The Body Covers: The 6th Conference on Retroviruses and Opportunistic Infections
Abstract No. 402: Phase I/II Dosing Study of Once-Daily Hydroxyurea (HU) Alone vs Didanosine (ddI) Alone vs ddI + HU
February 9, 1999
In earlier studies, hydroxyurea, when added to DDI or D4T increased the activity of a single or dual nucleoside therapy by 0.5 to 0.7 log 10 copies/mL. The authors, in this placebo controlled study, examined the activity and toxicity of two doses of hydroxyurea administered once daily in combination with DDI vs. DDI alone vs. hydroxyurea alone. Eligibility criteria included CD4 counts between 200 and 700. Patients had to be DDI naïve, and had to have ANC's greater than 1,000, hemoglobins greater than 8.8 in women and 9.2 in men; amylase less than 2X upper limit of normal; LFT's less than 5X upper limit of normal; and, no history of pancreatitis. No viral load criteria were established.
Drug treatment discontinuation in the first 24 weeks was analyzed as follows. Four patients withdrew because of treatment-related toxicity. Eight patients voluntarily withdrew due to toxicities. Physician request caused nine patients to discontinue. Patient requests caused seven patients to discontinue. Eight patients were lost to follow-up and one was non-compliant. At week 24, ninety-four patients remained on therapy. Twenty-three of these were on mono-therapy with DDI, nineteen were on low-dose 100,000 mg/day hydroxyurea, sixteen were on low-dose combo therapy, sixteen were on a high hydroxyurea mono-therapy at 15,000 mg/day, and twenty patients were on high combination DDI and hydroxyurea. The adverse event rate was as follows. There were significant hematologic abnormalities in 28% of the patients, the bulk of which (52%) were in the high hydroxyurea (1500 mg/day) mono and high combo groups. Abnormal chemistries caused discontinuation in roughly 3% which was equal across the board. Hematologic toxicities included: neutropenia, thrombocytopenia and anemia.
This study concludes that: 1) hydroxyurea increases the antiretroviral activity of DDI but does not inhibit HIV replication alone. 2) Hydroxyurea can be dosed once-daily together with DDI. 3) CD4 count increases are blunted in hydroxyurea recipients. 4) Adverse events associated with hydroxyurea and DDI are predominantly hematological and HU 1500 mg more toxicity than HU 1000 mg. HU does not impair lymphoproliferative responses.
This study does go some distance in answering the question of what doses of hydroxyurea should be used. It also again addresses the question as to whether or not there is an anti-HIV effect of hydroxyurea alone. I think most of the data that is available now suggests that there indeed is not. The value of the drug appears to be in its ability to improve intracellular dATP concentration by its effect on ribonucleotide reductase, thus improving the ratio of active nucleoside reverse transcriptase inhibitor. Also, due to cytostatic effects, this may have an ancillary effect reducing the levels of CD4 positive T cell activation. What remains unanswered is where hydroxyurea should be used. Is it an agent to be used as primary therapy? Is it an agent to be used as a maintenance drug? Is it an agent that should be used in salvage therapy? Lastly, is it a drug that should be used as part of intensification therapy in patients who are already achieving some success with standard regimens in order to eliminate persisting reservoirs?
Authored by: I. Frank, et al.
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