Clinical Conversations

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A combination of three antivirals — Kaletra (which is lopinavir plus ritonavir) and ribavirin — when given early and with interferon significantly reduces viral shedding, disease symptoms, and hospital stay in  patients with COVID-19 when compared with a control regimen of Kaletra alone. The drugs are active against other coronaviruses, but the key factors seem to be interferon and promptness of treatment.

When the triple-drug combo was administered without interferon 7 days or more after the onset of symptoms, the results were no better than with Kaletra alone. Prof. Ivan Hung, the lead author on the report, explains that the researchers were afraid of prompting a cytokine “storm” if interferon was given after 6 days of symptoms — they’re not sure that that reluctance was well founded now. In any case, no patients died in either group.

The study was conducted in Hong Kong and has just been published in The Lancet. (An earlier study by another group published in the New England Journal of Medicine found no special benefit from Kaletra alone — a result seemingly confirmed by this study in The Lancet.)

We were able to interview Prof. Hung over ZOOM from Hong Kong, where he was about to enjoy a Mother’s Day lunch with his mom. It was very generous of him.

Prof. Hung’s article in The Lancet

NEJM study on Kaletra’s ineffectiveness against COVID-19

Running time: 14 minutes

Links to other interviews in this series:

1. Dr. Anthony Fauci
2. Dr. Susan Sadoughi
3. Dr. Matthew Young
4. Dr. Julian Flores
5. Dr. Kristi Koenig
6. Dr. Renee Salas
7. Drs. Andre Sofair and William Chavey
8. Dr. Comilla Sasson
9. Dr. John Jernigan

Transcript __________________

Joe Elia: ________You are listening to Clinical Conversations. I’m your host, Joe Elia.

A study out of Hong Kong, just published in The Lancet, shows that a combination of three antiviral drugs has the effect of shortening the time from the start of COVID-19 treatment to when nasopharyngeal swabs are free of virus. The researchers used a combination of three drugs, all of which have shown activity against coronaviruses related to SARS-CoV-2. Some patients also received interferon.

The regime was compared against a regime using only two of the antivirals and no interferon.

The study’s first author, Professor Ivan Hung, has kindly agreed to talk with us. Professor Hung is with the State Key Laboratory of Emerging Infectious Diseases, Carol Yu Center for Infection, at the University of Hong Kong.

Welcome, Professor Hung, and thank you for agreeing to talk with us.

Professor Ivan Hung: ________Thank you, Joe. Very kind of you.

Joe Elia: ________Previous work on 2003 SARS and 2012 MERS was key here, wasn’t it?

Professor Ivan Hung: ________Absolutely. Yes.

Joe Elia: ________And can you briefly explain the rationale for using the three drugs that you did?

Professor Ivan Hung: ________Yes, the choices of the three drugs are based on our previous research, published in 2003 and also in, subsequently in 2015. The two studies were based on…in 2003, we were using the Kaletra, which is the lopinavir/ritonavir, together with the ribavirin, in patients with SARS in 2003. And we were able to demonstrate that with that combination that patients clinically, they actually performed better with fewer complication of ARDS and also fewer mortalities. Nevertheless, it was a pilot study.

Subsequently, we did another study on marmoset, which is the, you know, the South American monkey, and we did, in that animal model, we were able to demonstrate by using either interferon or with the Kaletra, we were able to suppress the virus and with better survival in the monkey model. And that’s the reason why we choose to use the interferon beta-1b, the Kaletra, and also the ribavirin as our combination for this antiviral.

Joe Elia: ________And you say in the paper, the interferon jumpstarts the immune system. It can, it has that effect. So, you limited the use of interferon to those whose symptoms had emerged less than seven days before starting treatment.

Professor Ivan Hung: ________Yes.

Joe Elia: ________And why did you limit it to early diagnosis?

