SF AIDS Fdn: BETA 10/98 -- DRUG WATCH: Hydroxyurea

Published in the Bulletin of Experimental Treatments for AIDS October 1998 issue, by the San Francisco AIDS Foundation.

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DRUG WATCH: Hydroxyurea

Christopher Gortner

Hydroxyurea, a drug developed over 30 years ago and used as a treatment for cancer and sickle-cell anemia, continues to demonstrate significant promise as a component of anti-HIV drug regimens. Hydroxyurea’s most common side effect is bone marrow suppression, which can lead to low blood cell counts.

Hydroxyurea as an HIV Treatment Option

For people with HIV/AIDS who are either intolerant to or have exhausted the benefits of various anti-HIV drugs, a regimen that combines hydroxyurea with nucleoside analogs such as ddI (Videx) and d4T (Zerit), and/or a protease inhibitor or non-nucleoside reverse transcriptase inhibitor (NNRTI) may offer an innovative treatment alternative. Because of its potential suppressive effects on the bone marrow, hydroxyurea should be used cautiously with AZT. The hazardous effects of hydroxyurea on fetuses also make it unsuitable for pregnant women.

Unlike currently available antiretroviral drugs, hydroxyurea does not attack HIV itself, but rather targets the host immune system cells employed by the virus. Hydroxyurea blocks a cellular enzyme called ribonucleotide reductase that assists in the production of DNA building blocks, the same material the virus needs in order to reproduce. When hydroxyurea blocks this crucial enzyme, HIV must use the defective substitute building blocks provided by nucleoside analog drugs such as ddI.

Indeed, the potent in vitro combination of hydroxyurea and ddI is what originally sparked interest in hydroxyurea’s potential as an anti-HIV drug. Adding d4T to the mix has generated even more promise. Recent studies indicate that the unique synergy between hydroxyurea and ddI inhibits HIV in inactive infected host cells, while the addition of d4T enables the regimen to also target actively replicating cells.

The triple combination of ddI/d4T/hydroxyurea has generated both community interest and an array of clinical research, particularly in the wake of the news about unusual body fat redistribution and alarming rises in blood triglyceride and cholesterol levels that appear to be associated with the use of protease inhibitors. It also offers people a chance to use 3-drug therapy without using two classes of antiretroviral drugs -- protease inhibitors and NNRTIs -- which can then be spared for later use if necessary.

Another of hydroxyurea’s benefits is the fact that, to date, there are no documented reports of resistance to the drug, compared to the high level of drug-resistance mutations associated with the prolonged use of all the currently approved anti-HIV agents. Lastly, hydroxyurea is relatively inexpensive and widely available, which makes it a viable option for people with limited access to HIV/AIDS care.

Clinical Update

At the 12th World AIDS Conference in Geneva, several abstracts were presented about hydroxyurea. Perhaps the strongest and most impressive data came from a clinical trial known as BMS AI455-055. This was the first randomized, controlled international study to compare 3-drug regimens involving hydroxyurea, AZT, ddI, and/or d4T. The study was conducted in Argentina, Brazil, and Canada, and included 177 HIV positive participants. The four regimens compared were ddI/d4T, ddI/AZT, ddI/hydroxyurea, and ddI/d4T/hydroxyurea.

Results from the trial were presented by Sergio Lupo, MD, of the Center for Assistance and Clinical Investigation for the Immunocompromised of the National University of Rosario, Argentina, where part of the study took place. Nearly 80% of patients receiving the 3-drug combination (ddI/d4T/hydroxyurea) achieved undetectable viral loads (limit of detection 400 copies/mL) at 24 weeks. At 24 weeks, the mean CD4 count increase was about 20 cells/mm³ in the hydroxyurea arms compared to about 90 cells/mm³ in the non-hydroxyurea arms, indicating that hydroxyurea may have a detrimental effect on CD4 count. However, in all arms the CD4 cell percentage increased by about 40%. According to Lupo, "The results were superior to those seen with three different 2-drug regimens, and are comparable to results from trials of protease inhibitor-containing regimens."

Finally, Lupo stressed that hydroxyurea apparently is most effective when part of a triple combination, as it potentiates the effects of both ddI and d4T. Hydroxyurea combinations appear somewhat unique in that viral load rebound has not occurred in several cases after therapy was discontinued (see Hydroxyurea, BETA, March 1997).

Conclusion

Although the U.S. Food and Drug Administration has not officially approved hydroxyurea as an anti-HIV treatment, it is approved for other indications, and physicians may prescribe the drug at their discretion. From early European studies, hydroxyurea is known not to be very effective as monotherapy for HIV disease, and therefore should only be used in combination regimens.

Christopher Gortner is Editor of the Spanish edition of BETA.

Federici, M. and others. Hydroxyurea in combination regimens for the treatment of antiretroviral-naive, HIV-infected adults. 12th World AIDS Conference. Geneva, Switzerland, June 28-July 3, 1998. Abstract 287/12235.

Page last updated 6 October 1998