Antiviral medicines and the treatment of COVID-19

A range of antiviral medicines are currently being trialed as potential treatments for COVID-19 infection.

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.

Update 25 October 2021

On 15 October 2021, the Therapeutic Goods Administration (TGA)  provisionally approved the combination monoclonal antibody treatment casirivimab + imdevimab (Ronapreve) by Roche Products Pty Ltd for the treatment of COVID-19. 

The provisional approval is for the treatment of COVID-19 in adults and adolescents (aged 12 years and over and weighing at least 40 kg) who do not require supplemental oxygen for COVID-19 and who are at increased risk of progressing to severe COVID-19.

Ronapreve is a combination of two monoclonal antibodies – casirivimab and imdevimab. It is designed to block infectivity of the SARS-CoV-2 virus, which causes COVID-19. The two monoclonal antibodies bind to two different sites of the SARS-CoV-2 spike protein and flag the virus as ‘foreign’, prompting the body’s immune response.

Ronapreve can be administered intravenously in a healthcare facility and is expected to be targeted for use in unvaccinated people who are at risk of developing severe disease.

Ronapreve has been shown to reduce the risk of severe infection and hospitalisation by up to 70.4% in patients with confirmed COVID-19 compared with placebo.

Update 31 August 2021

On 20 August 2021, the TGA granted provisional approval to GlaxoSmithKline (GSK) Australia Pty Ltd for its COVID-19 treatment, sotrovimab (Xevudy). 

Sotrovimab is a monoclonal antibody that has been shown to reduce hospitalisation or death in patients with mild-to-moderate COVID-19 who do not require supplemental oxygen and are at high risk of progression to severe disease.

A range of different medicines to prevent and treat COVID-19 are at various stages of development in Australia and internationally. Potential COVID-19 treatments fall into three broad categories:

  • Antiviral treatments – these treatments stop the SARS-CoV-2 virus from replicating and causing more severe disease.
  • Immune modulators – help the immune system fight COVID-19.
  • Monoclonal antibody treatments – prevent the SARS-CoV-2 virus from invading cells and causing more serious disease.

The following have been provisionally approved by the TGA

  • regdanvimab (Regkirona)
  • tocilizumab (Actemra)
  • casirivimab + imdevimab (Ronapreve)
  • sotovimab (Xevudy)
  • remdesivir (Veklury). 

Several medicines are currently under evaluation by the TGA, including molnupiravir, PF-07321332 + ritonavir, and tixagevimab and cilgavimab (Evusheld).

Update on remdesivir

The TGA granted provisional approval of Gilead Sciences Pty Ltd's antiviral treatment, remdesivir (Veklury) on 10 July 2020, for use in adults and adolescent patients with severe COVID-19 symptoms who have been hospitalised. Remdesivir has been shown to reduce hospitalisation time for those suffering from severe COVID-19 and offers the potential to reduce the strain on Australia's healthcare system.

 

What antiviral medicines are being trialed for COVID-19?

Antiviral medicines and COVID-19: a 2020 wrap up

NPS MedicineWise published a wrap up in January 2021 to update the evidence for remdesivir, lopinavir/ritonavir and oseltamivir.

In summary, research investigating lopinavir/ritonavir and oseltamivir did not support the use of these medicines to treat COVID-19.

Read full update

Oseltamivir (Tamiflu)

Oseltamivir phosphate is an oral neuraminidase inhibitor. In its active metabolite form, oseltamivir carboxylate, this medicine is selective for the influenza viruses A and B.4 Oseltamivir is indicated as a treatment for influenza infection, and also as prophylaxis.4

Two early studies describing clinical characteristics of hospitalised patients with COVID-19 pneumonia reported treatment with oseltamivir (likely due to the emergence of the condition during the influenza season).5,6 Patient numbers in these studies were small (n = 41 and n = 99). Outcomes relating to the use of the antiviral oseltamivir were limited. One study made no further mention of outcomes for oseltamivir-treated patients, the other reported no statistical difference between oseltamivir-treated patients who were or were not admitted to the ICU (92% vs. 93%, p=0.46).6

Concomitant use of oseltamivir to treat influenza in patients with confirmed COVID-19 has been described (n = 5) although the clinical benefit of such an approach remains unclear.7

Lopinavir in combination with ritonavir (Kaletra)

Lopinavir with ritonavir (Kaletra) is a combination antiretroviral agent used for treating HIV.8 It has previously demonstrated some antiviral activity against the viruses that cause SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome).9,10

