Article from Antiviral Agents Bulletin, September 1995, p. 263
Hydroxyurea, an inhibitor of ribonucleotide reductase used for decades as a cancer treatment, has entered clinical trials in the U.S., Italy and France for treatment of HIV-infection. Bristol-Myers Squibb Co. (New York, NY) currently markets hydroxyurea (Hydrea) in the U.S. for treatment of leukemia, skin and other cancers. Hydroxyurea's ability to reduce deoxynucleoside triphosphate levels represents a new therapeutic approach for inhibition of HIV-1 replication. The drug may be particularly useful in combination with DDI (2',3'-dideoxyinosine; Videx from Bristol-Myers Squibb Co.) and other dideoxynucleosides.
Results from a French clinical trial combining hydroxyurea (500 mg orally twice daily) with DDI (200 mg orally twice daily) were published in the August 28 issue of the Journal of Acquired Immune Syndromes and Human Retrovirology. The combination was tested for 90 days in 12 asymptomatic patients with CD4+ T-cell counts above 250 (median of 343). A median increase in T-cell count of 120 was observed. A decrease in viral load (HIV plasma RNA) of 1.71 log (nearly 100%) was observed in six patients and HIV RNA was reduced to undetectable levels in the other six patients. Side effects were not sufficient to cause any patient to drop out of the study. These results generally confirm anecdotal reports indicating that hydroxyurea combined with dideoxynucleoside drugs is useful for treatment of early stage HIV-infection. Considerably more clinical testing is required to determine the appropriate dosage, adverse effects and efficacy of hydroxyurea combination therapy.
Dr. R.C. Gallo and co-workers, National Cancer Institute (NCI; Bethesda, MD), have reported that the in vitro efficacy of DDI and other anti-HIV nucleoside analogs is significantly increased in the presence of hydroxyurea without additional toxicity. In an article in the November 4, 1994 issue of Science (p. 801-5), hydroxyurea was shown to inhibit HIV-1 DNA synthesis in activated peripheral blood lymphocytes by decreasing the amount of intracellular deoxynucleotides available for viral replication. The inhibition of HIV-1 replication by hydroxyurea was dose dependent, with a 90% inhibitory concentration (IC90) of 0.4 mM, a plasma concentration readily tolerated by cancer patients. At lower doses (< 0.1 mM), hydroxyurea potentiated the antiviral activity of the dideoxynucleosides DDI, AZT and DDC against HIV-1, with the potentiation of DDI greater than that for AZT or DDC. In the presence of 0.1 mM hydroxyurea, the IC90 of DDI was reduced by 6-fold in activated peripheral blood mononuclear cells. This potentiating effect was time dependent, with the greatest inhibition of HIV-1 growth observed when hydroxyurea was present during and after virus adsorption (during retroviral DNA synthesis).
Hydroxyurea's greater potentiation of the activity of DDI, compared to the other dideoxynucleosides, is apparently due to the more effective inhibition of dATP synthesis compared to the synthesis of the other deoxynucleoside triphosphates (dGTP, dTTP, and dCTP). In some instances, inhibition of HIV-1 by hydroxyurea was irreversible, even for several weeks after suspension of drug treatment. The indirect inhibition of HIV-1 by hydroxyurea is not expected to generate high rates of escape mutants and hydroxyurea may be useful to reduce HIV drug resistance. In combination with DDI, hydroxyurea may lessen viral replication so that there is less virus able to mutate which could potentially delay the onset of DDI-resistance. At the recent Consensus Symposium on Combined Antiviral Therapy (Lisbon, Portugal), Dr. S.N. Pancheva, Bulgarian Academy of Sciences, reported that methotrexate, a widely used cancer drug, similarly lowers available deoxynucleoside triphosphate levels and potentiates the antiviral activity of thymidine kinase inhibitors against herpes simplex virus type 1 (HSV-1).