Two Italian studies that will enroll 100 asymptomatic HIV positive individuals with CD4 counts between 300 and 500 are exploring the combination of hydroxyurea (500 mg twice daily) plus AZT (250 mg twice daily) or plus ddI (200 mg twice daily). In the U.S., the government-sponsored AIDS Clinical Trials Group (ACTG) this fall will start a study of hydroxyurea plus ddI. In vitro studies show that anti-HIV activity is enhanced without obvious increased toxicity when hydroxyurea is used in combination with ddI (Science 266: 801-806. 1994).
Hydroxyurea does not act directly against HIV, but rather depletes cells of deoxynucleoside triphosphates (dNTP), which are crucial components (building blocks) of DNA synthesis. "When HIV enters a cell depleted of dNTP by the action of hydroxyurea, there is not enough of the building blocks present for the virus to survive," explains Franco Lori, MD, of the research Institute for Genetic and Human Therapy in Pavia, Italy. In combination with ddI, Lori says, hydroxyurea decreases viral replication so dramatically that there's less virus available to mutate, possibly delaying the onset of resistance to ddI.
"Hydroxyurea may permit a significant reduction in the toxicity of ddI, since we would like to combine the 2 drugs at low doses," says Lawrence Fox, MD, of the National Institute of Allergy and Infectious Diseases (NIAID). Fox says he is skeptical about hydroxyurea in combination with AZT because both agents cause bone marrow toxicity. A controlled, triple combination study of hydroxyurea plus ddI plus d4T is scheduled to start in August, sponsored by the Shared Medical Research Foundation of Tarzana, California. See also page 71 of the March 1995 issue of BETA.