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Being Alive
FROM THE 5TH NATIONAL CONFERENCE ON RETROVIRUSES: Hydroxyurea-More, But Is It Enough?
Mark Katz, M.D.
March 5, 1998
Being Alive 1998 Mar 5: 6

Fueled by numerous prior reports of efficacy, as well as a treating community searching for new options in patients who have failed existing regimens, hydroxyurea (brand name Hydrea) has become a part of many anti-HIV regimens, especially over the past year.

The amount of new information available at this Conference seemed inappropriately small-five posters displayed at Wednesday's session-and makes some (including this writer!) wonder if part of the explanation might be a political one: When a substance is already FDA-approved or otherwise easily available, is there less pharmaceutical support for research? (Consider interleukin-2, pentoxifylline, N-acetylcysteine, cimetidine, and even vitamin C.) Nevertheless, several of the studies presented do have unique features-including reports of hydroxyurea compared with a placebo, hydroxyurea in a protease-containing combination, and hydroxyurea's potential salutary effects on the immune system.

The Past Hydroxyurea has been available in the U.S. for more than 30 years, and has been FDA-approved for the treatment of certain types of leukemia (and more recently, sickle cell disease as well). Its purported mechanisms of action-both in leukemia and in HIV disease-have been extensively published elsewhere and an excellent review appeared in the March 1997 Bulletin of Experimental Treatments for AIDS.

It was at the First National Retroviral Conference, held in December 1993, that a team from the Research Institute for Genetic and Human Therapy in Europe reported that hydroxyurea inhibited HIV replication in peripheral blood mononuclear cells and macrophages. In the presence of ddI, synergy was observed to occur as well.

Over the ensuing years, at least four human clinical trials were held, using hydroxyurea in addition to ddI and/or d4T. These were generally open label trials, most of them conducted outside of the U.S. As the results of these trials gained publicity, showing increased viral load suppression and/or increased CD4+ T-cell counts with little toxicity, many clinicians began to prescribe this relatively inexpensive drug for patients with HIV. Its cost of less than 30 cents per day for the usually prescribed 500 mg twice-a-day dose, and the fact that it is FDA-approved, no doubt add to its appeal. (Hydroxyurea as well as ddI and d4T are manufactured by Bristol-Myers Squibb.) Its purported efficacy lies in its ability to suppress nucleoside triphosphate production by inhibiting the enzyme ribonucleotide reductase. This leaves fewer deoxyribonucleotides (DNA building blocks) available, causing greater amounts of nucleoside analogue medications to be incorporated into DNA. Cell replication is blocked (hence its use in leukemia).

In addition, since the target of this drug is a human cellular enzyme, and not an HIV-specific enzyme, there should be less chance for resistance to occur than occurs with reverse transcriptase or protease inhibitors. Further studies have led to the postulation of some immune boosting effects as well.

Hydroxyurea In Open Label Combination One Conference report was of 31 antiretroviral-experienced patients (prior monotherapy experience: 15 AZT, 7 ddI) with mean viral load of 105,700 copies/mL and mean CD4+ T-cell count of 231 cells/mm<. They all received a single daily dosage of 1000 mg of hydroxyurea in addition to ddI and d4T. For the 14 patients evaluable at 12 weeks, the mean decline in viral load was 1.3 log; during this time the CD4+ T-cell count increased by approximately 80 cells/mm< for 12 patients at 16 weeks of therapy. Two of the patients developed neutropenia (low white blood cell count) which was reversible upon cessation of the drug. This study had neither placebo nor control group, and thus it is difficult to interpret the results as definitively favoring the use of hydroxyurea. A decline of 1.3 log is not uncommon with two nucleoside analogues.

Finally, A Placebo-Controlled Trial! An abstract from the Swiss HIV Cohort Study looked at comparing hydroxyurea 500 mg twice per day vs. placebo in 144 subjects, all of whom also received ddI 200 mg plus d4T 40 mg twice a day. Three-quarters of the group was antiretroviral-na�ve, and the mean viral load at study onset was approximately 30,000 copies/mL.

The viral load suppression at 12 weeks was significantly greater in the group which received hydroxyurea-2.3 log, versus 1.7 log in the placebo group.This study is important in that it demonstrates the added efficacy of hydroxyurea in a placebo-controlled trial. It also had a significant number of subjects, allowing for better statistical interpretation of the data.

Yes, and What About the Immune System? Another poster, which was presented by Dr. Galpin of the Shared Medical Research Group, focused on the immune response to hydroxyurea. Since HIV infection is characterized by a progressive loss of naive, programmed (memory), and long-term memory cells, the authors asked if effective viral suppression could reverse these trends An interim analysis at week 20 showed a statistically significant increase of naive and long-term memory lymphocytes.

Finally (Again), Hydroxyurea With a Protease Inhibitor! In what might be the first controlled study involving hydroxyurea with a reverse transcriptase inhibitor and a protease inhibitor, Dr. Frano Lori described eight patients with relatively recent HIV infection (mean duration 13 months) who were placed on hydroxyurea 300 or 400 mg thrice daily plus ddI 200 mg twice a day and indinavir 800 mg three times a day. These were compared to a control group of eight patients with comparable HIV infection who were not treated. After an average treatment period of five months, all members in the treated group achieved undetectable viral loads (average starting value had been 494,000 copies/mL) and a statistically significant rise in CD4+ T-cell count of 116 cells/mm< (starting value 448 cells/mm<). Also, immune system parameters which were measured all showed significant improvement in the treated group as compared to the control.

Further study will help define how much immune reconstitution might occur with the use of hydroxyurea therapy.

Where We're At Today The various studies presented at the Conference added to the pool of data indicatingthat hydroxyurea may play some role in HIV treatment, but that role has yet to be validated in a large double-blind placebo-controlled randomized human clinical trial. It is likely this will never happen, since hydroxyurea is already an FDA-approved drug. But the tireless advocacy of persons with HIV as well as their providers, in this era when failure of existing regimens and the threat of widespread resistance looms wider than ever, indicates that such a study could shed invaluable light on the role hydroxyurea can play in treatment strategy.

Among the many questions which remain: How truly effective is hydroxyurea's antiviral and immune boosting activity? What is the most appropriate dosage? Since it has a half-life of 2.5 hours, should a four-times-daily dosing be considered/tested? What is the risk of long-term side effects in using an antimetabolite such as hydroxyurea which suppresses cellular replication (drugs which have been used to treat leukemia and cancers have sometimes caused variations thereof)-especially in someone who is already immunosuppressed? If it is to be used in HIV treatment, what is the best timing of administration? Should hydroxyurea be used as initial therapy with nucleoside analogues, perhaps to "spare" protease use until later? As an adjunct to a regimen once most or all approved anti-HIV regimens have failed? (This is where most of its use in the U.S. has occurred to date.) As part of a maintenance regimen? What is/are the best drug(s) with which to prescribe hydroxyurea? (There is a paucity of data on its combination with 3TC, NNRTIs, or any protease inhibitor other than indinavir.) Does hydroxyurea's claimed penetration of the blood-brain barrier afford additional advantage in reducing viral burden in the CNS? Are there other antimetabolites which might have comparable (or better) efficacy in treating HIV disease? These are the issues and questions we must examine fully before we can determine hydroxyurea's role as a weapon against HIV.

This article is reprinted (and slightly condensed) with permission from Healthcare Communications Group, LLC. This article is from a program made possible thanks to unrestricted educational grants provided by Agouron, Amgen, Roche Laboratories and Roxane Laboratories. Full summaries from the Fifth Retrovirus Conference are available at http://www.healthcg.com/HIV

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