An Update on the Present -- and Future -- of HIV Eradication

While at CROI 2009, I had the opportunity to sit down with Robert Siliciano, M.D., one of the world's foremost researchers on the topic of HIV eradication. In August 2008 at the XVII International AIDS Conference, Siliciano offered evidence that modern highly active antiretroviral therapy [HAART] had essentially stopped viral replication in a patient's body. Here at CROI 2009, Siliciano presented further findings to suggest that residual viremia in patients with a suppressed viral load on HAART was caused by as-yet-known reservoirs of HIV. I asked him about these findings and other developments in his field.

How have things changed since the summer? Have there been any new understandings about eradication? There's been a lot of talk about the Swiss statement, there's a lot of talk about the cure -- the so-called "Berlin patient."

Robert Siliciano, M.D.

The Berlin patient: Since that hasn't been published, I don't want to comment on that. But there is a big swing in interest in eradication. I think people are now realizing that we need to put some energy into this and try to do it.

It's going to be very difficult. To me, the most encouraging thing is the fact that the drugs will stop replication. This is still very controversial. But unless you can stop replication, it's never going to work.

Why is this controversial?

I think when virologists see a virus in the blood, they think it's got to be replicated. It's a different concept to say that the virus in the blood is coming from a cell that was infected 10 years ago, before the patient started HAART. It's conceptually very difficult for people to understand.

A virus has a very short half-life. You think it's being produced by a cell that just got infected, and the whole thing is a cycle that keeps going and going. So this is a very different concept, and I think people have a hard time understanding it.

I notice that at CROI there are going to be some studies about the detection in seminal fluid of HIV [despite an undetectable viral load in the blood], and about how that poses some risk for transmission. Can you talk about that?

There are latently infected cells, essentially, all over the body, and they pose in principle a risk for transmission even in a patient who's doing well on treatment. I think quantitatively the risk is very low, but it's still there.

But there seems to be a reluctance by medical professionals in America to discuss this. In Europe, they're more willing to talk about it.

Well, there are good studies of the relationship between viral load and the chance of transmission. Basically, it's just like you would think: the more virus, the more chance of transmission. When the viral load is very low, the chance is low, but you don't want to tell patients that there's no risk because, in fact, there is a risk.

I think it's a bit hard to quantitate, and that's not really my expertise. I think the safest thing to say is that it's a low chance but you should always take precautions. Right?

A lot of people get confused when you're talking about eradication versus "the cure." Is there any difference?

No. Eradication means that there's no more virus.

And it will not come back if you stop treatment. [Dr. Siliciano nods.] OK. So what are the steps that must be taken to reach that?

There are three steps. You have stopped the virus from replicating -- that's done, in my opinion. Second, you find all the reservoirs. We know at least two exist. And then third, you find a way to get rid of each one. Those are going to be very difficult to do.

How many reservoirs are there?

We don't know. But the one that we identified a long time ago in resting T cells is there in everybody. But there appears to be a second one, and there may be others, as well.

Is anyone currently doing that work?

A lot of groups are trying to target the latent reservoir in resting T cells with small molecules.

How close are we to this understanding?

We're not close because we don't even know how many reservoirs there are, and we don't know how to get rid of them -- any of them -- yet. I think one optimistic recent development -- not published yet by our group, but other versions have been published by others -- is that there are model systems in which you can generate these latently infected cells in a test tube. That makes a big difference, because now you can begin to use those to screen for drugs that might target these reservoirs. That's what we're doing and I think that's going to really help.

Have the reservoirs in elite controllers of HIV been studied, as well?

They are hard to study because they are much smaller. It's hard enough to study the reservoir in a patient who is not an elite controller. They probably have reservoirs, but they are extremely small.

You mentioned before why eradication is suddenly being talked about again. Could it also be because the antiretroviral pipeline is somewhat dry?

I think the pharmaceutical companies are realizing that they have very good drugs now, but they're never going to cure anybody. They're going to keep people healthy if they take the drugs, but they're never going to cure anybody. So now I think it's natural that people would say, "Well, the next step is to try and go after the reservoirs."

But it's a funny moment in time, because the pipeline is kind of dry, and we don't know what's going to happen when these patients become resistant to all these new drugs.

Yes, but I would say that resistance is not inevitable. There's this whole argument of whether HAART stops replication. If HAART stops replication, resistance will never arise if the patients [continue to] take the drugs. Now, of course, if the patients don't take the drugs, then all bets are off -- if they don't take them correctly.

Right. And that seems like an ongoing problem.

It certainly is a problem, but as John Mellors mentioned, resistance is decreasing, which is quite amazing, in the U.S. That's because the newer regimens are easier to take and they don't have so many side effects, so patients actually take them.

What will happen five years from now, who knows? Ten years from now? It's hard to say.

We have a new way of evaluating the antiviral activity of drugs, and it allows us to estimate how well the drugs are going to control replication in vivo. In this analysis, certain protease inhibitors have an extraordinarily high potential, on the order of 10 logs, 10 billion-fold inhibition.

But for two classes of drugs, the nucleoside analogs and the integrase inhibitors, there's an intrinsic limitation that keeps those drugs from reaching that same high level of inhibition. The rapid drop in viral load seen by patients on raltegravir [Isentress] is really just a consequence of the fact that the drug acts later in the life cycle. Drugs acting later in the life cycle automatically produce a more rapid drop in viral load, even if they're not any more potent than other drugs.

So how do you explain the head-to-head comparison between raltegravir and efavirenz [EFV, Sustiva, Stocrin]?

I think it's a consequence of the fact that the drug is used in combination and in both of those combinations, what we call the inhibitory potential is sufficient to completely stop replication. Once you stop replication, it really doesn't matter if you have a regimen that has the ability to stop, let's say, 14 logs of replication. If there's only 6 logs occurring, it doesn't really matter. Both of those combinations have reached the limit where they control all the replication that's occurring.

In terms of raw antiviral activity: All of the integrase inhibitors have this intrinsic limitation that puts them, in terms of raw antiviral activity, below the best protease inhibitors.

Do you think this has implications for care, then?

I think this is a basic science finding, the significance of which has to be explored.

This was published where?

We have a paper in Nature Medicine, and in PNAS.

Great, thank you.

This transcript has been lightly edited for clarity.

Additional Interviews With Dr. Siliciano:
CROI 2009 Study Summary
AIDS 2008 Interview
View Dr. Siliciano's CROI 2009 Presentation