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25th October 2022
Use of remdesivir for patients hospitalised with COVID-19 does not reduce the risk of continued symptoms after one year any more than standard care according to the findings of a study by Finnish researchers.
Though the majority of patients make a full recovery after infection with COVID-19, a proportion continue to experience what has been defined by the World Health Organisation (WHO) as post-COVID-19 condition. Throughout the pandemic it has become increasingly recognised that after an acute infection, patients continue to experience symptoms or develop new ones. While post-COVID-19 condition is the WHO preferred term, the persistence of symptoms has also been referred to as the short-term and long-term persistent post-acute sequelae of COVID-19 (PASC). Using this definition, a 2021 systematic review that included 57 studies with 250 351 survivors of COVID-19 found that more than half experienced PASC 6 months after recovery.
Treatment of COVID-19 with the anti-viral agent remdesivir in hospitalised patients is effective and reduces mortality for non-ventilated patients with COVID-19 requiring supplemental oxygen therapy. However, given that post-COVID-19 condition occurs in a number of patients, an equally important question is whether treatments such as remdesivir would reduce the risk of developing post-COVID-19 condition? One Italian observational study of 449 hospitalised patients found that use of remdesivir was independently associated with a reduced risk of what the authors referred to as ‘long-COVID syndrome‘. Nevertheless, no other studies have addressed this question and there remains a high level of uncertainty over whether vaccines or in fact, any treatments reduce the risk of post-COVID-19 condition.
In the present study, the Finnish researcher sought to try and answer this question for remdesivir in the SOLIDARITY trial, which was designed to examine the effects of remdesivir plus standard of care (SoC) compared to SoC alone, on post-COVID-19 condition, at one- and two-years post-discharge from hospital. The trial recruited adult patients with a PCR-confirmed diagnosis of COVID-19 and who received remdesivir 200 mg on the first day and then 100 mg daily until discharge or for a maximum of 10 days with SoC or SoC alone. In the follow-up, participants self-completed questionnaires to assess long-term recovery based on continued symptoms and quality-of-life measures.
Remdesivir recovery at 12 months
The SOLIDARITY trial recruited a total of 208 patients with a mean age of 58.3 years (64% male) were recruited and randomised to remdesivir (114) or standard care. After one year, data were available for 181 survivors although at this point in time, 4.4% of the remdesivir group and 5.3% in the standard of care group had died (relative risk, RR = 0.82, 95% CI 0.25 – 2.76).
Self-reported full or largely full, recovery occurred in 85% of those in the remdesivir arm and 86% in the standard of care group (RR = 0.94, 95% CI 0.47 – 1.90). In addition, a similar proportion (15.3% vs 14.5%) of participants reported that they were about halfway recovered to not recovered at all.
Moreover, exertional dyspnoea was experienced by a similar proportion in both groups (RR = 0.61, 95% CI 0.20 – 1.85) and there were similar scores between the two groups for all quality-of-life domain scores.
The authors concluded that there were no discernible effects of remdesivir on long-term recovery, quality of life or long-COVID-19 symptoms. However, they added that since the confidence intervals were wide this included evidence of substantial benefit and harm.
Nevalainen OPO et al. Effect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial Nat Commun 2022
17th October 2022
The anti-viral drug remdesivir was the first medicine against COVID-19 to be recommended for authorisation in the European Union for adults and adolescents (from 12 years of age and weighing at least 40 kilograms) with pneumonia requiring supplemental oxygen (low- or high-flow oxygen or other non-invasive ventilation at the start of treatment). However, according to the summary of product characteristics of the drug, remdesivir should not be used in patients with eGFR < 30 mL/min. Nevertheless, death from COVID-19 has been reported to be as high as 30.5% among haemodialysis patients highlighting the need to improve the prognosis of this patient cohort after infection with the virus. In an observational study of 48 haemodialysis patients infected with COVID-19, when remdesivir was given at a dose of 100 mg 4 hours before the dialysis sessions, there were no significant effects on liver function tests. In addition, more than two-thirds of patients showed an improvement in oxygen requirement and the duration of hospital stay was reduced to a mean of 5.5 days.
