Hydroxyurea: overview of clinical data and antiretroviral and immunomodulatory effects

Data from comparative trials involving more than 500 patients indicate that hydroxyurea is safe and augments suppression of HIV-1 replication when used in combination with didanosine or didanosine/stavudine as initial therapy or in patients without extensive antiretroviral experience. Additional studies will determine the optimum dosage and schedule for hydroxyurea and its effects when used with other agents and in patients with advanced disease or extensive pretreatment. Activities of hydroxyurea include inhibition of HIV-1 in active and resting CD4 lymphocytes and macrophages, potentiation of the activity of nucleoside reverse transcriptase inhibitors (NRTIs), compensation for resistance to adenosine analogue NRTIs, and potential increased phosphorylation of pyrimidine NRTIs. Recent attention, however, has focused on the potential immunomodulatory effects of hydroxyurea. The cytostatic effect of this agent on both CD4 and CD8 T cells may provide immunological benefits by reducing immune system overactivation, thus preventing both CD8 T cell exhaustion and CD4 T cell depletion. Accumulating evidence indicates that hydroxyurea-containing regimens may be associated with decreased levels of activated CD8 T cells, increased levels of naive CD4 and CD8 T cells, and preservation of the HIV-1-specific immune response. Further study of the potential for beneficial immunomodulation with hydroxyurea-containing regimens is needed to ascertain the clinical implications of these initial findings.