Eric Arts Explains Why There Are So Few New Treatment Options for HIV

Descriptive Transcript

music // Title card reads Back to Basic Toronto, 2014. Dr. Eric Arts. Repurposing your HIV. Eric Arts stands alone on the main stage at the Back to Basic conference. An on-screen graphic identifies him as Chair, Department of Microbiology and Immunology, Western University.

Eric Arts: We wrote this article a few years ago, and it just, kind of, highlights the antiviral discovery, and the antiretroviral discovery, over the last, basically, 40 years. And, basically, we all know in this room that there was very little done in antiviral discovery in history because it’s a very difficult thing to do.

If you look at bacteria, all bacteria have a very similar replication scheme, and they all have very similar targets. So, you make one antibiotic and, typically, it works against all other bacteria. With viruses, every virus is developed differently. It evolves from different hosts, it steals things from the host, it’s a non-living entity, and, as a consequence, the targets are varied. And, in addition, because all of those proteins — everything the virus has — has been stolen from the host, it’s very easy to get a lot of side effects, and a lot of secondary events, that are related to host toxicity. So, antiviral discovery is probably one of the hardest things we do in drug discovery.

And so, as a consequence, a lot of the drugs that were discovered early in the 60s are sometimes still used today. And, we didn’t even know how they worked. Examples are rimantadine and amantadine. And, now with the new developments that we have, specifically looking at the actual protein structure, we can design and make designer drugs that target these proteins and viruses.

Arts displays a slide showing the timeline of antiviral and antiretroviral drug development. The details of the timeline are unintelligible from the audience, but the names of specific drugs are noted along the sides of a large arrow. There is a steady progression of antiviral drug names across time and a surge of antiretroviral drug names starting in the 1990s.

So, what I like to show here, and I can’t really show it, visually, is, you know, there’s a steady rate of antiviral drug discovery on the bottom, in the black. And what you can see is this incredible burst of antiretroviral drug discovery, starting in the early 90s, and then with triple combination, more and more drugs coming on board. But, if you can, kind of, notice, starting at around 2010 and ‘11, we’re coming down on that curve. And, unfortunately, it’s not going back up. So, the latest drugs that have been approved are things like maraviroc, dolutegravir, raltegravir. These are drugs that are very potent, very effective — well, a question mark about maraviroc, but, basically, it’s now pretty well established in pharma industry that we have the arsenal that we need.

Which is interesting, because I recently was at a symposium very similar to this, for amfAR, about two weeks ago, and the symposium was all about cure. So, how we’re going to cure HIV. How are we going to take the patients — many of you that are in this room — and, basically, kill off the virus so you no longer have to be on drugs. And most of the community that was in that room didn’t care about cure. What they really cared about was, “I’ve been infected for 30 years. I’ve been through the whole drug arsenal. What’s coming next?” And the sad thing, really, is not a whole lot.

So, next slide, please. [laughing] Oh, that’s — that would be me.

Arts displays a slide depicting a complex diagram and several charts. The details of the diagram and charts are unintelligible from the audience. The bottom portion of the slide includes a lengthy list of drugs, roughly a third to a half of which are printed in bold text.

So, I kind of outlined, here, and you can’t really read it — that’s not really necessary — but pretty well everything in bold, the text at the bottom, and the different colors, are the approved anti-retroviral drugs that we have in our treatment arsenal. And many of you know that we use combinations of three of these drugs, now, typically, to block HIV. And, in the lighter text at the bottom, were drugs that were in development but, unfortunately, a lot of these drugs have just been stopped. It’s sometimes in early phase 1, phase 2, clinical trials. An example was [unintelligible] which was, you know, a potentially successful drug and just never really moved beyond phase 1, phase 2 trials. And there’s just not a lot of impetus. Pharma companies, now, and I’m not criticizing them, in some ways, but they’re much more focused on anti-hepatitis C drugs, because, really, that’s where the market is. If you look at HIV, when you have this many drugs, except for the small proportion of the HIV-infected population that has been infected for 20 or 30 years, the market just isn’t there anymore. So, there’s no market pressure to develop those drugs, anymore.

