Terri Wilder: Richard, in the antiretroviral therapy section of the Pipeline Report, you write about the fact that the past year was a fallow period when it comes to the emergence of new antiretrovirals [ARVs] onto the market, and that the most significant news regarding FDA review of new ARVs was actually an approval that didn’t happen. You were, of course, referring to the application to approve the first once-a-month, long-acting, injectable ARV combination, which goes by the trade name Cabenuva, comprised of the integrase inhibitor cabotegravir and the NNRTI rilpivirine.
Can you tell me about what happened, and if we will have an injectable in the United States anytime in the near future?
Richard Jefferys: You know, the timeline is a little bit unclear. There’s nothing wrong with the data on the drugs. The FDA apparently had some concerns about the process of scaling up of manufacturing, because the company’s trying to scale up, obviously, for when they can market the drug. And there was some kind of technical issue, which is in the process of being addressed, and nobody’s really made any predictions about when approval might happen. But it seems unlikely that it’s going to be a long time, particularly since approval was given in Canada. So I don’t think it’s an unsurmountable issue; it’s just some kind of technical thing to do with manufacturing that needs to be sorted out in order for the FDA to be comfortable with giving their approval.
TW: Do you think that the fact that we’re in the middle of the COVID-19 pandemic could be impacting any kind of drug development?
RJ: I think there’s a bunch of ways. One issue is that it may be contributing to that particular slow-up and that there might need to be FDA inspections of manufacturing, which have been delayed for Cabenuva. So that could be going on there.
But in terms of broader drug development, I think the main factors have been on ongoing clinical trials; and that’s mostly involved clinical trials being placed on hold, and the FDA has issued some guidance around handling data collection, and so on. So I don’t think it’s—hopefully, it’s not going to be devastating to a lot of research; it’s just going to be a pause with some follow-up happening virtually, where possible, and so on.
The other issue is, I think, too, maybe some people are being torn away from their HIV drug development work to do work on COVID for the time being. And so there may be some kind of issues of staffing, particularly in the industry, where people are switching roles, at least temporarily. But I would be hopeful that, depending how things go more broadly with the COVID pandemic, that this is not going to be a big factor this year. But we’ll have to keep an eye on things and see.
TW: In the document, you also write about islatravir as both the treatment for HIV, and as a potential for PrEP. Can you talk a little bit about that drug? Just kind of explain what it is, how it could be used both for treatment and for PrEP?
RJ: Sure. It fits in within a broader array of anti-HIV drugs. What seems to be a little bit special about it, and what makes it a new class of drug, is the way that it hits part of the virus that a lot of other drugs target, the reverse transcriptase enzyme. AZT, the first reverse transcriptase inhibitor, the first HIV drug; and we now have lots of other reverse transcriptase inhibitors, but islatravir does it in a slightly different way. And I don’t really—I’m not smart enough to understand all the biology and the science that’s involved. But somehow it inhibits the reverse transcriptase in multiple different ways. And that seems to be why it’s very potent. And when they say potent, they mean that it inhibits HIV replication very strongly, even at low doses.
So, in the treatment trials, they’re using a daily dose of .75 mg, which is low; and it’s to do with the potency that the drug has in treating HIV. And it also means that they can potentially give higher doses, less frequently. So, in a trial that’s just getting started soon on pre-exposure prophylaxis for HIV-negative people, they could give it in a monthly dose.
They’ve also looked at whether it could be possible to administer it via a subcutaneous implant, which could last for up to a year, which would be obviously a very different and potentially helpful approach if it could be done safely. But that’s in an earlier stage in development. I think the main hope is that it’s going to be something that just inhibits HIV very strongly in doses that are low and with no major detrimental side effects.
TW: The other drug that I wanted to ask you about could be helpful for folks who are heavily treatment experienced, people with HIV who have multidrug-resistant virus. I’m wondering if you can talk about this drug that you wrote about, fostemsavir, and what that drug could potentially do for folks who have multidrug-resistant virus.
RJ: Sure. These are individuals who have often been on treatment since maybe the early ’90s, or sometimes even earlier, that have developed—the virus has developed resistance to all types of approved HIV drugs. And it can be a population for which there are very few options. So it’s good to have something new arriving that seems to have a reasonable degree of activity. It’s an example of how the TAG Pipeline Report can be out of date almost instantly. The day that we published the Pipeline Report, there was a press release announcing that fostemsavir has been approved by the FDA. So it’s actually going to be available for prescription to people who need a new option, which is good news.
