The Bay Area Reporter - October 17, 1995
Matthew Sharp, ACT UP/Golden Gate Writer's Pool

Here he speaks about one of the more promising AIDS therapies on the horizon.

MS - You have recently been doing clinical trials at the VA on the cancer drug hydroxyurea for HIV. Could you share with us some of the background of the drug and how it was discovered as a possible therapy for AIDS?

LM - Hydroxyurea has been around for 30 years. At that time it was used alone and in combination to effectively treat certain types of cancer. Roughly eight to ten years ago work was done looking at the drug in sickle cell anemia. With respect to HIV, in the normal mass screening that the NIH and drug companies do, hydroxyurea was found to affect the growth of HIV in the test tube. A few additional investigators have shown us that you can limit the growth of HIV in the test tube with hydroxyurea, and that discovery led to pursuing clinical trials.

This drug works differently from current antivirals used in AIDS. Can you describe how it is different?

When HIV infects a cell it goes through a couple of steps before its own genetic material becomes part of ours. one of those steps is when the reverse transcriptase enzyme is involved. When the virus is reproduced, it is copied like a photocopy machine. We think hydroxyurea may work in that inside of the cell we need certain pieces of our genetic material building blocks called nucleotides.

You can equate nucleotides to copy fluid in a copy machine so that if they are low, the cell may not be able to copy new viruses or complete new cells. Indeed it can affect the growth of HIV but may also be at the expense of cells in the body.

In 1993, Robert Gallo, the co-discoverer of HIV, was the first to publish in vitro data on hydroxyurea What other work has been published on hydroxyurea?

In terms of what has been published, there is a study by a group of French researchers looking at a small group of HIV-positive individuals using hydroxyurea/ddI combination, which was recently in the Journal of AIDS. Earlier, in vitro studies showed the combination looked so good that French, Italian, and Spanish researchers designed studies that found results in decreasing of HIV viral load that is greater than when you use ddI alone.

Our group chose to design a study looking at hydroxyurea in a study of 12 weeks monotherapy and then we crossed over patients to combination with ddI. Not only did we find roughly a 50% intolerance to the drug but, as expected, we saw falling blood cell counts including CD4s. We expected these drops because this drug is used in cancer chemotherapy mainly to knock down white blood cells in people with very high white blood cells. However, we did see an effect on decreasing viral load. We thought that by lowering HIV in the blood we could offset the side effects of bone marrow suppression from hydroxyurea, but we weren't able to do that.

Were the side effects reversible?

In most of the people in the study we saw some degree of their WBC fall and we saw a little anemia with hydroxyurea alone. Once we stopped the drug the counts rapidly reversed.

The major problem with current antivirals in HIV is that they become resistant due to HIV mutations. Does hydroxyurea - like AZT, ddI, and ddC - become ineffective over time?

What is different about hydroxyurea is that it's affecting nucleotides, the building blocks of the virus in our cells. The way the body could overcome this would be to produce more of these building blocks so that even if hydroxyurea were there, the body could overpower it. It's not an issue of resistance, it's that the body is able to overcome what is there. The virus is not resistant, but the body resists. Pulsing dosages or modification of how the drug works may be a more effective way to use the drug. The other question we have is, by having hydroxyurea around are we able to prevent resistance to ddI or other drugs that may be used in combination?

It sounds like more studies need to be done to answer your questions. What is planned for the future of hydroxyurea?

Our first study answered some questions and we want to move on. We know that when hydroxyurea is used alone, half the people can tolerate the drug. We saw side effects, we saw that it did decrease the viral load, but at a cost: it lowered t-cells and other hematalogic parameters. The next studies are designed to figure out how hydroxyurea works, and what the combination of ddI and hydroxyurea does over a long period of time. It will be a small cohort due to financial restraints. Bristol-Myers, the company that makes both ddI and hydroxyurea, says that they have five or six groups applying for INDs [investigational new drug status] for studying hydroxyurea and ddIs. Before summer of next year there will be four or five hundred people scattered across the U.S. in hydroxyurea trials, and I think that will be helpful.

What are your concerns in people with AIDS using this drug off-label?

I would not use the drug alone; it should be used in combination. The dose we have most experience with is 500 mg. twice a day, and I think that anyone on any medication that can cause bone marrow suppression should be extremely careful about using hydroxyurea with these drugs.

ACT UP/Golden Gate has always encouraged combination studies. Why not look at hydroxyurea in combination with ddI and a protease inhibitor?

I think that makes complete sense. What we're going to find is that with the drug companies merging, we're going to see a lot of triple drug studies. Up to this point we've had only two viral targets for therapy, reverse transcriptase inhibitors and protease inhibitors. Hydroxyurea or drugs like it may give us a third antiviral target.

For years AIDS activists have been urging pharmaceuticals to look on their shelves for old drugs that may be effective for AIDS. Are there any hydroxyurea-like drugs that are gathering dust that may be safer or more effective for HIV?

A lot of companies skip over drugs that may cause harm and may not be a priority financially. I think in the future companies will go back and ask if the drug is structurally similar ... does it work? These drugs are around, it's just a massive project to screen and study them. The drug companies do have financial incentives to get medications out there, and I believe they will.

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