Roy Gulick, Professor of Medicine and Chief of the Division of Infectious Diseases, Weill Medical College, Cornell University
The Future of Antiretroviral Therapy
ART regimens have improved significantly over the years. What’s next? Will new regimens and new delivery mechanisms improve care and adherence?
Thanks a lot Sharon. Thanks to Jean and the organizers for inviting me, and welcoming me to Toronto. It’s a quick flight from New York. Only an hour so. You heard a little bit about me. I’d like to know a little bit about you. How many are healthcare providers? Raise your hand. Okay. It’s funny, you’re all sitting together. Right. And how many are case managers, social workers? You guys are sitting together too. Pharmacists. Any pharmacists in the room? Community? Community here? Who did I miss? Okay. I think I got everybody. Right. Okay. Welcome.
So we’re gonna talk about the future of antiretroviral therapy and then you’re gonna enjoy your dessert. I have no disclosures. I have no disclosures. Okay. So to know where we’re going, we have to know where we are. Where are we with ART, antiretroviral therapy, today in 2018? Where are we? So we now know all guidelines around the world say start a RT at all CD4 cell counts. There’s no more debate about that. We have 32 drugs approved for the treatment of HIV infection. They cross five broad classes that we know well. The nucleocides, the non-nucleocides, the protease inhibitors, the integrase inhibitors, and some of the more recent ones are entry inhibitors of three types. We have up to seven recommended first-line regimens worldwide, but they use one basic strategy that we’ve been using for over twenty years, and that is two nucleocides plus a third drug, either a non nuke, a protease inhibitor, or increasingly an integrase inhibitor.
And then we choose our regiments based on ART properties. What is the antiretroviral activity? Safety and tolerability, as we ask people to take these meds for years or even decades? Convenience is paramount for people to be able to stick to regimens over the long term. And finally what’s the whole impact on life expectancy? So what I’d like to do with my talk today is say where we are with these properties, and where we’re likely to be going next? With antiviral therapy. The question of when to start? We might have previously had a whole plenary on this or a debate on this, and as I said it’s over. We now know based on randomized clinical trials data that there are benefits both to the person taking ART and benefits in prevention from reducing transmission to others. So what you see here is a list of guidelines from around the world. The US Department of Health and Human Services, that’s the US government guidelines.
I’m the co-chair of those. The other leading brand in the states is the International Antiviral Society USA, the IAS USA. European guidelines are here, the British guidelines, and the WHO guidelines which are for low and middle income countries. And you see that the guidelines around the world say the same thing. Anyone with AIDS or symptomatic HIV disease, or who is asymptomatic now, regardless of CD4 cell count, recommended to be started on treatment when they’re ready to take the treatment. You’ll notice that the WHO draws a line at 350, and though in antiretroviral therapy is recommended above and below that line, they make a priority for below a CD4 of 350, and that’s an economic consideration. If you have limited resources target people below 350. As mentioned, we’ve now had antiretroviral drugs since 1987 and that was AZT, and here’s the three-letter codes for them, and as you can see there has been a parade of drug approvals over the last 30 years of antiretroviral therapy.
2018 which is almost over, we’ve actually had three new antiretroviral drugs approved in this year, so if you count them all up we have 32 drugs to treat HIV infection. Here’s what the guidelines say about which regimens to start. So they some call them recommended, some call them preferred, but we’ll call them first-line. And these are again the simple structure two nucleocides plus a third drug, and the same guidelines are listed along the left-hand side. Now what’s interesting to me about guidelines is that all of these guidelines put together a panel of experts, who review all the data and then make recommendations, either for the US or North America, for Europe, for the UK or even for the entire world at the WHO. They’re all looking at the same data but sometimes they come up with different recommendations. So it’s interesting to see how these recommendations are similar across some and how they differ among others.
So if you look at the column NRTI, those are the nucleocides, you can see that there’s several combinations recommended. Either form of Tenofovir, the older TDF or the newer TAF, together with FTC, and then Abacavir 3TC recommended first line in some patients. You’ll notice that the IAS USA no longer recommends the older form of Tenofovir, TDF, because of toxicity. They only recommend TAF, so that’s it that’s a difference among guidelines. You’ll notice the British guidelines omit Abacavir 3TC, considering it alternative rather than first-line, that’s an economic consideration. And you’ll notice the WHO only recommends TDF 3TC in its generic form, and again that’s because of economic considerations. When you look at the third drug there are also important differences. So again the three big classes would be non nukes and NRTIs, protease inhibitors or PIs and integrase inhibitors, II.