It works a little bit differently than most of the approved drugs. Most of the approved drugs block steps in the HIV lifecycle while it’s inside a cell. And this drug blocks attachment to the cell when the virus tries to glom onto the cell to start the infection process; this is where the action of this particular drug happens. It seems like maybe 50% to 60% of people that receive it have had CD4 T-cell count increases, got good long-term suppression of viral loads. There’s been a study out to 96 weeks. The side effects seem relatively infrequent; maybe about one in five people get an adverse event. But in the trials, only 7% had to stop to address them, which is not so bad. The main problems have been nausea, diarrhea, and headache.
So I think, as there tend to be very few options in this situation, it’s good to have something new out there.
TW: You have these really nice charts that have lots of other potential drugs coming down the pipeline. And I’m wondering if there are any others that you find particularly exciting or interesting to talk about right now.
RJ: There’s been another novel long-acting drug that may be helpful, both in the same population with a lot of resistance, but also might work for people who haven’t been on treatment yet. It’s called a capsid inhibitor. The HIV capsid is this enclosure within the virus that contains virus genetic material. And it has a role in multiple steps of HIV infection. And this is the first drug to inhibit the capsid from doing what it does.
It’s called lenacapavir. There’s a couple of studies being started now; one for people with resistance and one for people without. The dosing is about once every six months, so that’s a really long dosing interval. It will be interesting to see how that drug works out.
The other new thing in terms of what’s happening with antiretroviral research is the first trial combining the long-acting antiretroviral drug cabotegravir, an integrase inhibitor, with what’s called a broadly neutralizing antibody. So this is actually an antibody generated by the immune system, which can be isolated and produced as a potential therapeutic. And there’s a particular broadly neutralizing antibody called VRC07 that’s being combined with cabotegravir in a study. It’s combining an immune-mediated intervention with a drug. And they’re both long-acting. So, this could be possibly a wave of the future, of maybe combining these approaches.
Another good thing about antibody-based therapeutics is that they tend to be safe because they’re derived from somebody’s own B cells; they were made by the human immune system, originally. So that is something we may start to see more of.
TW: Let’s move on to the section that you wrote about HIV vaccines, passive immunization, and antibody gene transfer. What are some of the key areas of interest here?
RJ: There are two big vaccine efficacy trials testing whether a particular HIV vaccine candidate works. One is in several—I think five different African countries involving women that are at high risk of HIV infection. It’s a vaccine developed by Johnson & Johnson. The trial is named Imbokodo; and it was announced at AIDS 2020 that this trial is now fully enrolled and they’ve administered all the vaccine doses. So it’s now in follow-up to see whether the vaccine did have any effects in terms of protecting against HIV. We might get results before the end of the year or early next year.
That would be important, because that’s really the lead vaccine candidate right now. It’s based on a viral vector platform, which delivers fragments of HIV into the body to generate an immune response.
There’s another study looking at the same vaccine, pretty much the same vaccine regimen, in gay men and transgender individuals. The study is called Mosaico, but that’s only just getting underway. That’s going to be the next big HIV vaccine result to look out for.
And the other big efficacy trials that people are waiting on results from are called the antibody-mediated prevention studies, or the AMP studies. This falls into the category of passive immunization. And it’s centered around the broadly neutralizing antibody VRC01, to see whether it has any effect in preventing against infection. That could be an important benchmark, because it’s the first time researchers have tested whether a broadly neutralizing antibody can prevent infection. This may not be the best broadly neutralizing antibody, because it’s one of the earliest that was discovered. But if it works, then that would be a strong impetus to develop more and better broadly neutralizing antibodies. And there’s an array of more potent and longer-acting broadly neutralizing antibodies that are in development.
And there’s collaborative work going on. Some of it was announced during the AIDS 2020 conference, where National Institutes of Health, IAVI, and Scripps are partnering to try and bring all their resources for doing this research together. And IAVI is also partnering with the Serum Institute of India, because broadly neutralizing antibodies can be costly to produce—they’re proteins that have to be grown in these big bioreactors. And so this partnership is working out how you can make those efficiently and cheaply so that if they are effective, they could be something that people could access globally.
TW: I also want to talk about cure and immune-based therapies. In particular, at the International AIDS Conference, information was presented about the Brazil patient who may be cured. So, we now have Timothy Brown, the London patient, the German patient, and, hopefully, the Brazil patient. And I hope to interview Dr. Diaz about the Brazil case. But I’m curious about your thoughts on it.
RJ: Every time we have a case where somebody seems to be controlling or containing the virus from rebounding without ongoing treatment, that’s really going to be encouraging news.
