Q&A with John Mellors on Cure Research, Truvada for PrEP

John Mellors is the chief of infectious diseases at the University of Pittsburgh. His research focuses on antiretrovirals (ARVs), such as HIV resistance to them, using them for preexposure prophylaxis (PrEP) to prevent HIV infection in individuals, or modeling to see how PrEP affects the HIV epidemic. He also studies HIV reservoirs in patients on antiretroviral therapy (ART) and how to eliminate them. Mellors is also a member of the scientific advisory board of Gilead Sciences, the maker of Truvada, a combination of the ARVs tenofovir and emtricitabine. On May 10, Mellors spoke on behalf of Gilead at a hearing, where an expert advisory panel recommended to the FDA to approve Truvada for PrEP. The FDA is expected to make a decision in September. If approved, this would make Truvada the first ARV to be approved for PrEP. At the recent Cold Spring Harbor meeting on retroviruses, Mellors gave a Keynote address on how to eradicate HIV from the individual and from the world, focusing on cure research and antiretroviral drugs. I had the chance to talk to him about recent progress in cure research, and about what FDA approval of Truvada for PrEP would mean.   

What do you think is the most important challenge right now in terms of eradicating HIV from the individual? 
The greatest challenges are determining where the reservoirs are; how much you can affect the reservoir by inducing HIV expression; and what fraction of the reservoir you really have to affect to alter the outcome when therapy is stopped. There are probably 1,000 proviruses per a million CD4+ cells that are resting. Do we need to get rid of all of those? 10 percent? 50 percent? One percent? And where are the proviruses? Just in resting CD4+ T cells? In brain, in microglia, in alveolar macrophages? These are critical questions.   

Are we anywhere near solving that problem? 
No, just the beginning. Very early days.   

What has been achieved, and what are the obstacles? 
The most interesting data is [from David Margolis] that a histone deacetylation (HDAC) inhibitor, SAHA, induces an increase in cell-associated HIV RNA after a single dose. The questions that arise from that are: Is that enough to kill the cell, or does the cell return to a resting state and there is no net change? What happens with repeated dosing? What happens to the reservoir? These are all answerable questions, not simply, but with the right methodology, they can be answered.   

So you believe that HDAC inhibitors could actually maybe help find a way to eradicate reservoirs? 
As an initial step forward. I just want to emphasize these are very early days.   

At the Keystone meeting on HIV Pathogenesis earlier this year in Whistler, Tae-Wook Chun reported that cell free HIV RNA does not go up in cultured cells if you treat them with the HDAC inhibitor SAHA. What do you think about that? 
I don’t know about that. Well, in our own laboratory, depending on the HDAC inhibitor, free virion production goes up in response to treatment in a dose-dependent manner with resting CD4+ T cells. Again, the observation that results don’t always match up is no surprise in science in general and no surprise in this field. The devil is always in the detail: How you isolate the cells, what conditions you culture them under, etc. etc. But a consensus will generally arise from multiple labs doing it. That’s how science goes forward.   

Other than HDAC inhibitors, is there anything else that you think is interesting right now to address the reservoirs? 
There are some compounds that have been identified through screening that show activity in vitro and in cells ex vivo. So again, early days, but there are some leads.   

Shifting gears to PrEP: On May 10, an expert panel recommended that the FDA should approve Gilead’s Truvada for PrEP. You were there? 
I summarized the data for the sponsor, who is Gilead Sciences. I gave the last presentation before the panel discussion, and the data are fairly clear: That it works. If you take it and have blood levels, it works. It’s protective in the 75-90% range.   

It works in what setting? 
In MSM [men who have sex with men], in serodiscordant couples, and in heterosexuals.   

What was the hearing for? 
The FDA, before they consider drug approval, often convene a panel, where benefits and concerns are fully vetted. In this case, the benefits are that an individual can protect themselves if they take the medication. The concerns are about toxicity, about increased risk-taking behavior that might result, about resistance, and about cost. On balance, the panel felt that the benefit outweighed the risk with some cautionary notes.   

What does the panel recommendation mean going forward? 
Now the decision to approve or not will be made by the FDA. The FDA often makes a decision that is synchronous with the panel—not always.   

