The 23rd International AIDS Conference (AIDS 2020) was held virtually for the very first time and featured discussion about the current direction and future prospects for HIV prevention, diagnosis, and treatment. It was followed by a virtual COVID-19 conference on July 10 and 11. This conference was the first abstract-driven scientific conference dedicated to the global COVID-19 pandemic. It featured 140 late-breaking studies addressing urgent questions related to COVID-19 epidemiology, prevention, treatment, and care.
During the summit, researchers gave a presentation entitled, “Sofosbuvir and Daclatasvir as a Potential Candidate for Moderate or Severe COVID-19 Treatment, Results from a Randomised Control Trial.” During the official press briefing, Andrew Hill, Ph.D., the principal investigator, reviewed promising results from the study.
Hill graduated from Oxford University and then gained his Ph.D. from the University of Amsterdam. He’s been working on clinical trials of drugs to treat HIV and hepatitis C for the past 28 years. He’s a senior visiting research fellow at Liverpool University and also works as a consultant for the World Health Organization and Unitaid. Hill spoke with Terri Wilder, M.S.W., after the COVID-19 conference.
Terri Wilder: Dr. Hill, can you start by giving me an overview of the trial, the preliminary results, and how you were involved?
Andrew Hill: There were three studies conducted in Iran at the peak of their first epidemic there in March and April 2020. I was involved with them because they had used the same drug to cure thousands of people with hepatitis C in Iran. I actually contacted them at the beginning of the epidemic and suggested they try using the hepatitis C drugs to actually treat COVID-19, as well, because there were some early studies suggesting that these drugs might be active, not just against hep C, but against the SARS-CoV-2 virus, as well.
TW: The drugs that were used, as you mentioned, were hepatitis C drugs. Can you talk a little bit about the dosage of the drugs that were given to the patients? And then also, what was the control treatment that was given?
AH: These are standard doses of sofosbuvir and daclatasvir, standard drugs used to cure hepatitis C. So, 400 mg of sofosbuvir and 60 mg of daclatasvir, once a day. There were three different studies with slightly different designs. But basically, they were looking at sofosbuvir/daclatasvir versus control. Now, sometimes the control included hydroxychloroquine. Sometimes it involved lopinavir/ritonavir. But we know from other studies that those drugs don’t really work. So, we can probably rule them out in the equation.
TW: The trial was for moderate to severe COVID-19. How were the patients recruited or selected, and what was the inclusion/exclusion criteria?
AH: When the trial started, there was a policy in Iran, and as in many countries, when they reached the peak of their epidemic, there just wasn’t enough room in hospital [for people] with mild symptoms. So, people would only come in if they were really ill. And the study start point was people who needed to be in hospital. They had rapid breathing; they had low oxygen saturation, high temperature. A lot of them also had other conditions, like diabetes and hypertension, that can make the risk of COVID-19 greater. So, that’s where we started. And the objective of all the studies was to get people recovered and out of hospital alive.
TW: Tell me about what some of the preliminary results were from the trials.
AH: We had 176 people across the three studies. There was one in the North, in Sâri; one in the capital, Tehran; and then one in the South, in Abadan. Between the three studies, we showed a significantly higher chance of recovering from COVID-19 and being discharged from hospital. And it was consistent across the three studies. Two of the studies were randomized, and one was not randomized. But even if you just looked at the two randomized studies, it was still a significantly faster rate of recovery and coming out of hospital. In the two randomized studies, it was 96% recovery by 14 days, versus 80% in the control arm.
But it wasn’t just that; we also saw better survival. So, the death rate for the sofosbuvir/daclatasvir was 5%. And for the control patients, it was 20%. So, we actually saw a statistically significant apparent survival benefit in these studies.
TW: During the press conference, you mentioned that laboratory studies show that daclatasvir has antiviral activity to SARS-CoV-2 and it penetrates well into the lungs. Can you talk about how it actually penetrates into the lungs?
AH: There have been studies done by pharmacologists looking at the molecular characteristics of different drugs, and which drugs should get into lung tissue most efficiently. And this is a prediction that’s been done based on analyses of other drugs. But the concentration of daclatasvir will be three times higher in the lung, compared to in the blood. So that’s potentially an advantage; that’s what you’re looking for in a drug to treat COVID-19—that it’s there where it’s needed.
