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Gay Men's Health Crisis
Hydroxyurea Continues to Show Promise
Luis Santiago
February 1, 1996
GMHC Treatment Issues 1996 Feb 1; 10(2): 8

Further human trial data on hydroxyurea and compounds with similar effect were presented at the Third Conference on Human Retroviruses and Opportunistic Infections. The new data confirm the positive impression that hydroxyurea, especially, has made in past investigations (see the September, 1995 Treatment Issues, pages 1, 2-4).

Hydroxyurea and the related drugs act by restricting the cellular pathways by which new DNA nucleotides are made. These gene-creating building blocks are taken up by the HIV enzyme reverse transcriptase as HIV infects new cells. The resulting scarcity of natural nucleotides allows nucleoside analog drugs like ddI or AZT, which are defective nucleosides, to play a greater role in disrupting HIV.

Canadian Study The most significant new piece of information on hydroxyurea (abstract 406) was presented by Julio Montaner, M.D., head of a Canadian pilot study of hydroxyurea among a group of patients with CD4 counts between 100 and 350 (average CD4 count of 241) and at least six months prior ddI experience. The objective of the study was to assess the viral load effect of adding hydroxyurea to ddI monotherapy.

The study was set up as follows: all trial participants (26) received ddI monotherapy for four weeks (200 mg twice a day). The ddI alone therapy was followed by four weeks of ddI plus hydroxyurea, with half of the group (13) assigned randomly to a low dose (500 mg once a day) and the other half to a high dose (500 mg twice a day) of hydroxyurea. For the last four weeks of the twelve-week study, everyone was put back on ddI monotherapy. Viral load (plasma levels of free HIV) and CD4 counts were measured on a daily basis.

For study purposes, an individual was defined as a "responder" if he or she registered an HIV viral load reduction greater than one log (90 percent). Based on this definition the investigators found that during the four weeks on ddI/hydroxyurea combination, nine out the 26 patients were responders. Six out of the nine responders were on the hydroxyurea high dose, with the remaining three on the low dose. This difference is only great enough to statistically suggest, but not demonstrate, that a greater viral burden reduction can be achieved with the higher dose.

The average viral load reduction (70 percent and 90 percent at week seven in the low and high dose arms, respectively) was statistically significant, as was the viral load rebound after discontinuation of hydroxyurea therapy at week eight. This return to baseline HIV levels occurred during the first week off hydroxyurea.

In the initial laboratory experiments at the National Cancer Institute, inhibition of HIV-1 was still seen several weeks after stopping drug treatment. The rapidity of the rebound in the present human trial indicates that continued viral suppression after withdrawal of hydroxyurea may not occur, at least in this population with advanced HIV infection and high CD4 turnover. (The CD4 cells arising after treatment cessation would be unaffected by the previous exposure to hydroxyurea.) Many hydroxyurea researchers argue that the ddI/hydroxyurea combination will be of significant benefit only for a relatively healthy, ddI-naive population since this is where a synergistic effect would be seen and toxic side effects (bone marrow suppression) should be minimal.

Considering the advanced disease status and long treatment history of the trial cohort, the viral load reductions were impressive. Investigators are currently analyzing the prevalence of ddI resistance in study participants' HIV and its association, if any, with the magnitude of the response. No serious toxicities were reported in the study, although some conference attendees pointed out that the time on hydroxyurea was too short to evaluate any negative effects on blood cell counts. Likewise, no change was observed in CD4 counts probably because of the trial's brevity.

Follow-up to the French Trial Interest in hydroxyurea had been considerably heightened by the results of a French study involving twelve asymptomatic HIV-positive patients (CD4 count above 250) with no previous anti-HIV therapy. (See the September, 1995 Treatment Issues, page 1.) The group received ddI (200 mg twice a day) and hydroxyurea (500 mg twice a day) for three months.

In a follow-up report (abstract 291), researchers presented data on those twelve patients, six of whom stopped the study regimen at the end of the three-month observation period. They also reported on an additional group of six patients that started treatment with this combination since then and also have completed three months of therapy.

At eight months, HIV viral load increases were reported in five out of the six persons that stopped treatment. The other one was stable. CD4 counts held more or less steady in four of them. Of the six patients who have remained on therapy, two have stable HIV levels, one had a major increase and two had slight increases. (No data were reported for one member of the group.) CD4 counts continued to increase in three members of this group.

Of the six patients that started the combination recently, two had HIV levels below detectable limits at three months, one experienced a two log (99 percent) decrease, and the other three a one log (90 percent) decrease. This study is not a rigorous clinical trial and leaves a lot of room for argument over its interpretation. Along with the Canadian trial, it does at least provide a basis for more sophisticated testing of hydroxyurea Where's the Placebo? Here in the U.S., ACTG 307, a pivotal ddI/hydroxyurea study, was due to start last fall. According to the trial's principal investigator, Joseph Eron, M.D., the lack of a placebo has been a big stumbling block. Bristol-Myers Squibb, producer of hydroxyurea (brand name: Hydrea) has yet to provide the placebo pill, which has to resemble the real thing. A company in Maryland is currently working on it, but researchers are not ready yet to start recruiting. For the latest information and current trial sites, call 800/TRIALS- A. Other Compounds Alternative experimental medications utilizing the same strategy as hydroxyurea are also waiting for more extensive testing.

Dr. W-Y Gao of the National Cancer Institute described compounds that block the cellular enzyme known as thymidylate synthase (abstract 5). This enzyme helps process the nucleotides for which AZT and d4T are defective analogs. (See Treatment Issues, September 1995, page 5. Hydroxyurea inhibits a different enzyme, ribonucleotide reductase.) In the test tube, very low concentrations of the anticancer drugs FUdR (floxuridine) and 5-FU (fluorouracil) potentiated both AZT and d4T as predicted. FUdR raised d4T's potency eight times, and AZT's effect was six times greater in its presence.

Dr. Gao's presentation was seconded by a report from the Robert Johnson School of Medicine in New Jersey and the University of Rochester (abstract 344). This group used FUdR to potentiate AZT in the test tube.

Both FUdR and 5-FU are extremely toxic, which could limit their use. These drugs' success as antiviral agents depends on their effectiveness within the body at the very low, presumably nontoxic concentrations used in the laboratory experiments.