Antiviral medicines and COVID-19: a 2020 wrap up

An update on the current evidence for remdesivir, lopinavir/ritonavir and oseltamivir

Please note: Information, evidence and advice relating to COVID-19 is constantly changing. The information in this article was correct at the time of writing.

In the months following the announcement of the COVID-19 pandemic, researchers across the globe began investigating different medicines in the search for a potential COVID-19 treatment or prevention.

One group of medicines initially thought to hold strong potential were antiviral medicines that had previously been used to treat other viral illnesses including HIV and Ebola virus.1

In May 2020, NPS MedicineWise published an article that considered the then-current evidence for remdesivir, lopinavir/ritonavir and oseltamivir.

Below is an update to the evidence presented in that article.

 

Oseltamivir (Tamiflu)

While a number of clinical trials involving oseltamivir have been conducted or are still ongoing,2 current research does not support the use of oseltamivir as a treatment for COVID-19.3

NPS MedicineWise will not provide further updates regarding this medicine for this indication at this time.

 

Lopinavir in combination with ritonavir (Kaletra)

A number of clinical trials involving lopinavir in combination with ritonavir for the treatment of COVID-19 have been conducted or are still ongoing.2 Evidence from available clinical research does not support the use of this combination medicine as a treatment for COVID-19.4-7 

The National COVID-19 Clinical Evidence Taskforce advises against the use of lopinavir/ritonavir for COVID-19, although it may still be considered in the context of randomised trials with appropriate ethical approval.4

NPS MedicineWise will not provide further updates regarding this medicine combination for this indication at this time.

 

Remdesivir

Remdesivir is an antiviral medicine that inhibits viral RNA synthesis. Before the COVID-19 pandemic, clinical experience was in the context of treatment for Ebola virus infection.8

In vitro studies have reported that remdesivir is active against a number of novel coronaviruses including SARS-CoV-2.9,10Across the globe, trials continue to investigate remdesivir (alone and combination with other agents) as a treatment for COVID-19.2

Documented experience in the COVID-19 setting for remdesivir currently includes compassionate use*, small case reports, randomised open-label trials and randomised placebo-controlled trials.6,11-17 These studies vary greatly in subject numbers, severity of disease, length of follow up and findings of efficacy.

For example, the largest of these trials (the WHO Solidarity Trial, n= 5451) concluded that remdesivir had no definite effect on the primary outcome of in-hospital mortality for patients hospitalised with COVID-19, when compared with local standard of care (control).6 In the next largest trial (ACTT-1**, n = 1062) the primary outcome was time to recovery for patients hospitalised with COVID.16 Treatment with remdesivir was associated with a reduction in median time to recovery when compared to placebo (10 days vs 15 days; rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001).16 In ACTT-1 mortality was a secondary outcome, and varied considerably according to baseline severity.16

Such heterogeneity contributes to the lack of consensus among key guidance groups regarding the use of this medicine.

In Australia, the National COVID-19 Clinical Evidence Taskforce’s current position on remdesivir is a conditional recommendation for use among adult patients (including those who are pregnant or breastfeeding) who are hospitalised with moderate to severe COVID-19 and do not require ventilation.4 The agent is not recommended for use in these patient groups if ventilation is required, and should not be considered for use in children or adolescents with COVID-19 outside of a clinical trial setting, and only then in exceptional circumstances and in consultation with an appropriate clinical reference group.

This position varies from that of the WHO, which offers a conditional recommendation against the use of remdesivir in hospitalised patients, irrespective of disease severity.18 Differences in the way the two groups have approached data analyses and assessed evidence explains the variation.19

The safety profile for remdesivir is incompletely characterised in humans, as use remains limited. According to the WHO Collaborating Centre for International Drug Monitoring, data reported up to September 2020 indicates that kidney and liver function disturbances and skin reactions appear to be common for remdesivir.20 Cases of acute pancreatitis, linked to remdesivir, are also of interest.20

In May 2020, based on modest improvement in time to recovery reported by the ACTT – 1 trial, remdesivir was granted emergency use authorisation (EUA) for patients with severe COVID-19 in the US.22 In October 2020, following release of the final ACTT-1 findings, the FDA granted approval for use of remdesivir in adults and children over 12 years of age weighing at least 40 kg that require hospitalisation.23

During 2020, approvals for remdesivir were also granted in other countries including Australia, the European Union, Japan, Singapore and the UK.22,24,25,26-28

Remdesivir in combination with baricitinib

Findings from ACTT-2 published in December 2020 reported that in 1033 adults hospitalised with COVID-19, a combination treatment of remdesivir and the anti-inflammatory rheumatoid arthritis medicine baricitinib, reduced time to recovery by one day compared with remdesivir alone (median of 7 vs. 8 days; rate ratio for recovery, 1.16; 95% confidence interval [CI], 1.01 to 1.32; P=0.03).29 A larger eight-day difference was observed among a subgroup of 216 patients who required high-flow oxygen or non-invasive ventilation at enrolment (median of 10 vs 18 days for combination vs control; rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). Patients from this same subgroup were also the most likely to experience the secondary outcome of improved clinical status at day 15 when treated with the combination (odds ratio, 2.2; 95% CI, 1.4 to 3.6). Based on this data, and the experience of baricitinib for rheumatoid arthritis, the FDA has granted EUA for this treatment combination for adults and paediatric patients 2 years of age or older, hospitalised with COVID-19 and requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).30

In Australia, recommendations have not been made yet on the available evidence regarding the use of baricitinib, with or without remdesivir, for the treatment of COVID-19.4,31

Baricitinib is approved as a treatment for some Australians living with rheumatoid arthritis. People prescribed this medicine for an indicated condition should continue to take it as advised by their treating doctor, and should also continue to follow COVID-19 safe procedures as outlined by Commonwealth and local Departments of Health.31

* a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available (FDA definition provided as this was a US-based study).21

** Adaptive Covid-19 Treatment Trial

 
 

References

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  24. Gilead Sciences Inc. Gilead Announces Approval of Veklury® (remdesivir) in Japan for Patients With Severe COVID-19. Foster City, California: Gilead Science Inc, 2020.
  25. Therapeutic Goods Administration. Australia's first COVID treatment approved. Canberra: Australian Government, Department of Health, 2020.
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  28. Health Sciences Authority. HSA Grants Conditional Approval of Remdesivir for Treatment of COVID-19 Infection. Singapore: 2020.
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  31. Australian Rheumatology Association. Information for people with Rheumatoid and other Inflammatory Arthritis, Systemic Lupus Erythematosus (SLE) and other Autoimmune Diseases in the COVID-19 (Coronavirus) pandemic. ARA, 2020.