Professor Ivan Hung: ________We worried about the pro-inflammatory effect of the interferon, and as we know that from, you know, other studies, we know that the viral load actually peaks in the COVID-19 very early, 24 to 48 hours from symptom onset. So, that’s why we chose, we decided to use the interferon within seven days because we worried that if we would give it to patients who presented to us late, beyond seven days, there would be an adverse effect of having activating the inflammatory cytokine storm in these patients, and it might worsen their clinical presentation.

Joe Elia: ________Just because it, as you say, it jumpstarts the immune system, and you don’t want to put it into overdrive, I guess.

Professor Ivan Hung: ________Absolutely. Yes, that’s the reason.

Joe Elia: ________It seems very important to start treatments, at least with the triple regimen of antivirals, within seven days. Is it because the viral load peaks early?

Professor Ivan Hung: ________Yes. From our research in influenza and also other respiratory viruses, we know that if you have treatment very early on, within the seven days from symptom onset, we will be able suppress the viral load, you know, especially for the first few days. By suppressing the viral load, you actually prevent complication from happening in the second week, which is usually complicated with activation of the immune system and you have the cytokine storm, and that is when you get most of your complications, including your severe pneumonia, your respiratory failure, followed by multi-organ failures.

So, it is key, in fact, to treat COVID-19 or influenza within the first few days, or at least within the first week from symptom onset. So, that is very, very important.

Joe Elia: ________And some people who received the triple drug regimen started the drug regimen after the seven days of symptoms. They started…

Professor Ivan Hung: ________No, in this trial, we actually just give two drugs for those who were presented beyond, seven days or beyond. So, in fact, in the treatment arm for those who presented seven days or beyond, we did not give the interferon because of the adverse effects that we worry about from inflammatory effect. So, we only give the Kaletra and the ribavirin for those late presenters.

Joe Elia: ________Let me just be clear. Some of the patients received the Kaletra and ribavirin, but not interferon.

Professor Ivan Hung: ________Yes. Yes.

Joe Elia: ________Okay.

Professor Ivan Hung: ________That is within the combination group, but those patients who presented seven days or beyond, we only give the Kaletra and ribavirin without interferon because of fearing the pro-inflammatory effect of the interferon. In the control group, we only give the Kaletra as a control.

Joe Elia: ________In your table that you describe the results, I think it’s Table 3 or something, the people who received the triple drug regimen, the combo, the combination regimen, and not interferon, did not do significantly better than the people [on the two-drug regimen]…

Professor Ivan Hung: ________Absolutely.

Joe Elia: ________Okay.

Professor Ivan Hung: ________The table is based on subgroup analysis, so we actually split the group back according to when they actually presented with the symptoms, so…which was the fairer comparison, because for those who actually take the triple therapy with interferon, there are 52 of them within the combination group, and we compared these to the control, which is 24 of them who was also presented in the control group within seven days. So, that is the fairer control, a fairer comparison. Whereas, for those who only received the two drugs, that means that they present seven days or beyond, they are compared with the control, with the only-Kaletra group, and there’s no difference between the two groups.

Joe Elia: ________Right. Right. There were no statistically significant [differences]…

Professor Ivan Hung: ________Absolutely. And that actually proved that interferon probably is the big, you know, the backbone of the triple therapy.

Joe Elia: ________Yeah. Well, it’s either interferon or early treatment.

Professor Ivan Hung: ________Yes. As I say, I think it’s both.

Joe Elia: ________Yeah. Yeah. So, it’s…

Professor Ivan Hung: ________If you compared with the control, it would actually show a difference, so…which is also an extra treatment. So, that means interferon is likely to be the key factor.

Joe Elia: ________Yes. Okay. And so, you didn’t use a placebo, and you mentioned in the discussion that there’s a reluctance to use a placebo…

Professor Ivan Hung: ________No. We discussed this in our treatment panel or committee within our hospital authority, and in fact, all the panel members said, you know, placebo is…will not be accepted by the patient, given our painful experience in SARS. So, that’s why we have the Kaletra as the control rather than placebo.

Joe Elia: ________I see. And now, did the results surprise you? Were you expecting that interferon would have the effect that it did have?

Professor Ivan Hung: ________The result was more or less what we expected, although we were a little bit surprised in terms of the difference between the combo and the control in terms of the viral suppression.