If the FDA did approve this, what would that mean for people out there and for PrEP in general? 
It would change that it’s an FDA-approved indication, which has implications not only for the U.S. but the rest of the world, because many approval agencies in the rest of the world follow the U.S. FDA. So if it was not approved by the U.S. FDA, it would be very unlikely that it’d be approved by another country’s agency.   

For what group of HIV-uninfected people would it be most important that this was available as an approved treatment? 
It’s prevention. The greatest benefit will be for high-risk individuals who want to protect themselves, adhere with it and who have no control over prevention measures from their partner—i.e. condom use or antiretroviral therapy. The sponsor, Gilead Sciences, will support educational programs and monitoring programs, so that the drug will have a sponsor, a champion that ensures that it’s used properly, promotes HIV testing, and makes sure that individuals are placed on the drug and monitored. With approval, monitoring is required.   

What could I do if this was approved that I can not do now? I could already get it now for prevention, right? 
You might be able to get it, written by a physician who is using it off label. That’s a lot different than physicians being able to pick up a variety of resources and say that this is approved for HIV prevention. Many physicians are reluctant to prescribe anything off label.   

And it wouldn’t be paid for by health insurance? 
There is no chance it would be paid for by health insurance. The other really important thing is that condom use is highly efficacious for HIV prevention, but to require condom use means that you are inhibiting a partnership’s ability to procreate, and in many cultures, that’s completely unacceptable.   

So promoting condom use alone is not enough in a lot of countries? 
No, because fertility and reproduction are incredibly important parts of society across cultures.   

If this kind of PrEP was going to move forward and spread in the population, would that ever be sufficient to eradicate HIV? 
I think it would be difficult. I think in the near term it can prevent infections. Eradication of the epidemic worldwide is going to take a massive effort for both treatment and PrEP.   

In your keynote address at the recent Cold Spring Harbor meeting, you mentioned recent modeling you and your colleagues did of the effect of PrEP on the epidemic. Can you elaborate on those numbers? 
The modeling says that even with 96% efficacy in reducing transmission, you are going to have to treat people well above a CD4 count of 500, and even doing that, it’s going to be hard to get the basic reproductive number below one.   

And that number means? 
If you have an infected individual, how many other individuals become infected from that individual. If it’s less than one across all infected individuals, the epidemic will eventually die out. If it’s equal to one, then the epidemic will be at a dynamic equilibrium, i.e. steady state without change in the number of infections, incidence or prevalence. If it’s greater than one, the epidemic will grow.   

You also mentioned potential problems because the same drugs are used for treatment and prevention? 
There is overlap between treatment and prevention. So all our modeling shows that the prevalance of drug resistance increases with exposure to drugs. The more drug exposure, the more selective pressure on the virus, the more resistance. If you are using the same drugs for treatment and prevention, then you are likely to get spread of resistance to both agents.   

What would be the solution to that? 
Developing non overlapping drugs.   

Is anybody working on that? 
There are a variety of products that are in development for prevention that don’t overlap, for instance [the CCR5 inhibitor] Maraviroc is in development for prevention. A study in MSM of an oral regimen of Maraviroc is going forward. It’s a phase 2 study called HPTN 069.   

In your Cold Spring Harbor meeting keynote address, you mostly spoke about ARVs and cure. What’s your advice for the vaccine field from your perspective? 
My advice is to keep working hard. The most interesting thing that’s arisen is antibodies that seem cross-protective in challenge studies. Keep an open mind about how you deliver those antibodies to individuals, whether you have to induce them with an immunogen, or whether you can come up with a means of delivering them to an individual short of an immunogen, i.e. through an expression system. It is conceivable that you can make an antibody last a very, very long time. You could engineer an antibody and either transiently express it or transiently infuse it to keep levels high for a long time. This is kind of pie in the sky but should be explored. The science of inducing an immune response is still incredibly complicated, and difficult to overcome. Immunogens generally work, or don’t work. The science of why they do and do not work is evolving, but it’s by no means as well defined as how you get a small molecule into the body and prevent it from being metabolized.   

So in terms of eradicating the epidemic—vaccine or ARVs? 
Vaccine, vaccine, vaccine, vaccine, in theory. In terms of tools available now: Antiretrovirals, antiretrovirals, antiretrovirals.