Antiviral medicines and the treatment of COVID-19

A range of antiviral medicines are currently being trialed as potential treatments for COVID-19 infection. This article considers current evidence for remdesivir, lopinavir/ritonavir and oseltamivir.

A range of different medicines are currently being trialed for potential treatment or prevention of COVID-19 infection. One group of medicines under investigation are antiviral medicines that have previously been used to treat other viral illnesses including HIV and Ebola virus.1

Prevention or treatment of COVID-19 with antiviral medicines remains experimental, with no medicines yet proven effective.1,2

Early reports of antiviral medicines being used to treat some severe cases of COVID-19 have yielded mixed results.1 Multiple clinical trials are currently registered to investigate antiviral interventions for the treatment of COVID-19 and this number is continuing to grow.3

Update 5 June 2020: Remdesivir receives conditional recommendation

The National COVID-19 Clinical Evidence Taskforce have released a conditional recommendation regarding the use of remdesivir in the treatment of Australians with COVID-19. It was made following consideration of the available evidence from two randomised, placebo-controlled trials, Wang 2020 and Beigel 2020 (preliminary report). These results were considered in the context of certainty regarding the likely benefits and harms associated with this treatment, as well as issues that might impact on the equity, acceptability and feasibility of the recommendation.

Whenever possible remdesivir should be administered in the context of a randomised trial with appropriate ethical approval. Use of remdesivir for adults with moderate, severe or critical COVID-19 outside of a trial setting may be considered.

The guidelines and all Taskforce updates can be found here.

 

What antiviral medicines are being trialed for COVID-19?

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

Update 5 June 2020

Please note that our remdesivir content below is currently  being updated to reflect recently published studies and a conditional recommendation made today by the National COVID-19 Clinical Evidence Taskforce.

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 has not yet been licensed or approved for treatment of COVID-19 anywhere else in the world including Australia.26 The European Medicines Agency has also started a rolling review process which may expedite approval of remdesivir once an application is made.27

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 do not recommend the use of this medicine for people with COVID-19 except in the ‘context of randomised trials with appropriate ethical approval’.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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