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expert reaction to a study about a phase 2 trial of a triple antiviral drug combination treatment for COVID-19

A study, published in The Lancet, has looked at the efficacy of a triple anti-viral drug combination treatment for COVID-19.


Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:

“This seems to be a well-conducted, though small, randomised trial carried out in Hong Kong. It was ‘open-label’ which means those involved knew which treatments were being given. This is not ideal, but matters less if objective outcomes are assessed, especially mortality.

“It had unequal randomisation with two patients allocated to the treatment of interest for every patient allocated to the control treatment.

“All patients received the control treatment of combined lopinavir–ritonavir which has been in use for about 20 years for the treatment of HIV. It was also used for treatment of SARS in the Far East. This combination of drugs comes as a single tablet (or solution) with fixed doses of each drug. In HIV it is often used in combination with other drugs.

“The treatment studied was also a combination, using ribavirin with interferon beta. Ribavirin has been used for over 30 years, primarily in the treatment of hepatitis, but has also been used for other viral diseases (not HIV). Injectable Interferon beta has been used for the treatment of multiple sclerosis(MS) and was found to have some efficacy, combined with ribavirin in other diseases caused by coronaviruses. Interferon beta is being used in an aerosol form directly into the lungs in a UK trial against Covid-19. In the Hong Kong trial, the interferon was given (as it is for MS) by injection.

“The treatment given depended on how long it was after symptom onset that the patient entered the trial. The earlier after symptoms the patient entered the trial the more injections (up to 3) of interferon that they could receive, but if their symptom onset was 7 or more days before they could start treatment (and they could enter the trial up to 14 days after symptom onset) they did not receive any interferon but did receive the ribavirin. The concern was that there could be inflammatory effects of the interferon at longer durations of time since symptom onset.

“All patients received oxygen and other clinically indicated treatments as necessary.

“Although the trial was planned to assess mortality, no-one in either group died within 30 days of entry to the trial, so no conclusions can be drawn regarding any effect on mortality. They were able to measure the amount of virus at various sites in the patients and there was strong evidence that the time to reach the point of no virus being detected was about 5 days shorter in those who were allocated to receive interferon. A similar reduction in the time spent in hospital was also seen in this group. For those who started treatment less than 7 days from symptom onset (and hence received at least one dose of interferon) the difference in time to zero viral count was about 6 days, while no difference was seen in those whose symptom onset was earlier and hence received no interferon there was no difference between the groups.  This comparison is less reliable than the comparison involving all patients but is undoubtedly an indicator that it is the interferon (combined with ribavirin) rather than the ribavirin component alone that shows the benefit. It is also possibly the case that had everyone received interferon in multiple doses the effect could have been greater, but this needs testing in another trial. There is no evidence that the benefit seen in the group allocated to interferon was in any way exaggerated by some patients not getting it, if anything it is the converse.

“While adverse effects were also studied, in this small trial there were no unexpected adverse effects of interferon, combined with lopinavir–ritonavir and ribavirin, seen. Larger trials are need to be sure there are none.

“The authors are appropriately cautious about the findings and say that larger trials, perhaps comparing interferon beta with a placebo might be carried out. A large proportion of the possible patients in Hong Kong during the period were entered into the trial so it could not be much larger if carried out only there. It is also true that these patients had relatively mild symptoms and the conclusions clearly can only apply to those treated no more than 14 days after onset of symptoms and it suggests the earlier the better. The results cannot be applied to those who are already critically ill.

“This is so much better information than many of the small, or even some large, observational studies and definitely justifies the consideration of adding interferon beta to the list of genuinely, evidence-based, promising treatments to be tested in further randomised trials.

“It has been clear from long experience that HIV is best treated with combinations of different drugs and this could also be the case with Covid-19.”


*‘Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial’ by Hung et al was published in The Lancet at 23:30 UK time on Friday 8th May.


All our previous output on this subject can be seen at this weblink:


Declared interests

Prof Stephen Evans: “No conflicts of interest.  I am funded (1 day/week) by LSHTM.  They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator or any grants obtained from them.  I am the statistician to the “meta-Data Safety and Monitoring Board” for CEPI [].  I will probably be paid for my attendance at meetings and expenses for travel.”

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