With a suggestion that the drug was potentially safe and likely to be effective in patients with reduced renal function, for the present study, Korean researchers examined use of the drug in hospitalised patients receiving haemodialysis. The drug was given at a loading dose of 100 mg and then 50 mg for the next 2 to 4 days depending on the patient’s status. The primary outcome was a composite of in-hospital mortality, use of a high-flow nasal cannula or transfer to an intensive care unit.
Haemodialysis patients and COVID-19 outcomes
A total of 118 patients with a mean age of 68.5 years (66.1% male) were included in the analysis and of whom, 44 (37.3%) received remdesivir.
The composite primary outcome occurred in 2.3% of the remdesivir group and 13.5% of those not given the drug (p = 0.042). In addition, disease worsening was also lower (6.8% vs 20.3%, p = 0.049) in the remdesivir group.
In regression analysis, remdesivir use was independently associated with a lower occurrence of the primary outcome (adjusted odds ratio, aOR = 0.01, 95% CI 0.001 – 0.31, p = 0.009) and disease severity worsening (aOR = 0.08, 95% CI 0.02 – 0.42, p = 0.003).
The authors also reported no anaphylaxis or hypersensitivity reactions to the drug and that the incidence of liver enzyme elevation during hospitalisation did not significantly differ between the groups (22.7% vs 17.6%, p = 0.494).
They concluded that remdesivir was safe to use in haemodialysis patients and was associated with better clinical outcomes and a reduced risk of disease worsening.
Lim JH et al. Clinical Effectiveness and Safety of Remdesivir in Hemodialysis Patients with COVID-19 Kidney Int Rep 2022
12th April 2022
Remdesivir use among patients hospitalised with COVID-19 requiring ventilator or oxygen support did not improve clinical outcomes after 15 days compared with standard care. This was the conclusion of a European, multi-centre, open label, randomised, controlled trial.
Remdesivir is a pro-drug that is converted into a nucleoside analog and incorporated by the RNA-dependent RNA polymerase of COVID-19 into the growing RNA product before RNA synthesis stalls. The drug was approved by the EMA in June 2020 for the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen. Moreover, early data on remdesivir was encouraging and in a study of over 1000 patients, those randomised to remdesivir use had a median recovery time of 10 days compared with 15 days in those who received placebo. In contrast, however, the World Health Organization (WHO) Solidarity Trial, concluded that remdesivir, along with hydroxychloroquine, lopinavir and interferon regimens, had little or no effect on hospitalised patients with COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay.
With such conflicting results, the European team undertook the DisCoVeRy trial and which was designed to evaluate the safety and efficacy of possible therapeutic agents in hospitalised adult patients diagnosed with COVID-19. Recruited patients were adults hospitalised with COVID-19 who presented with either evidence of rales/crackles on examination and a SpO2 < 94% on room air or had a requirement for supplemental oxygen, high flow oxygen devices, non-invasive ventilation and/or mechanical ventilation. Patients were randomised 1:1 to either remdesivir use (200 mg on day 1 followed by a 100 mg 1-hour infusion once daily for 10 days) or standard care, which included the use of corticosteroids and anticoagulants. The primary outcome was the patient’s clinical status at day 15 as recorded on the 7-point ordinal WHO scale. The scale, which represents increasingly severe disease, ranges from 1 represented those not hospitalised and with no limitation on activities, through 5 (hospitalised on non-invasive ventilation or high flow oxygen) and 6 (hospitalised on invasive mechanical ventilation or extracorporeal membrane oxygenation) and 7 (dead). Several secondary outcomes were also used including in-hospital mortality and 28-day mortality.
Remdesivir use and clinical outcomes
A total of 857 participants with a median age of 64 years (69.5% male) were randomised to remdesivir (420) or standard care and, at randomisation, 39.4% of individuals had severe COVID-19.
Overall, 73.6% of participants had at least one co-morbidity with the most frequent being obesity (34.1%), cardiac disease (28%) and diabetes (27%).
