This year, the annual Conference on Retroviruses and Opportunistic Infections (CROI) was held in a virtual format due to the COVID-19 coronavirus outbreak. For the first in our video coverage series for 2020's meeting, we're revisiting a feature from 10 years ago on the future of HIV research, which is not so different from the most pressing research issues today.
Here are comments by , then and now the director of the National Institute of Allergy and Infectious Diseases (NIAID), in an exclusive 口袋女优 video from the 2010 CROI meeting. Following is a transcript of his remarks, along with updates by 口袋女优 since the video was recorded:
Anthony Fauci: We know that we can treat people to the point where decades ago before there was treatment that the mean survival was 26 weeks from the time a sick patient came in. Now if you do the same thing, someone comes in, you treat them with the 30 plus choice of drugs that we have in combination, you can extend their life span to being 69, 70, 70 plus years old. So we know we can do that. So the first part of the agenda is to seek, test, and treat as many people as you can because we know it works. The problem with that, is that if you do the math of that, the math tells you that 2.7 people get newly infected. That for every person you put on therapy, two to three people get newly infected. So 2.7 million people get infected each year. Every time you put one on therapy, you have two and a half people get infected.
That's not a sustainable paradigm as a vacuum, which leads to the second component, which is what about the possibility of getting some people off therapy who are on therapy? The quote, "cure" -- very, very high bar expectation but worth going for.
口袋女优: Treatment as prevention has become a cornerstone of trying to end the HIV epidemic, with "U equals U" (undetectable equals untransmittable), where research has now proven virally suppressed people do not transmit the virus to their partners.
Fauci: But the real underscoring that I did in the talk was to talk about prevention. There are a couple of ways that we've got to get prevention and that is really the answer. We can't, even though we have good treatment that's not in a vacuum alone going to do it. So the three ways that I spoke about treatment as prevention were microbicides. First of all, we failed in the microbicide trials because microbicides have not worked because they weren't antiretrovirals in the microbicide. They were more of a detergent. A big trial just recently failed just a few months ago.
Prevention and early PrEP research
Fauci: So the next trials that are ongoing are trials that use a microbicide like a vaginal gel, but incorporate into that a long acting antiretroviral. So we're looking forward to the results of those trials. Secondly is what's called prep or preexposure prophylaxis. We know it works with other diseases like malaria, number one. Number two, we know postexposure prophylaxis works and we know that mother to child transmission prevention works. We're doing a number of clinical trials to test the concept of whether we can actually prevent infection by preemptively treating people who are practicing high risk behavior.
口袋女优: Ten years later, pre-exposure prophylaxis (PrEP) has also become a mainstay of HIV prevention, with Truvada, and the recent approval of Descovy for HIV prevention in certain populations. However, wider access to PrEP, especially among medically underserved populations, remains elusive.
Fauci: And then the other was a broad, very, very challenging concept of test and treat, which is a mathematical model that was put forth about a year and a half ago where you go out and test as many people as you possibly can, preferably 95% of the people that you can get to and if they're infected immediately treat them regardless of their CD4 count or their viral load so that you bring down the mean viral load in the community, which would then help prevent those people from passing the infection on to other people. That's called a test and treat.
And finally I spoke a bit about vaccine and the challenges we have with vaccine. We have a very encouraging but small positive signal with a recently worked out Thai trial with 16,000 participants. So I laid out the agenda where I think we need to go over the next several years in the vaccine and putting all those things together. Very high bar for expectations, very high risk projects, but very high impact and we're going to go for it.
RV144 and HIV vaccine trials
Fauci: We have a trial that gave a positive signal in acquisition efficacy, 31%. But when you examine the immunological response, we don't see any neutralizing antibodies that are of any substance. We don't see the kinds of T-cell responses that we had been looking for in other trials. So what we've learned is what is not necessarily needed. That doesn't mean that neutralizing antibodies are not going to be important. I'm sure they will be important to a certain extent as will cell mediated immunity, but we had a positive signal without any of the known immunological parameters being overwhelmingly present, so we learned a lot. We're looking now for the correlates of immunity and hopefully we'll find them. If we do, as I said in the talk, then we'll design trials to enhance or optimize those correlates of immunity.
口袋女优: Despite the recent failure of HVTN 702, which built off the RV144 trial to which Fauci referred, several HIV vaccine trials continue. These include trials of a vaccine that uses a "mosaic" antigen designed to target a variety of HIV subtypes around the world.
Test-and-treat
Fauci: Now, test and treat as a concept is something that may or may not be implemented. Before you implement it, you have to determine feasibility. So we need to determine, can you actually access people by wide voluntary testing when you get to the people you need to. When you get to them, will they be tested? When they're tested, if they're positive, will they have access to drugs? If they have access to drugs, will they take the drugs? And if they do, will it be effective? So there's a whole series of feasibility studies before you can implement a very bold policy.
口袋女优: Test-and-treat seemed to prove its mettle in African communities, with a more aggressive, community-based approach to treating HIV in the community that reduced rates of infection versus standard of care. But recent research also indicates varied success with this strategy, depending on the community.
On the Berlin Patient and cure
Fauci: It's not practical for several reasons. One, doing a STEM cell transplant and ablation of the host is a very, very serious undertaking. This person happened to have a leukemia that needed that transplant and they got as the donor, someone who was not only histocompatibility matched but had that defect, the homozygous Delta-32, which does not allow the person to express one of the important receptors for HIV. And the reason that after the transplant, the person did not have any viremia is that whatever virus is in there can't go anywhere because the cells that are now populating the body don't have the receptor. That is totally non feasible on a large scale basis. But what it does show is a proof of concept that if we're able, for example, to silence the expression of a CCR-5 gene by gene therapy, maybe, and that's a big maybe, then maybe you can assume the possibility that in some people you may be able to have a cure. But to talk about STEM cell transplants and ablation on a wide scale is just not feasible.
口袋女优: Almost 10 years later, a second patient achieved HIV remission, the so-called "London Patient," who received a similar type of stem cell transplant, and remains in remission after 30 months, though this remains an anomaly and not a scalable approach for cure.
Kick-and-kill
Fauci: We know we have very good drugs and those drugs can drop the viral load to below detectable level to the lowest you could possibly imagine for an extended period of time. Give people decades of life. What the currently available drugs that are truly antiretrovirals don't do, they don't eliminate the latent reservoir. So we spoke about a whole series of chemical, molecular, activating elements that could perhaps purge or flush the virus out, block it from expression, totally different concept than suppressing the replication of the virus. It's like getting rid of that integrated virus that's in the lately infected cell.
口袋女优: Despite many trials, kick-and-kill, or shock and kill, has yet to prove itself as an effective HIV cure.