Published results from a randomised, controlled, open-label trial conducted in hospitalised adult patients with confirmed SARS-CoV-2 infection (n = 199) have reported no difference in time to clinical improvement (HR 1.31; 95% CI, 0.95 to 1.80; P=0.09) or 28-day mortality rate (19.2% vs 25.0%; 95% CI, −17.3% to 5.7%) for patients receiving lopinavir with ritonavir compared to standard care.11 Similar lack of effect, and possibly more adverse events, has also been described by small, not yet peer-reviewed, exploratory and pilot studies looking at lopinavir with ritonavir alone or in combination with the antiviral compound arbidol (umifenovir) for hospitalised patients.12,13

Current Australian guidelines advise against using this combination antiviral in people with COVID-19, except in the ‘context of randomised trials with appropriate ethical approval’.2 European guidelines advise against using this medicine combination in critically ill adults with COVID-19, outside of research studies.14

With the lack of clear evidence, more clinical trials are underway to provide more definitive information about whether lopinavir with ritonavir is effective in treating COVID-19.1,11,14

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.15

In vitro studies have reported that remdesivir is active against a number of novel coronaviruses including SARS-CoV-2.16,17Across the globe, there are now a number of trials investigating remdesivir as a treatment for COVID-19.3 Experience in the COVID-19 setting for remdesivir is limited to compassionate use*18, small case reports19,20, a published randomised controlled trial21 and preliminary findings from a large, but as yet, unpublished or peer-reviewed US Adaptive COVID-19 Treatment Trial (ACTT) 22 (see Table 1). These studies vary greatly in subject numbers, severity of disease, length of follow up and clinical outcomes measured.

* Compassionate use: 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. 23

(FDA definition provided as this was a US-based study)

Based on the modest improvement in time to recovery reported by the US ACTT trial, remdesivir has been granted authorisation, for emergency use for patients with severe COVID-19 in the US, and regulatory approval in Japan as a treatment for SARS-CoV-2 infection.24,25 Remdesivir was provisionally approved in Australia in July 2020. 

Given the heterogeneity among the data, reported outcomes are mixed and a definitive recommendation cannot yet be made for remdesivir. Australian guidelines for the clinical care of people with COVID-19 recommend consideration of remdesivir in adults hospitalised with moderate to severe COVID-19 who do not require ventilation. The Taskforce gives a conditional recommendation for remdesivir both within and outside the context of a randomised trial.2

Table 1. Clinical data on remdesivir in COVID-1918,21,22,28

Reference Type of study Main results Comments

Grein et al

Case series of compassionate use

N = 53 patients

(22 Europe/Canada, 22 US, 9 Japan)

Remdesivir i.v. as single daily infusion; 200 mg day 1, 100 mg days 2-10

During a median follow-up of 18 days:

- 36/53 patients showed clinical improvement (as measured by oxygen-support requirements)

- 17/30 patients receiving mechanical ventilation were extubated

- 7/53 patients died

- 32/53 patients had at least 1 adverse event.

Designed, conducted and funded by Gilead Sciences.

Limitations of study include small cohort numbers, short follow up, potential missing data including loss of 8 patients from follow up.

Moreover, without a randomised control group it is difficult to identify improvement due to other concomitant treatments or even natural history of the condition over the impact of remdesivir.
Wang et al

Randomised, double-blind, placebo-controlled, multicentre trial

N = 236 patients

Remdesivir i.v. vs remdesivir placebo i.v.- as single daily infusion; 200 mg day 1, 100 mg days 2-10

Primary endpoint: time to clinical improvement up to day 28.

Outcome: remdesivir use was not associated with a statistically significant difference in time to clinical improvement compared with placebo (HR 1·23 [95% CI 0·87–1·75]).

Adverse events were reported in 102 of 155 (66%) in the remdesivir group and in 50 of 78 (64%) in the placebo group.

Treatment stopped early due to adverse events in 18 (12%) patients receiving remdesivir and 4 (5%) patients receiving placebo.

First RCT for remdesivir in adults with COVID-19.

Limitations include the study being under-powered to detect differences due to small cohort numbers, early termination and starting treatment late in infection phase.

The trial was stopped early because there were not enough people suitable to be included. This is thought to be due to the effective lock down measures introduced by the Chinese government.

Adaptive COVID-19 Treatment Trial (ACTT)

Preliminary results made available on 29 April.

Adaptive, randomized, double-blind, placebo-controlled, multi-centre trial

N = 1063

Remdesivir i.v. as single daily infusion; 200 mg day 1, 100 mg days 2-10
Primary outcome: time to recovery up to day 29.

Preliminary results from 1063 patients report:

- a 31% faster time to recovery for the remdesivir group compared to placebo (median time 11 days vs 15 days; p<0.001)

- a survival benefit for remdesivir group compared to placebo (mortality rate 8.0% vs 11.6%; p=0.059).

No information was provided about adverse events.

Adaptive trial design allows for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial.

Final results not yet published.

Primary outcome measures changed during trial and time frame extended.



 
 

References

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