But because it’s a small number and they’re very individual, it’s very tough to be sure what the implications are for the majority of people living with HIV. And so, in this case in particular, the individual had received some additional treatments added on to a standard antiretroviral treatment regimen during a trial and then, quite a long time later, about two-and-a-half years later, had undergone what we call analytical treatment interruption to see if viral load rebounded. And they didn’t detect a rebound. The individual has been off HIV treatments for over a year now without detectable virus rebound. So that’s good news.
But it’s uncertain whether—it seems that this was a person that was treated relatively fairly early after they became HIV positive. It might have been within six months. And then they stayed on antiretroviral therapy for a long time.
And there have been other cases like that, where people become what we call post-treatment controllers when they interrupt treatment; so it’s a bit unclear whether it might have happened even if the person hadn’t been in this particular trial. And the trial involved giving them three additional interventions: an integrase inhibitor, dolutegravir; maraviroc, which blocks HIV from interacting with the CCR5 receptor on T cells; and nicotinamide, which is a form of vitamin B3, which may have some activity in waking up the dormant virus that persists in the body when people are on treatment.
But because there were 30 people in the trial getting various combinations of these interventions, and just this one person hasn’t rebounded, we don’t really want to mislead people into thinking that those interventions may be curative, because the evidence really isn’t there. That’s something that needs to be further investigated. I believe the investigator, Ricardo Diaz, is going to get funding to do a large trial, which will help shed light on whether this individual might have been just able to control naturally, or if it was something to do with the interventions in the trial.
And also, there’s a little bit of difference with the people that you mentioned that received stem cell transplants. Scientists have a pretty good idea of what’s going on in those cases, or at least evidence about what’s happening in terms of when someone gets a stem cell transplant: There’s a lot of what’s called conditioning, because you’re getting a new immune system from a donor. So your own immune system has to get knocked out first before you receive the donated cells. Because immune system cells contain HIV, the process depletes the number of HIV-infected cells in the body very drastically, and that’s known from a lot of studies in people only getting stem cell transplants.
And then in each case, the donor of these stem cells had a genetic mutation which blocks CCR5 and makes the immune cells resistant to HIV. That seems to be a part of how cure was achieved in Timothy Brown and, hopefully, these two other cases in London and Germany. And so, there is a certain amount of clarity there about what happened. But we don’t have that clarity regarding this case in Brazil yet.
It’s possible that there was actually a brief viral load rebound that was missed, because the time between when they stopped antiretroviral therapy and the first measurement of viral load was three weeks. And one of the data graphs that was shown suggested that the CD4 count did decline somewhat after the treatment interruption, which maybe suggests that there was some HIV activity there.
And so this individual might turn out to be more of a post-treatment controller, where the virus is then being contained by the immune system, rather than necessarily a cure case. And it will all take some time to figure that out.
Sorry; that was a really long answer!
TW: That’s OK. I mean, you actually brought up two points that I wanted to talk about. In the Pipeline, you mentioned that scientists Jennifer Zerbato and Sharon Lewin provided some commentary to something that was published in the Lancet. It speaks to something that I think a lot of us talk about, think about, in terms of how do you define a cure? What they stated was a cure for HIV might be better defined as no intact virus, rather than no detectable virus.
What do they mean by that?
RJ: When they go looking for virus in the body using tests for HIV genetic material—so, tests for HIV DNA or HIV RNA—they can pick up a lot of fragments of virus because it’s pretty sloppy as it replicates; it’s just made of a tiny bit of RNA. It doesn’t have any sort of mechanism to make sure all the copies that it makes, when it’s trying to replicate, are intact. And so a lot of people have a reservoir of HIV copies in the body that are really fragmentary and can’t actually generate virus that’s intact and capable of replicating. And sometimes those tests have picked up low-level fragments of virus in Timothy Brown and the London patient.
It doesn’t mean that those people aren’t cured. It just means that there might be some fragments of virus still existing in some of their cells. What seems to be important is whether there’s any virus that’s intact and capable of replicating.
There’s a test in development that’s starting to be used now, which really tries to assess whether the virus that’s been picked up is intact and capable of reproducing. And there’s some evidence that people who naturally control viral load without treatment, that we call elite controllers; it seems that they have much less intact HIV measurable in their body. It’s like their immune responses seem to be preferentially depleting the functional viruses and the cells containing that virus from their bodies. And that may be contributing to their ability to control HIV. It may even be possible that that’s part of what’s happened in the case of Brazil—that he had a particularly good immune response against the cells that contained the most dangerous kind of intact HIV, and not just the junk, the sort of dead-end, fragments of virus.