And the two US guidelines now only recommend integrase inhibitors as the third line drug. Note the difference there. So you do see the non-nuke Rilpivirine in the European and UK guidelines, and you see the protease inhibitors, Darunavir, and the Brits still include Atazanavir as first-line protease inhibitors, but that has been a change in the U.S. guidelines. And then you’ll notice that some of the integrase inhibitors are now missing, they’ve been omitted from the list, so Elvitegravir, which was a common one to start with has now been omitted from the list. Why? Because it has a low barrier to resistance, and because it needs the booster Cobicistat, which can cause side effects and drug drug interactions. So that’s now omitted. Note the addition of Bictegravir, the newest integrase inhibitor to be included. And the IAS USA also left out Raltegravir, again because of several pill requirement and the lower barrier to resistance.
So it’s interesting to watch these changing guidelines. And then look what the WHO has done, one regimen for everybody. TDF TDF 3TC and the third drug now, Dolutegravir, that’s just a recent change since this summer. So lots of changes there. If you look at the alternative list, here’s where some of the other ones come up, so now you see Abacavir 3TC for the nukes. You can see TDF appearing, the non nukes are now including several others, so the newer non-nucleocide Doravirine, now appears on the alternative list. Efavirenz which used to be the treatment of choice for the world, is now alternative on all guidelines lists. And you could see some of the other changes. And then some of the interesting regimens that we’re looking to as data emerges, are over on the far right column. Now what’s interesting about many of these is that they’re not three drug regimens, but two drug regimens.
And again based on clinical trials we’re beginning to see these coming up in the guidelines, at least as alternative choices. So lots to know, but note even with the drugs that we’ve had over the last five to ten years, there are changes and we’re turning to drugs which are more potent more convenient and less toxic. Okay. So how we doing on antiretroviral activity? My colleague Andrew Carr from Australia just presented an update of what’s called a meta analysis, and that is you put together all available data and you see if there are trends. He looked at 354 antiretroviral studies that were done from the mid-1990s through 2017 in a standard intent to treat ITT analysis. And you can see these circles here, each circle represents a study, and the bigger the circle the more people that were enrolled in the study. A total of almost 78,000 people contributed data to this graph.
So what is this graph showing us? It’s looking at the year of the study versus how many people were suppressed below detection on the regimens that were studied in the various trials? If you go back to the mid-1990s, only about 45 percent, less than half of people on triple combination regimens were suppressed below detection or undetectable. But look what’s happened since then. You can see that blue line is showing us better and better every year, so by the time you get to 2016, 77 percent of people on clinical trials are now suppressed, below detection. So great. Our regiments have gotten more effective, more efficacious over time, and it didn’t stop, so this is continued. Here’s some recent studies that have been presented and you could see the references over on the left side, the second column is the number of people, so over 300 in each of these study arms.
The regiments are shown in the third column, and you could see many of these or integrase inhibitor based regimens, and then the punchline of the slide is the far right column. How many people are suppressed at the end of forty eight weeks? And scan down that list here, we’re now seeing suppression rates of 89, 90, even up to 94 percent of people being suppressed on clinical trials with our current regimens. So continuing to see more efficacious regiments as time goes by. And some of these have been compared with one another. And these are data that support integrase inhibitors emerging as the treatment of choice. So the AIDS clinical trial group, or ACTG in the first reference there, tested a boosted Atazanavir regimen, versus a boosted Darunavir regiment, versus the integrase inhibitor Raltegravir. All three did well as you can see from the suppression rates, but the star next to 94 percent was Raltegravir because that was statistically significantly better than either of the other two regiments. So integrase inhibitors pulling ahead.
The single study our own Sharon Walmsley presented and then published this in New England Journal. Did I hear someone boo? Oh thank you for that clarification. They said it wasn’t a boo it was an Oooh. So this table was Ooohing our own Sharon Walmsley. Okay. Phew. It’s like wow, tough crowd in Toronto. Sharon presented this landmark study, which was head-to-head Dolutegravir versus Efavirenz. And Dolutegravir was statistically significantly better. And that really changed how we thought about that drug. And the Flamingo study, similar approach but showed that Dolutegravir statistically significantly better than Darunavir. Again a trend here showing integrase inhibitors, better than other regiments that we’ve used. Those are clinical trials. How are people doing in clinical care? Well my own City actually looked at this.
