Important note: Information in this article was accurate in 1998. The state of the art may have changed since the publication date.
PR Newswire; Monday, June 29, 1998
"Close to 80% of patients receiving a three-drug combination of hydroxyurea, ddI and d4T achieved undetectable viral loads at 20 and 24 weeks," said Sergio Lupo, M.D. "These results were superior to those seen with three different two-drug regimens, and are comparable to results from trials of protease inhibitor-containing regimens."
"The data clearly show that hydroxyurea works best when part of triple combination therapy for HIV, as it pontentiates the effects of both ddI and d4T," commented Dr. Lupo, who is affiliated with Centro de Asistencia e Investigacion Clinica en Immunocomprometidos (C.A.I.C.I.) at the National University of Rosario, Argentina. "This is based, in large part, on what appears to be a unique synergy between hydroxyurea and ddI. Hydroxyurea blocks a cellular enzyme called ribonucleotide reductase, which helps produce the DNA building blocks that HIV uses to replicate. By blocking this enzyme, hydroxyurea reduces the pool of the building blocks ddI competes with for incorporation into the RNA chain, and increases HIV's use of building blocks that are rendered defective by ddI. Recent studies have demonstrated the effectiveness of hydroxyurea and ddI in inhibiting HIV in quiescent, or 'resting' cells. By contrast, d4T acts preferentially in cells that are actively replicating, as do the protease inhibitors. Adding d4T to the hydroxyurea/ddI combination enables targeting of both 'resting' and 'active' cells, and this 'protease-sparing' strategy preserves two different classes of drugs -- non-nucleoside reverse transcriptase and protease inhibitors -- for subsequent treatment."
Dr. Lupo presented results from the BMS AI455-055 trial, the first randomized, controlled clinical trial comparing ddI+d4T+hydroxyurea to other anti-HIV regimens. In this trial, 177 patients were randomized to receive either ddI+AZT (zidovudine, Retrovir(R)) ddI+d4T, ddI+hydroxyurea, or ddI+d4T+hydroxyurea. The three-drug combination was associated with a 2.0 log mean drop in viral load, a statistically greater reduction than that seen with ddI+hydroxyurea alone. The difference between the three-drug combination and ddI+hydroxyurea was statistically significant.
Among patients taking the three-drug regimen, viral load was undetectable in almost 80% at 24 weeks, compared to 53% in the ddI+d4T group, 43% in the ddI+hydroxyurea group, and 36% of those taking ddI+AZT. "These results suggest that ddI+d4T is one of the most potent double nucleoside regimens, and that the addition of hydroxyurea enhances their efficacy," Dr. Lupo noted.
Dr. Lupo and colleagues also reported that hydroxyurea therapy appeared to result in a more limited rise in CD4+ cell counts. However, increases in percentages of CD4+ cells were comparable among study groups. "This is not surprising, given that hydroxyurea is a cytostatic agent -- one that prevents the multiplication and growth of cells," Dr. Lupo commented. "Our findings mirror those from other studies in which hydroxyurea-based combinations were associated with further reductions in viral load."
Dr. Lupo added that hydroxyurea is not recommended in combination with AZT, which, like d4T, is a thymidine nucleoside analogue. "Because myelosuppression, or suppression of white blood cells, is the major side effect associated with hydroxyurea, it should not be used with AZT, which has an overlapping toxicity profile with hydroxyurea. This is not the case with d4T, which has been shown to be well-tolerated when administered with hydroxyurea and ddI."
Dr. Lupo concluded by noting that hydroxyurea is one of the least expensive drugs that might be used for treatment for HIV/AIDS. "This makes hydroxyurea-based combinations therapy a very cost-effective treatment option, one that can be made widely accessible to patients, even in countries with limited budgets for AIDS patient care," he said. "The relatively low cost of this combination further strengthens the rationale for three-drug therapy with hydroxyurea, ddI and d4T."
SOURCE Centro de Asistencia e Investigacion Clinica en Immunocomprometidos
CONTACT: Lori Agin, in Geneva until July 2, 41-079-629-3818; or Sara Messeloff of Medisphere Communications, 212-213-4211, both for Centro de Asistencia e Investigacion Clinica en Immunocomprometidos/ (BMY)
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