TW: And you also stated that sofosbuvir has only marginal antiviral activity. So, when you said that, I was kind of like, so then why use it? I don’t know if I’m missing something.
AH: Yeah. So, we’ve just got to be clear about what we know and what we don’t know. What we know is if you give people sofosbuvir/daclatasvir in these studies, we seem to have improved survival and better recovery.
Now, before we throw out the sofosbuvir, we’ve got to be really careful. We’ll make sure that we follow this up and do other studies. And there are studies now looking at—perhaps there’s something about having both drugs in there, that one potentially leads to the other [working]. So it might be that you have what’s called synergy, where you give two drugs at the same time and they work as a pair. We don’t know that that’s true, but we don’t want to just switch straight to daclatasvir at the moment. We think that there might be something in the combination itself.
TW: I’m curious, because if a person doesn’t really recover from COVID-19, there’s this group of people called COVID-19 long-haulers; they’re complaining of brain fog and some other cognitive issues. So, I’m curious. Do these drugs actually pass the blood-brain barrier, and maybe could help with that, as well?
AH: It’s possible. We are actually looking at long-term follow-up. So, we do have a 30-day post-trial evaluation to see whether people have any lingering symptoms, like—the classic one is just tired. These people are very tired afterwards. People can still have shortness of breath. There have been all sorts of different symptoms described. So, we are looking at that in the longer term.
TW: Yeah. Dr. Tony Fauci was part of the press briefing that, you were there. I had posed a question to him about COVID-19 long-haulers and the possibility of them developing myalgic encephalomyelitis, which, unfortunately, is still referred to as chronic fatigue syndrome. And so with those folks, having that debilitating fatigue, the brain fog, the cognitive issues—the hallmark symptom of myalgic encephalomyelitis is post-exertion malaise. And I think that a lot of activists want government and academia and pharma to really look at repurposing drugs, which is basically what you had suggested, to expedite stopping the virus.
I’m wondering if, in particular, with these COVID-19 long-haulers, do you think there may be other drugs that should be looked at and pulled off the shelf for another disease to help folks with COVID-19?
AH: Yeah. There is this big push now to try and just go through everything that we have and see whether it works against COVID-19. Now, it’s a long shot, because drugs are targeted at particular infections. There are antivirals for a particular virus. You can’t assume because a drug works for one viral infection it will work for others.
But there are many examples. If you look, say, at 3TC [lamivudine], it was originally developed to treat HIV, and it also treats hepatitis B. If you look at sofosbuvir, it works against hepatitis C. But there are lab studies showing that it has a degree of activity against a whole range of other foreign infections, like dengue [and] West Nile fever.
The advantage of repurposing is if you have a drug and you’ve already characterized its safety profile, you’ve got factories all over the world that are making it—perhaps it’s already generic, and perhaps it’s already super cheap. If you find that that drug works, all you have to do is just get it from the pharmacy and start treating people. It’s much quicker and easier than developing a drug from scratch, getting it out of the lab, putting it through all of the pharmacology studies, setting up a safety database; that can take ages. This repurposing could get us drugs potentially by the end of this year.
TW: I also had another question about—I realize that the trial, you just have preliminary results here, and we have to be very careful about that. I’m wondering, there’s been some conversation about having a PrEP (pre-exposure prophylaxis), like we have in HIV, for COVID-19. And I’m wondering if it’s possible that these hep C drugs could be considered as a PrEP for COVID-19.
AH: Yeah. To answer your question about preliminary, we do need to be very careful that this is a set of three studies in 176 people. It’s not enough to get the drug approved. And it might be that there was some freak thing that happened during the study: Maybe there was some bias; it was open-label; it wasn’t placebo-controlled.
But we have a backup program of studies, much bigger studies, in well over 2,000 patients—in Brazil, in South Africa, in Egypt, and in Iran. And if those studies show what the early study’s showing, we should know by October. Then we have a treatment that could cost about $7 USD per person. And it has already got its safety profile. So that’s something really to push for.
