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

Selected Highlights from 5th Conf. on Retroviruses and Opportunistic Infections Main Page

• New Anti-HIV Drugs
• Hydroxyurea
• Protease Inhibitor and Other Drugs Combinations
• Opportunistic Infections
• Miscellaneous

April 1998 Table of Contents

Main Page

beta@sfaf.org

Selected Highlights from the 5th Conference on Retroviruses and Opportunistic Infections

Hydroxyurea

Harvey S. Bartnof, MD

Hydroxyurea in Combination Regimens Shows Benefit

• Hydroxyurea (Hydrea) in combination with ddI and d4T prevented HIV viral load rebound in 3 patients even after therapy was stopped
• Hydroxyurea combined with ddI plus indinavir led to CD4 cell count increases and undetectable HIV DNA in lymph nodes in 2 patients

Hydroxyurea is an FDA-approved anti-cancer drug that has been used in the U.S. for many years. Its potential utility in treating people with HIV/AIDS was first proposed by Robert Gallo, MD, at the IX International Conference on AIDS in Berlin in 1993. Because hydroxyurea blocks a human cellular enzyme called ribonucleotide reductase -- and because HIV enzymes are not involved -- resistance to hydroxyurea is extremely uncommon. The drug drastically reduced the available pool of nucleotide building blocks for HIV RNA and DNA. When combined with ddI, the anti-HIV potency of ddI is increased dramatically and ddI resistance is greatly reduced. Similar benefits may also occur for both ddI and d4T when hydroxyurea is combined with both drugs.

BETA has reported previously on small trials or case reports involving hydroxyurea. While most small studies to date documented significant HIV viral load reductions with hydroxyurea combinations, all showed a relative lack of CD4 cell count increases. This is likely due to hydroxyurea's blocking of cellular replication. Franco Lori, MD, from the Research Institute for Genetic and Human Therapy in Washington, DC and Italy, presented new data that documented CD4 cell count increases while being treated with hydroxyurea. The difference is that he combined hydroxyurea with ddI plus indinavir. The potent anti-HIV effect of a protease inhibitor allowed for significant CD4 cell count increases. Hydroxyurea and ddI both target resting cells, while d4T and indinavir target cells that are actively replicating.

In a late breaker session Lori reported using hydroxyurea plus ddI plus indinavir in 24 patients with acute or primary HIV infection. Mean baseline HIV viral load was 455,700 copies/mL and mean baseline CD4 cell count was 499 cells/mm³.

After a mean treatment period of 11.3 months, plasma viral load was undetectable (limit of detection 500 copies/mL) in all patients. Semen viral load was undetectable (limit of detection 400 copies/mL) in all 6 patients tested. The longest treatment period was 21 months. Unlike other hydroxyurea studies, in this study CD4 cell counts increased by a mean 168 cells/mm³. Examination of lymph node cells for HIV indicated undetectable HIV RNA (limit of detection less than 5 copies per 44 million cells) in 7 of 8 patients examined (87%), indicating no detectable HIV replication. HIV DNA was undetectable (limit of detection less than 5 copies per 44 million cells) in 2 of 6 patients examined (33%), indicating no detectable latent HIV. Other benefits were observed, including increased numbers of CD4 and CD8 naive T-cells, and increased immune responses to foreign antigens when tested in vitro. In 10 patients, the Western Blot confirmatory HIV antibody test never turned positive (the complete pattern of HIV protein bands never appeared). This usually indicates a lack of sufficient HIV antigen to stimulate a detectable antibody response.

Lori described one patient in detail because of some very interesting findings. This man was treated with hydroxyurea plus ddI plus indinavir for just under 5 months, at which time he contracted acute hepatitis A. His anti-HIV medications were stopped for 16 days, then restarted for 1 month, then stopped again for over 9 months. Surprisingly, his HIV viral load did not rebound during the periods when he was not taking anti-HIV therapy. The man was taking no other medications during this time. There are only 2 other reports in the medical literature of this lack of viral rebound while off treatment, and both involved hydroxyurea plus ddI, with or without d4T. With all other anti-HIV drug combinations, including those that include protease inhibitors, when the drugs are stopped, HIV viral load quickly rebounds, often to higher levels than were initially seen. There appears to be something unique to hydroxyurea as part of an anti-HIV combination regimen.

Hydroxyurea does have side effects, primarily affecting the bone marrow. This can lead to low levels of white cells, platelets and red cells (anemia). Other side effects may include nausea, vomiting, diarrhea, constipation, increased liver enzymes, abnormal kidney function and, occasionally, rash. Hair loss is a rare but recognized side effect. Further studies of hydroxyurea are ongoing.

Page last updated 5 May 1998