This is New York City data. Over 63,000 New Yorkers taking antiretrovirals. What was the suppression rate? How many were undetectable? And the answer was 88 percent. Now these aren’t clinical trials people, these are people followed in New York City clinics. And then they go one step further and show you individual Hospital data. So wait for it Cornell data. 92 percent. So we were all excited. So I was doing grand Rounds at one of our hospitals and Queens, and I presented this data, and a hand shot up and they said our data is 93 percent. Anyway the point is you’re seeing these numbers now literally throughout the developed world and increasingly in the developing world. People are doing well on our first line regiments.
There are new mechanisms of action. We talked about HIV entry, it’s the very first step in the lifecycle. So over on the left HIV is on top it’s got its glycoprotein GP120 which binds to the CD4 receptor, that’s the first step in infection of the T-cell. That allows binding to a second receptor called the co-receptor, also known as the Chemokine receptor, and when that occurs there is fusion of the viral membrane with the host cell membrane. These are the three steps of HIV entry. We can now interfere with each of these steps. So we’ve had a CCR5 antagonist for a while, that’s Maraviroc. We’ve had a fusion inhibitor for a while that’s Enfuvirtide or T20. And then more recently we’ve had CD4 binding inhibitor, so in the states Ibalizumab, just rolls right off the tongue, right, is a monoclonal antibody that binds to the CD4 receptor and prevents HIV from binding.
And then a new compound not yet approved is Fostemsavir, which is targeting the GP120. So we now can inhibit all three sub steps of HIV entry. So here is Ibalizumab. Top right hand corner. It’s an antibody. It’s not targeting the virus. It’s targeting the CD4 receptor. So it’s targeting the host not the virus. This is a monoclonal antibody. So it has to be given by injection. And the phase three study in forty people with heavily drug-resistant HIV showed that giving Ibalizumab over seven days was associated with a viral load decrease. And that makes sense, right. A drug that works a new way with a new mechanism of action, should have activity even in people who are infected with multi drug-resistant HIV.
How many of you care for someone, someone who has multi drug-resistant HIV? Raise your hand. Okay, so I asked audiences around the world, and I always get that response. So six percent of you. How did I do that? Right. So it the point is it’s very few, but everybody is seeing some patients like this. So they continued this, and ultimately forty three percent, when they gave Ibalizumab and optimize the background regimen, were able to continue to suppress virus through twenty four weeks, as published in the New England Journal. And then of those who could continue, almost 60 percent continued to be suppressed. So this drug is serving a place for people with multi resistant virus. And then I mentioned Fostemsavir is different. It’s an oral attachment inhibitor, not yet approved. It can be given once a day with daily dosing, and the phase 3 study once again enrolled people with heavily treatment experienced and resistant virus. We did this. We were part of this study at Cornell, the primary endpoint again is day 8.
So just showing that you have short-term viralogic activity and Fostemsavir did demonstrate that. Then they optimize the background and continue that, and you can see ultimately at week 48, that over half of the patients, 54 percent, were able to be undetectable with this strategy. So another example of a brand new drug offering new viralogic activity which can succeed in making people undetectable again. It was given breakthrough status by the FDA. It’s estimated that they will go to the FDA next year for filing and we may have that drug soon. Two other new mechanisms of action to focus on, one are the maturation inhibitors. We don’t yet have one of these. Over on the left hand side is HIV after it’s budded off the cell, and that long string is a poly protein of the virus that has to be chemically cleaved by the HIV protease for the viral particle to be infectious and mature.
Well we know how to inhibit protease. We’ve done that for years. But another thing that you could do, shown on the bottom, is you could bind two of these poly proteins together, and that’s how the new maturation inhibitors work. And there are lots of these that are in the laboratory waiting to come to clinical development. One of these actually made it into clinical development, it never got a name, just numbers and letters, but it’s further progress was abandoned because of toxicity in the patients. But more maturation inhibitors are likely on the way. And then the last new mechanism of action are the HIV capsid inhibitors. So the capsid is the structure of the virus that incorporates the genes of the virus, and it has to assemble, put itself together, and it has to disassemble. And these new capsid inhibitors, so brand-new mechanism, target both those steps. The first one of these just went into human study. So there are new drugs in the pipeline that that we look forward to and may help some people with multi-drug resistant HIV.