Joe Elia: ________Yeah, the shedding was shortened among the combo receivers, recipients from seven days versus twelve days with the controls.

Professor Ivan Hung: ________Yes.

Joe Elia: ________The symptom alleviation, symptoms were alleviated in the combo group in four days versus eight days in the controls.

Professor Ivan Hung: ________Indeed, yes.

Joe Elia: ________And the hospital stay was much shorter. It was nine in the combo group and about fifteen in the controls.

Professor Ivan Hung: ________In the control, yes.

Joe Elia: ________So, yeah. Something was at work, and so…but the two variables seem to be time and interferon.

Professor Ivan Hung: ________Absolutely.

Joe Elia: ________That’s right. So, are you doing more studies on trying to resolve the, trying to get a finer…?

Professor Ivan Hung: ________Yes. Yeah. Yeah, several things we are trying to do in the, you know, in another trial, which we just started, even though we have no patients now in Hong Kong. I think the limitations in our first study is that is all mild cases, mild-to-moderate cases that we have. Most of them come in with the NEWS score of 1 or 2, and the other problem, of course, is that we have very few severe cases, probably because we hospitalize our patients very early on and treat them, most of them, within the first week. So, that’s why we have very few severe cases, including we have, you know, less than 1,000 cases in Hong Kong, confirmed cases. Less than 3% was in the ICU, so…and it’s also, you know, less than 0.4% in terms of mortality. So, it’s very difficult to…you know, we want to recruit severe cases, but we couldn’t.

So, the next step, of course, is to see whether this regimen works in severe cases, if we have more severe cases in the coming winter, or that is that we will be looking at whether we can actually use interferon in patients who presented beyond seven days, which we think that this is not a, you know…a lot of the pro-inflammatory adverse effect is not a problem anymore. We can actually give interferon for patient who present beyond seven days. So, we’ll be looking at that, as well.

Joe Elia: ________But if you were looking for severe cases, then you would need to look no further than Boston. So, are you working with colleagues internationally at all, or…?

Professor Ivan Hung: ________Yes, we have collaborators in Europe, in UK, and also in US, which we’ve communicated with. So, you know, we will be very happy to look for further trials with our collaborators, you know, in the coming winter when more cases evolve.

Joe Elia: ________Have you started using the regimen…you don’t, you say you don’t have any severe cases at the university now. Have you started using the regimen on other patients in other hospitals in Hong Kong?

Professor Ivan Hung: ________Well, in fact, for this trial, we have included six major hospital, public hospital in Hong Kong that actually cover around 75% of the population in Hong Kong. So, in fact, we actually recruited most of the patients in the first, you know, two months up to the 20th of March, of all our confirmed cases. We only have our second wave, you know, in the late March, where we have a surge of cases from about 200 up to, now, 1,000 confirmed cases a day, and so, we have recruited more or less all the patients, a majority of the patients that we have in Hong Kong. So, if we are looking for, you know, more severe cases, then probably we have to look somewhere else with collaborators in other parts of the world.

Joe Elia: ________You mentioned a term I’m not familiar with. You call it NEWS2. It’s a National Early Warning…

Professor Ivan Hung: ________Indeed. National Early Warning Score 2, which was developed in the UK for assessing especially respiratory illnesses affecting with…presented even earlier. And that allows us to compare, you know, the treatment and the control arm in subsequent observations.

Joe Elia: ________So, the severity of the pulmonary…

Professor Ivan Hung: ________Indeed.

Joe Elia: ________Okay. So, pardon my ignorance about that. I want to thank you for speaking with me today, Professor Hung.

Professor Ivan Hung: ________Thank you, Joe. Very kind of you. And Happy Mother’s Day.

Joe Elia: ________Happy Mother’s Day to you. I hope you enjoy it.

That was our 266th episode. All the rest can be found at podcasts.jwatch.org. We come to you from the NEJM group, and our executive producer is Kristin Kelly. I’m Joe Elia. Thank you for listening.