Several new studies of hydroxyurea as an anti-HIV agent were presented at the 4th National Conference of Human Retroviruses and Opportunistic Infections in Washington, D.C. showing significant antiviral activity in patients with HIV infection. Hydroxyurea is an anticancer drug which inhibits a cellular enzyme, ribonucleotide reductase, which is required for syntheses of proviral DNA. In the largest study, presented by Rutschmann and colleagues from Geneva, Switzerland, 142 antiretroviral naive (80%) patients were randomized to receive either ddI (200 mg twice daily) + d4T (40 mg twice daily) + placebo or ddI + d4T + hydroxyurea (500 mg twice daily). The average reduction in HIV RNA was more pronounced among those who received the hydroxyurea-containing combination (-2.2 logs) as compared to the ddI + d4T group (-1.8 logs), and 55% versus 32% of patients in the respective groups were below the level of detection (200 copies/ml) after 12 weeks of therapy. The group receiving the hydroxyurea however had a smaller increase in CD4 cells (+10) than the group receiving hydroxyurea (+91), but the lack of an effect on CD4 counts could be explained by hydroxyurea-induced lymphopenia. Twenty patients stopped therapy due to neuropathy (2), nausea (6), psychiatric disorder (1), nail dystrophy (1), and voluntary withdrawal (10).

A smaller study conducted by Richard Pollard and others from the University of Texas evaluated the effect of ddI + d4T + hydroxyurea in 12 patients with a mean CD4 count of 216, most (11) of whom were on antiretroviral monotherapy. CD4 counts increased in half of the patients by an average of 84 cells and decreased in 3 patients by an average of 34 cells after 4 weeks of therapy. Viral loads decreased by 1.6-2.5 logs in these 9 patients, and was suppressed in four patients who continued the therapy for 12 weeks. The most common major side effect was neutropenia which developed in 4 patients entering the study with absolute neutrophil counts below 1700 cells/ul, but was reversible upon withdrawal of hydroxyurea.

In another poster presentation Franco Lori and colleagues from the Research Institute of Genetic and Human Therapy in Maryland presented data on over 40 patients who have received ddI and hydroxyurea combination therapy for over one year with no evidence of breakthrough viral replication. The combination of ddI and hydroxyurea was unable to prevent the emergence of mutations that confer ddI resistance, yet the mutants wer still sensitive to standard doses of ddI in the presence of hydroxyurea. Indeed in a comparative study of genotypic data from patients who received either ddI monotherapy or ddI + hydroxyurea, those in the monotherapy arm developed codon mutations in the 69-74 region less frequently (37.5%) than those in the combination arm (58.3%). They proposed that in vivo hydroxyurea lowers the levels of the cellular competitor of ddI, dATP which allows for the incorporation of ddI, even if the reverse transcriptase is resistant to the nucleoside analogue.

Hydroxyurea continues to be studied in various clinical trials in the United States and Europe, including an ACTG trial and an AmFAR sponsored trial which is fully enrolled and is expected to have results shortly.