Okay. So that’s activity, what about safety and tolerability? How are we doing? Go back to Andrew Carr, that same meta-analysis, 354 studies. But this time what he’s looking at is, How many people had to stop the study because of toxicity? So that would tell you something, right. So look back at the 1990s, it was over ten percent, over fourteen percent had to drop out because of the toxicity of the medications, and as you can see that orange line is going down. So by the end of 2014, only four percent. So the drugs are becoming safer, better tolerated. So do we stop there? No, the studies keep going. So here’s some of those recent studies I showed you. This time what we’re looking at is “What proportion of people had to stop because of toxicity?” So we were at four percent on Andrew Carr’s study. Look at this. You have two percent, one percent less than one percent, even zero percent of people having to stop studies because of toxicity of the drugs. So the drugs we’re using today are better tolerated. That’s good news. There are other approaches people are using for safety.
So could we reduce the doses of some of the drugs? There was a study done, designed in Australia called ENCORE 1, that used the standard dose of Efavirenz, which is 600 milligrams, compared it with a lower dose, thinking that that might reduce side effects, and the results from this study, ultimately large well powered randomized studies, showed that the lower dose was non-inferior, meaning just as good as the standard dose. This has now found its way in the guidelines. So Efavirenz 400 appears in several guidelines. A newer study that was presented at the Amsterdam meeting from South Africa, looked at a lower dose of Darunavir, so typically today we use Darunavir 800 milligrams with Ritonavir 100 milligrams.
This study looked at people who were suppressed on a protease inhibitor, and then either stayed on that switched to Darunavir, but at a dose of 400 milligrams with 100 milligrams of Ritonavir. Ultimately found that most people suppress on the study. So this approach was non-inferior. Now why would you want to lower the dose? Well maybe less toxicity, but what the South African author said was that would be much cheaper for us if we only needed half as much. So these kind of studies using lower doses are out there. Another one in progress is to look at a lower dose of Atazanavir. Another way we address safety and tolerability are new drugs. And you’re well aware that the new form of Tenofovir, Tenofovir alafenamide was developed with toxicity only in mind. So when it was compared TAF, that’s the new one versus TDF that’s the old one, head-to-head in over 1,700 people, it showed similar viralogic activity.
Well that’s good news, but they also showed that there were improvements in both renal kidney markers and bone loss markers. And several studies have looked at this, including enrolling people with low baseline renal function. And it’s looking like these markers may well translate to less renal toxicity and less bone toxicity. So that’s a reason to develop a new drug, and as you know we use that drug quite commonly today. I mentioned before that people are beginning to look at two drug regimens. Why? Well it could be less toxic, it could be cheaper to use two drug regimens. So people have used boosted protease inhibitors plus 3TC or FTC. A number of studies have shown that that might be a reasonable approach using a boosted PI plus an integrase inhibitor or another two drug regimen. Surprisingly they did okay but not as good as we might have thought, so that’s not a standard combination. And then a non-nucleocide plus and integrase inhibitor is actually the first two drug combination to be approved on the basis of randomized clinical trials in the SWORD studies.
Shown for you there the reference looked at Rilpivirine Dolutegravir, which is now combined into one pill for maintenance therapy and it was highly effective in continuing to suppress people. Now some of the excitement has been to really simplify to a regimen of Dolutegravir 3TC. So the PADDLE study now published. I found out what PADDLE came from by the way. I was like why did they call it the PADDLE study, but it’s a long acronym where they kind of picked out random letters or something that spelled PADDLE. They enrolled only twenty people, and they found that all of them were suppressed by week eight, below detection using that two drug combo. This shows you the power of a 20-person study to change the world’s thinking about that. That led to a bigger study which I was the co-chair of it in the ACTG, we studied 120 people and came up with the same number ninety percent remained undetectable at the end of twenty four weeks, and then ultimately that led to very large randomized studies called GEMINI ONE and TWO.
GEMINI get it cuz it’s double. Its like twin meds or something like that. And here’s the the bottom line. So people were randomized, everybody got Dolutegravir and one group got Dolutegravir and 3TC and one got the three drug regimen of TDF/FTC and Dolutegravir. What you see in the bars, are what percentage of people were undetectable at 48 weeks, and you can see it doesn’t matter which regimen you are on or which study you are on, over 90 percent of all people were suppressed below detection. So this study concluded two drugs non-inferior to three drugs. Does that mean we’re gonna switch everyone to two drugs now? Well no this is only forty eight weeks so people are being a little bit cautious this study will continue another one to two years and we’ll see if it holds up, but this may be one of the waves of the future. Convenience. How we doing with convenience? Well as you know, we’re doing well.
