Reevaluating Prospects for HIV Eradication

Last summer, before the 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Sydney, Dr. Tony Fauci [Director of the National Institute of Allergy and Infectious Diseases] wrote about eradication and said that, with the new drugs -- raltegravir [MK-0518, Isentress], for instance -- it might be possible now to reconsider the question of whether HIV can be eradicated.¹ What do you think?

As I said in my talk,² I think there are three steps that are necessary in order to eradicate HIV. First, you have to stop the virus from replicating. That part is working very well. The current drugs, if taken correctly, in our opinion, completely stop replication.

Robert Siliciano, M.D., Ph.D.

Do they stop replication, or are our tests unable to detect replication below 50 copies/mL?

No. The tests can detect down to a single molecule of HIV RNA. What happens in patients who are doing well on current treatment -- and I'm not talking about raltegravir; I'm just talking about standard HAART [highly active antiretroviral therapy] -- is that the level of viremia is between 1 and 50 copies/mL. If you add another drug, it does not go any lower. What that means is that most of that viremia is not susceptible to further inhibition. In other words, we have already reached the maximum potential of HAART. You cannot do any better. The reason is that that virus, in the plasma, is coming from a stable reservoir. It's a cell that was infected before HAART started.

I think there's been a big failure to understand how well the drugs work -- a lot of misinterpretation and misinformation. If the drugs are taken correctly, they work extremely well. When people fail HIV treatment, it's usually because of problems with adherence, absorption or pharmacokinetics. The drugs themselves -- as the new research I presented explained -- are actually working way better than we ever thought, because we weren't looking at them in the right way and measuring the amount of inhibition that can actually be achieved.

As I mentioned in my talk, some of the protease inhibitors cause a 10 billion-fold inhibition in just one round of replication. Thus, if you infected 10 billion cells in the presence of one of the best protease inhibitors, not a single cell would get infected. At that level of inhibition -- which we can demonstrate now in vitro -- it's very hard to understand how any replication could be occurring in patients on HAART.

Are these new tools that we didn't have before?

We have a new assay that measures single infection events in the test tube, and it's a new mathematical way of analyzing the replication. Basically, it's going back to a fundamental equation in pharmacology, which has three variables. One of the variables had been neglected in all of the previous research, and that turns out to be very important. You can't get the right answer if you leave out one of the variables.

What about the reservoirs? You talked a little bit about how we eradicate HIV from the different reservoirs.

We still don't know. The original approach that was tried was very crude. It was to activate all of the T cells and hope you turn on the one in a million that has latent HIV. That's clearly a crude way of doing it, and one that has too much toxicity. We need a selective way and we don't have that, but we are finally developing ways to make these cells in a test tube so that we can find a way to selectively turn them on.

Is there any work being done looking at which HIV meds may be better for the reservoirs?

It doesn't matter. If you have suppression to below 50 copies/mL, the virus is not replicating anymore. It doesn't matter what step in the HIV life cycle you block; as long as you have an effective combination, you're getting to the maximum potential. I think it's wrong to assume that blocking integration, for example, is any better than blocking any other step.

What's the next step?

The next step is, first of all, to make the drugs less toxic so they can be taken indefinitely -- and they will have to be taken indefinitely until we can find a way to get rid of the reservoirs. The next step after making the drugs less toxic is to find the reservoirs -- there are more than one, clearly. Each one will probably require the development of a specific approach to eliminate it and who knows how long that will take.

This transcript has been lightly edited for clarity.

References

1. Chun T-W, Justement JS, Moir S, et al. Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. J Infect Dis. June 15, 2007;195(12):1762-1764.

2. Siliciano R. HIV persistence on patients on HAART: reevaluating prospects for eradication. In: Program and abstracts of the XVII International AIDS Conference; August 3-8, 2008; Mexico City, Mexico. Abstract WEPL0101.