At day 15, a similar proportion of those assigned to remdesivir and standard care were categorised as 1 on the WHO scale (14.8% vs 17%, remdesivir vs standard care) and a similar proportion had died (5% vs 6%). Overall, there was no significant difference between those assigned to remdesivir use or standard care (odds ratio, OR = 1.02, 95% CI 0.62 – 1.70, p = 0.93). Additionally, there were no significant differences in the distribution of the 7-point scale at day 29 (OR = 1.11, 95% CI 0.87 – 1.43, p = 0.40).
Furthermore, there were no significant differences for each of the secondary outcomes or subgroup analyses according to age, sex, duration of symptoms prior to randomisation or in the level of detectable viral loads at each sampling time.
The authors therefore concluded that the remdesivir use had no impact on clinical outcomes compared with standard care at either day 15 or day 29.
30th November 2020
On 19 November, 2020, the FDA gave emergency use authorisation for the baricitinib combination therapy to be used in patients hospitalised with either confirmed or suspected COVID-19, from 2 years of age and who require mechanical ventilation, supplemental oxygen or extracorporeal membrane oxygenation.
The approval is based on preliminary results from the ACCT-2 trial, which compared the recovery time in patients receiving either remdesivir alone or in combination with the JAK STAT inhibitor, baricitinib at a dose of 4mg. Remdesivir is already approved by the FDA as an antiviral drug for hospitalised COVID-19 patients, aged 12 years and over. Baricitinib is currently only licensed for use in rheumatoid arthritis but since the drug blocks the JAK-STAT intracellular messaging system, which is an important inflammatory pathway, there was a potential benefit from combining the two drugs. ACCT-2 was a Phase III trial that enrolled 1033 participants, who were randomised to either intravenous remdesivir alone plus matching placebo (518) or oral baricitinib (515). Remdesivir was given as a loading dose of 200mg, followed by 100 mg daily while in hospital, for up to 10 days. Baricitinib was given at a dose of 4mg per day and limited to a maximum of 14 days. All patients were assessed daily and if discharged, they were followed-up at home on days 15, 22 and at the study endpoint, day 29. Recovery from COVID-19 was defined as either being discharged from hospital, no longer requiring supplemental oxygen or needing ongoing medical care.
Preliminary data published from the trial showed that the median time to recovery with remdesivir and baricitinib was one day shorter (7 vs 8 days) than using remdesivir alone and this difference was statistically significant. In addition, the odds of a clinical improvement at day 15 using the combined therapy was also found to be significantly lower. Under the emergency use authorisation, the manufacturer of baricitinib, Eli Lilly, is required to provide both health professionals and patients, fact sheets which include information on dosing, side-effects and drug interactions. The full results of the ACCT-2 trial will be published in due course.
30th October 2020
The approval requires that remdesivir is only used in a hospital or healthcare setting capable or providing acute care which is comparable to hospital care. This new approval does not however, include the entire population that was originally included via the emergency use authorisation (EUA) issued on 1 May 2020. In order to allow continued use in paediatric patients the EUA was amended for use only in laboratory confirmed COVID-19 cases for patients weighing 3.5 to less than 40kg less or hospitalised children under 12 years of age weighing at least 3.5kg. However, the FDA makes clear that this is NOT an approved use of the drug and that this authorisation is only temporary and could be revoked.
The approval in adults was based on three randomised clinical trials which showed that treatment with remdesivir lead to clinically meaningful improvements across multiple outcomes compared to placebo. For instance, in the most recent ACTT-1 trial, published in the New England Journal of Medicine, remdesivir significantly improved time to recovery by 5 days and reduced disease progression among patients requiring oxygen. It also showed an improved time to recovery among patients not requiring oxygen in the SIMPLE-Moderate trial conducted in hospitalised patients. Moreover, adverse effects with remdesivir were similar to placebo.
Remdesivir was approved under the early access to medicines scheme in the UK in May 2020.
FDA News release. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-covid-19