Arts displays two slides with artists’ renderings of nucleocide RT inhibitors — a patchwork of green, red, and blue lines — surrounded by a series of structural formulas.

I’m not showing this — this is just fancy, pretty pictures. And it just, kind of, shows you, again, how specific and how designer some of these drugs are, in how they can bind to the viral enzymes. And, here are nucleoside RT inhibitors — and some of those were discovered very early on, and not in relation to even HIV. These are things that bind very specifically, our non-nucleoside RT inhibitors. Efavirenz, delavirdine, nevirapine.

Arts rapidly cycles through a series of slides with similar artists’ renderings of protease inhibitors, ingegrase inhibitors, and entry inhibitors.

And then we have our whole host of protease inhibitors, and integrase inhibitors, if anybody wants to know. And entry inhibitors. But the point I’m trying to make, and it’s a sad point, and makes it an easy talk, in some ways, is we don’t have a lot that’s newly developed.

Arts displays a large line graph, mapping viral load against time post-treatment. The details of the graph are largely unintelligable from the audience.

I’m just going to go through — skip through — this, because I already have one minute left, but this is just to show you how we make mistakes in treatment and, if anything we learn from our mistakes, is that we can repeat those mistakes perfectly the next time. And hepatitis C might be in a classic example of that.

So, every company wants their miracle drug. They want to be the only drug to be utilized in monotherapy, so that it’s effective and they can make all the profits. And, as we know, in HIV, we quickly discovered that that doesn’t work, and that we need a combination of at least three drugs in order to effectively treat HIV. And we made those mistakes by going through monotherapy, dualtherapy, ineffective triple-combination therapy, more effective triple-combination therapy… And, some might argue, that the less effective triple-combination therapy, “Well, now we’re giving that mostly to patients in Africa. And the best triple-combination therapy we’re reserving for ourselves.”

With the last couple of slides, what I want to say is, resistance does occur to all of these treatments. Why does it occur? Mostly because patients are non-adherent to their ARVs. That might sound like a very critical statement, but it’s true. I mean, if I I can’t even finish an — a course of antibiotic treatment, and that’s only two weeks, so you can imagine people in this room that have to take their antiretroviral drugs for their entirety of their life — you go on a holiday, even for a month, you can develop resistance quite rapidly. Sometimes, you have some spontaneous mutations, and sometimes you just are unlucky and get infected with a resistant virus.

Now, the interesting thing is just the simple math that explains why three drugs work as compared to two and one.

So, we’re making about 10^9 particles a day. Incredible volumes of virus. Most of that is controlled and basically killed by the immune system. You’re making a mutation out of 1 out of every 1,000-10,000 nucleotides — bases; building blocks — of the HIV virus. And that virus is only about 10,000 bases long. What that amounts to is, basically, every pre-existing drug-resistant virus is in your system every single day, a hundred times over. So, you treat with one drug, it takes a matter of two or three days to develop resistance to that one drug.

That’s a lesson, I think, that’s not really well understood, yet, in hepatitis C treatment. And I’m afraid that they might learn that lesson difficult.

Now, you treat with two drugs, not every combination of two drugs can — mutations to those two drugs — are apparent at a high level. So, it’s only about maybe 10 viruses in your body that have every combination of two mutations, but that drug-resistance pre-exists prior to treatment. So, you treat with two drugs, resistance comes up. Where the math fails us is, not every combination of three mutations can appear in a virus in a patient prior to treatment. Just barely, okay? So, we’re just sitting on the borderline of math, there, and that’s why three drugs work so effectively. Now, what happens if you stop taking one of your drugs in your triple-combination therapy? You develop one drug-resistant, two will come along as passengers, and you’ll fail your treatment.

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