We’re also looking at the same treatment for prevention. So, we have a study of 2,500 doctors and nurses in South Africa, where one group gets sofosbuvir/daclatasvir; another group gets standard of care. And if we can show that it stops those doctors and nurses getting infected, that has huge public health implications. It could mean that you could stop the epidemic in the places where people are most at risk, such as care homes and hospitals.
TW: You named several countries that a larger trial will take place. Is there any reason why the United States is not included? The United States has been particularly hit hard.
AH: This is a treatment which has evolved over time, very rapidly. And we’ve put out feelers to different organizations. And we haven’t been approached yet by a group in the United States. But perhaps one will emerge. In fact, it’s quite likely, after people have seen this initial result. So, they would want to have a trial of this, because it’s treatment that’s freely available. It’s in the pharmacies. So, I think it’s a matter of time.
We are hearing about new studies, almost on a daily basis. I was in a conversation today about a study in Central Africa, another study in Saudi Arabia. So, people are desperate, and they will move. I’d welcome studies in the United States as soon as possible, if that’s what people want to do.
TW: Yeah. I guess I’m thinking about, you know, I’m in New York City and, obviously, New York was hit pretty hard. And now a lot of states that, unfortunately in the United States, opened up too early are now feeling the brunt of that. So, my family in Georgia is having to deal with the fact that their governor opened the state too early; and now they’re seeing 3,000 cases, new cases, a day. I think there’s certainly need for something like this to help potentially stop this from disabling and killing people.
AH: Yeah. I think one of the reasons those studies didn’t start immediately in the United States is that the companies that make these drugs—sofosbuvir is made by a company called Gilead, and daclatasvir is made by a company called Bristol-Myers [Squibb]—they did their own tests on the drugs. Those tests suggested that they would not be active.
But we’ve done more sensitive tests. In Brazil, we’ve got a specialist virology laboratory that has been published in Nature; it’s very well renowned. And with these more sensitive tests it looks like the drugs are active. So, perhaps people dismissed them too early. Perhaps now they need to come back to them.
TW: You know, as I’m listening to you speak, I can’t help thinking about this as a two-drug combination. It makes me think of how we treat HIV—where we had one pill originally; then we moved to two, then three drugs. And I’m just wondering, is there any similarity between COVID-19 and HIV, in terms of its lifecycle or how you target the virus with drugs?
AH: I think if we look at viral infections, generally, one of the mistakes that’s been made in developing the drugs is staying with single monotherapy for too long. If you look at HIV, we were treating with one drug for 10 years before we switched on to two; and then another few years before we switched on to three. If you look at hepatitis C, there was one drug; then two drugs. A lot of infections are treated with combinations. And I think there’s every reason to believe that we’re going to need two or three drugs to treat COVID-19.
If you look at remdesivir, the activity is marginal with one drug; it just about works. Dexamethasone is an immunosuppressant. It causes a very small reduction in death rates. So I think inevitably we’re going to have combinations. I guess the question is: How many drugs? Is it going to be three drugs, plus three antivirals, plus dexamethasone? Or two antivirals with a different drug to calm down the immune system in severe disease?
But the difference between HIV and this is it took 10 years to get that first treatment combination, with triple. And we don’t have 10 years. I mean, 10 weeks is a long time. We’re running these trials at this breakneck speed. And we’re having to make decisions very quickly.
My advice is to get into combination treatment as soon as possible.
TW: I want to ask you about the larger trials that you have planned. You talked about health care providers as an audience to enroll. But can you talk a little bit more about some of the inclusion/exclusion criteria, in terms of who would be considered, who wouldn’t be considered, for these larger trials?
AH: Looking at the treatment studies, those are, as I said, 550 patients in Egypt, 720 in Brazil, 700 in Iran, and at least 200 in South Africa. Most of these people are like the ones in the first Iranian studies—they’re ill. They’ve got moderate to severe COVID-19. They’re hospitalized. And the endpoint is getting them out of hospital.
We’re starting to look at milder cases, as well, as outpatients. But you need a lot of patients, then. Because a lot of people just get well on their own; they don’t necessarily need treatment.