TW: I’ve heard of elite controllers before. But in the Pipeline, you also talk about what is being termed as exceptional elite controllers. I’m curious: What is the difference between an elite controller and an exceptional elite controller?
RJ: Science does love its terminology. New terminology often pops up for things, but this does seem to be an important distinction. Elite controllers are people that have acquired HIV and have a very strong immune response that suppresses viral load to undetectable levels, without going on antiretroviral therapy—or at least not needing to go on for a number of years. There are certain immune response genes that seem to be predictive of that happening. It seems to be more common in women than men.
But for most of these elite controllers, if you use the research tests that are very sensitive, they will find virus and perhaps evidence of virus replication still ongoing, but at a very low, controlled level. And they’ve done detailed studies and found that even among elite controllers there can be differences. Because it turns out that some elite controllers really show no detectable intact virus by any of the tests that they can do. And so that’s how they’ve gotten the designation exceptional elite controllers.
One case that’s been studied in particular detail, who’s publicly identified herself, is Loreen Willenberg. Loreen has participated in many studies over the years since being diagnosed with HIV in the early ’90s. And she seems to be a case of an exceptional elite controller, where it’s possible that her immune system, over time, has depleted all of the cells containing intact HIV. So it’s possible that it may be a kind of natural cure, resulting from immune response against HIV.
A huge goal of research now is studying individuals like that to figure out if you can learn how it happened and translate that to therapies for the majority of people with HIV, who aren’t naturally able to control the virus.
TW: It’s great that she has been so involved for so long, in terms of research, which kind of makes me think of something else that was mentioned in the Pipeline, that women still remain underrepresented in HIV cure research and looking at issues around that topic, as well as who is an elite controller, how are they an elite controller. Why do you think women tend to still remain so underrepresented in research and, in particular, in HIV cure research?
RJ: Sure. I think I may not be the best expert on this; I should start by saying that. It’s not a unique thing to cure research. There’s also analyses of cardiovascular disease trials, for example, which have shown underrepresentation of women. There’s an analysis that was done by the AIDS Clinical Trials Group that the most commonly cited reason was lack of information. Clinical trial sites may rely on cohorts of people that they’re familiar with over a long period, which in HIV has tended to be gay white men. There have also been issues identified related to women having more competing priorities. Childcare can be an issue at research sites; and lack of incentives to compensate for the costs of participation. Also the sense that the recruitment that’s being done for research is really targeted to other people, and not really being targeted to women. There can be some restrictions that I think people are trying to address around when there are concerns about potential toxicity to a developing fetus, such as onerous requirements about using two forms of contraception, for example.
And so I think most of the work that’s really looked at this in detail has cited the need for more specific outreach and education to make people aware of the research that’s happening.
But it’s also important to understand that people make rational decisions about why they might not participate in a study. And a lot of cure research right now, it’s very early stage. It often involves risks without offering any direct benefits to participants. So people may be making perfectly rational decisions to wait a little bit and see how the research progresses, before they participate in a trial.
One of the pre-conferences before AIDS 2020 was called Pathways to a Cure. And there was an excellent presentation by Eileen Scully on this issue. Eileen Scully has conducted a lot of research in this area, including an AIDS Clinical Trial Group trial that was for women only. It involved studying the effects of tamoxifen on the HIV reservoir. And it enrolled very quickly—so it can be done.
Also, the last thing, the locations where cure research is happening right now are still primarily in the U.S., Western Europe, Australia. The countries where women make up a far greater proportion of the HIV-positive population, such as South Africa, have not been well represented. But that’s beginning to change. There’s a cohort of women with newly diagnosed HIV in South Africa called the FRESH cohort. And there are trials planned there of interventions that might hopefully lead to post-treatment control.
TW: I wanted to ask about immune-based therapy development as an adjunct to ART. It seems there has been relatively little activity in that realm. Why is that?
RJ: I think the biggest challenge is proving that an adjunctive therapy works. Because, for most people, suppression of HIV viral load by antiretroviral therapy has a really beneficial effect. It reduces the risk of disease progression or clinical events very greatly. But there’s a population that doesn’t experience good immune reconstitution despite having suppressed viral loads. It tends to be maybe around 5% to 10% of people, and it’s a bigger risk for people who start antiretroviral therapy late, a long time after diagnosis. There’s evidence that they are at a slightly greater risk for comorbidities and perhaps mortality. But proving that a therapy can reduce that risk; it’s really challenging. You’d have to do a very large trial involving thousands of people, because the incidence of the bad outcomes is thankfully pretty low, even in people that don’t get great immune reconstitution.
