study, and nonrandomization. This study population includes patients admitted from one tertiary care hospital in Bengaluru and data collected from hospital records and followed up. Subgroup analyses of comorbidities with COVID were unadjusted for confounding factors. No information on other viral diseases during the peak COVID pandemic days was assumed during treatment.
| Conclusion|| |
RDV increases mortality by more than 9 fold but reduced duration of stay or hospitalization by 50%. The non-RDV group though associated with high biomarkers of inflammation had better outcomes. CR was 78% with RDV in the present study and recovery time was decreased by 50% with RDV treatment.
The presence of comorbidities increased chance of COVID infections and influenced the outcomes with increased mortality rates with RDV treatment. The present study suggests that early RDV treatment in hypoxic patients benefits in reduction of recovery time as refuted from other studies. Increased pathophysiological disturbances due to systemic effects of corona complications cannot be prevented even with RDV treatment. Furthermore, strategies and large sample size are needed to enhance outcome measures.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]