Then, looking at health care workers—we’re recruiting, as I said, over 2,000 doctors and nurses in Johannesburg, in South Africa. They’re going to be people on the front line at risk of being infected.
And the whole thing moves very quickly. You only need to treat people for 14 days. We’ve already started recruitment into some of these studies. And they are countries at the peaks of their epidemics. So, we expect to see results probably by October, if things run to plan.
TW: Who is funding these trials?
AH: It’s very important to say we get no funding from the pharmaceutical companies. This program is done for no profit. Nobody wants to make any profit out of it. The aim is to get a treatment delivered worldwide at the cost of production—so, around $7 USD per person, per treatment. And the funding we have is mainly from Unitaid, which is an independent funding organization. We’re getting some money from various different other donors. The Gates Foundation has been involved in some of the studies. So, it’s just a variety of different donors. And also from government ministries of health—so, the Iranian Ministry of Health; there are various parts of Brazil that are contributing their hospital resources towards this. So, it’s all nonprofit.
TW: Are you having to pay for the drugs? Or does the pharmaceutical company donate it?
AH: We have a separate fund. We pay for the drugs. The drugs are not provided by pharma companies. We get them ourselves.
TW: Great. If people want to learn more about this trial, where can they get more information?
AH: That’s a good question. This is running so quickly. We’re putting a coordinating group together, but we are an independent group of researchers. We have a central team. And we will put results online as they emerge. We’ve released our first results, and we expect to have things ready within the next eight weeks, with a platform so people can see what’s going on. The details of the trials, a lot of them, are already available on clinicaltrials.gov, which is a standard NIH website.
TW: Great. Well, thank you so much for speaking with me. This is actually really exciting. And I, again, realize it’s preliminary. But I think it gives folks some hope. And what I said earlier—a lot of activists have been saying, “Repurpose drugs. Look at these drugs to see if there’s something that can be quickly done to stop this.”
AH: I just want to finish by saying I don’t want people to get carried away. I don’t want people just to think this will necessarily work. We have had these false dawns. A few months ago, people thought that hydroxychloroquine worked, or lopinavir/ritonavir. We cannot be sure that this will lead to a significant benefit. We have to stay scientific and objective and run the studies.
But if this stuff works, then we’ve got a treatment that could be used anywhere, by anybody, at a low price. And so, we will have access and supplies. There are enough supplies of these drugs to treat literally millions of people worldwide. We’ve been in touch with the large suppliers. So, we’ve just got to get this stuff to work in the next 10 weeks. And then we’ve got a solution.
TW: I just wanted to piggyback on something that you just said. I know that you do a lot of work around drug pricing. So, if this shows to be a treatment that should be distributed globally, what do you think needs to be done to make sure it’s accessible to all?
AH: Well, the bad news is that, whereas this drug costs $7 USD per person in India—in Pakistan, in Egypt, in Iran, it’s very, very cheap; you can look across low-income countries, and this treatment is available very cheaply—the same drug in the United States will cost over $10,000 USD. Now, the reason it’s that expensive is it’s normally used to treat hepatitis C. And that’s the hepatitis C price.
It’s going to take somebody at a high level in U.S. politics, if this works, to say, “Look. The drug companies have done nothing in the development of this drug. They even believed that the drug didn’t work.” If this drug does show effectiveness, the companies have no right to charge premium pricing. The drug should be imported at cost price to treat anybody, anywhere.
It’s rather like the situation with pre-exposure prophylaxis, or PrEP, where independent groups did all the work, and now there’s the big debate about whether Truvada [emtricitabine/tenofovir disoproxil fumarate] in the U.S. should be provided at cost price.
Now, we haven’t had any support from the pharmaceutical industry for these trials. We don’t know if they’re going to work. But if they do, I don’t see any reason that the drug companies should claim to have any premium price. The drugs should be available at cost price. Because we’ve run the studies. And that’s an issue for another day.
First of all, we need to show that these drugs work. But if they do work, we’ll have another debate on our hands about how much this should cost. But our aim is to deliver a treatment for COVID-19 that’s effective and is affordable for anybody in any country.