And so, proving that a therapy was effective at preventing those outcomes is very difficult.
TW: So, let’s talk about the REPRIEVE study that had enrolled 7,557 participants to evaluate whether pitavastatin calcium can reduce the incidence of heart disease in people with HIV, with overall morbidity and mortality included as a secondary endpoint.
In the Pipeline Report, you said the results are still pending. I’m just wondering if you can kind of talk about this and what we’re hoping will happen with this.
RJ: Sure. It’s fully enrolled, and so it will generate an answer, we’ll have to wait and see what it is. The main thing it’s looking at is whether a statin drug—pitavastatin calcium—can reduce heart disease in people with HIV. The main mechanism is thought to be decreasing bad cholesterol and triglycerides, while increasing good cholesterol.
But it’s known that these drugs can also decrease inflammation, and high levels of inflammation are associated with a greater risk of comorbidities in people on antiretroviral therapy. And so the trial should help to show whether a drug that reduces inflammation actually also benefits health by reducing the incidence of comorbidities. In smaller studies where something shows some ability to reduce inflammation, the incidence of health outcomes is too low to know whether the anti-inflammatory effect had a health benefit. When you have so many people, when there are thousands in the study, you’ll be able to see whether modulating and reducing inflammation actually had the effect that you care about—stopping people from getting sick and dying.
TW: There are lots of conversations around the inflammatory process that HIV creates. And I was thinking about it as I was reading the Pipeline. I’m wondering if anyone has ever thought about looking at low-dose naltrexone for inflammation. It’s something that is prescribed off-label. It wouldn’t be covered by insurance in the United States, because it has to be—you have to get it through a compounding pharmacy.
And I know it’s prescribed for people who have myalgic encephalomyelitis (ME), which has an inflammatory element to that disease. And I was just wondering what your thoughts are. Have you heard if anybody’s looking at low-dose naltrexone as something for inflammation for HIV?
RJ: There’s no trials at the moment. It’s something that’s been on and off the radar screen. It was first proposed by—at least my recollection is that it was first proposed by a doctor in New York, Dr. Bihari, in the mid-’90s, based on some apparently beneficial effects in maintaining CD4 count, in the pre–combination antiretroviral therapy era.
There’s been a few studies since, but there’s a lack of real detail on any anti-inflammatory effects and some suggestion of possibly maintaining CD4 count a bit better, but not really all that convincing. And at the moment, it’s not being looked at.
I think it’s also been studied for its approved indication, on which I’m not an expert at all, which is potentially being used for opioid or alcohol addiction.
TW: We’ve kind of woven into our conversation some topics covered during the International AIDS Conference. But I’m just curious, in closing, what were some of your impressions? And what were the most important developments out of AIDS 2020?
RJ: Circling back almost to where we began, maybe the biggest news was about the long-acting cabotegravir injectable, but not in the treatment realm; in the pre-exposure prophylaxis realm. There was a study called HPTN 083, looking at long-acting cabotegravir, given not monthly, but every eight weeks, for HIV prevention, which found that it was actually superior to the currently approved Truvada PrEP. It reduced the rate of HIV infection by about 66% compared to Truvada. There were 13 infections, I think, in the cabotegravir arm, versus 39 in the Truvada arm.
It doesn’t mean that it’s better, necessarily, than Truvada for someone who’s still able to take daily Truvada pills and is doing fine with it as PrEP. But it’s an option for people that may want something that’s less frequent. It looks like it could be important.
But it’s going to be necessary to wait for results from a separate trial called HPTN 084, where it’s being looked at in [cisgender] women. And there were some infections in the CAB LA arm that occurred while people were on the drug. So they’re trying to figure out exactly what happened there, whether it was due to drug resistance or something else.
And there are implementation issues to address in terms of, logistically, it’s a bit complicated to start and stop the long-acting cabotegravir because it persists in the body so long. But it looks like it could be an important new option for pre-exposure prophylaxis.
I think it’s going to be critical to look for what kind of pricing is going to be proposed. The researcher, Rochelle Walensky, has pointed out that generic Truvada is going to be available very soon. So the company that makes cabotegravir, ViiV Healthcare, should be pricing it cheaply. Because it’s going to be competing with generic Truvada. They shouldn’t be charging a premium, because that’s going to make it problematic for people to access.
I think the other news that’s worth looking at is the big analysis of the Veterans Administration Cohort, looking at people with HIV that became infected with COVID-19. And they didn’t find any significant difference in outcomes based on HIV status, which is a little bit reassuring. There had been some differences in prior studies. And this was the largest study to date.