So we go from twenty pills, divided every eight hour regimens, to one pill once a day. The very first one we had of these 2006, so we’ve now had this around for 12 years. And this was very popular with both patients, and providers. One pill once a day, triple drug therapy. It’s so popular that each year since then we’ve had more of the one pill once a day as approved, and in fact, 2018 so far, we’ve seen three of them. So look that hand is now full of one pill once a day regiments to result in undetectable HIV. Can we do better in terms of convenience than one pill once a day. Oh you think so. Okay. I like that. Alright lots of enthusiasm in Toronto. Okay. So for many years in our field we said “the Holy Grail is one pill once a day”, if we can do that we’ve really succeeded. Well we’ve done that for 12 years, but there are people that have challenges even with one pill once a day.
And so what are people thinking? Well as you know, less frequent dosing. So Raltegravir as you know was a twice a day drug when it was approved, and now there’s a daily formulation. So that’s a modest improvement. Albuvirtide is a new medicine related. It’s a fusion inhibitor so related to T20. Now if you remember Enfuvirtide, you have to inject it twice a day. Albuvirtide, once a week, and that’s been recently improved in China. And then there’s new co-formulations putting more than one drug into a single pill, these have been very popular in the field. But the big excitement are new injectable drugs. So could you inject anti retrovirals. So Rilpivirine has a long-acting formulation which has reached clinical trials.
And there’s a new integrase inhibitor, not yet approved, called Cabotegravir, which can also be injected. So the very first study to put all this together was called LATTE-2, which sounds pretty good right now, and it looked at an all injectable regimen to try to maintain suppression of viral loads. It was a phase 2 study, they put people on pills for four weeks, and if they got suppressed then they randomized them, either one group stayed on pills or the other two went to injections of the Cabotegravir and the and the Rilpivirine. One group got the monthly, one group got them every other monthly, but look at the suppression rates at two years. Eighty Four, Eighty Seven, Ninety Four percent suppressed. So this strategy worked.
This is the first time we have an all injectable regimen which looks like it worked. This was phase two, so smaller study only three hundred people, but this has now supported much larger studies to look to see if this will work in larger numbers of people, if it does work then this will be submitted to the FDA for approval and we could have the first all injectable regimen. Are there people that you could think of that would benefit from an all injectable regimen? Yeah, I think so, and more importantly people want choices. So some may choose one pill once a day, other people may like to have injectable, either every month or every other month. So more on that to come. Then there’s two other compounds that are being developed with convenience in mind. This one doesn’t have a name yet, MK8591 or EFDA, very attractive names. But importantly this is a nucleocide analog, and the important thing about it is bullet point number four. It has a half-life of 150 to 160 hours. What does that mean? You take one drug one dose of the drug, and you have levels of it for a week.
Okay, that’s what’s shown for you in the graph there. This was the one of the first in man studies, and we’re looking at change in viral load with one pill at baseline at different doses, and look at the purple and blue lines: 10 days later they still had significant suppression of HIV after just one dose. So this could support a once weekly regimen for HIV if it has partners to go with it. Would that benefit people? Well maybe. Maybe on some days this is the day you take your HIV meds and then you don’t have to worry all the other days. So people are thinking along those lines. And then what about, besides injections, could you do an implant? So as you know contraceptives and some psychiatric medications are available as implants and people are thinking about that for anti retrovirals. So this is what the implant looks like. Pretty simple structure. It’s a little tube, it’s got holes in it, TAF in this case is the the drug.
It’s inside there and it’s slowly elutes, and comes out of the holes, and in dogs it achieved detectable levels. So this is an interesting idea. Could we do anti retrovirals in implants? And this is taken a step further. Here’s that drug I just mentioned with the really long half-life, they did drug eluting implants, some of them were bio erode-able. What’s that mean? You put it in and then it just disintegrates over time. So it elutes the drug for months, and then disintegrates. You don’t ever have to take it out. And they did rat studies and monkey studies, and showed you could get achievable levels. So down the road might we have an all implantable antiretroviral regimen? And with some people like that? Yeah maybe so.
Or could you combine it with oral contraceptives and have everything in one implant? Could you add STD treatment and put that in the implant too? Okay this is what people are thinking of today. This may be the future. So I just got the stop sign, and I will tell you, my conclusion for antiviral therapy. In terms of activity we’re doing very well. We need drugs active against multidrug-resistant virus. In terms of safety we’re doing well. These days in terms of convenience we’re doing well. Newer injectables and implantables offer at least something to think about over dessert. And finally as you know the life expectancy of someone today with HIV who is appropriately treated is now the same as the general population. So a huge success. So I will stop there. And thanks for your attention over lunch. [Applause]