Lowering the Dose of Hydroxyurea Minimizes Toxicity and Maximizes Anti-HIV Potency

Abstract

The goal of this study was to optimize the hydroxyurea dosage in HIV-infected patients, and to minimize the toxicity and maximize the antiviral efficacy of the hydroxyurea-didanosine combination. In a randomized, open-label study (RIGHT 702, a multicenter trial performed in private and institutional practices), three daily doses (600 microg, 800-900 microg, and 1200 microg) of hydroxyurea were administered in combination with didanosine and stavudine to 115 chronically HIV-infected patients, one-third antiretroviral drug naive, with viremia between 5000 and 200,000 copies/ml regardless of CD4+ cell count. The primary efficacy end point was the proportion of patients with plasma HIV-1 RNA levels below 400 copies/ml after 24 weeks of therapy. In the RIGHT 702 intent-to-treat population the lowest (600 mg) dose of hydroxyurea was better tolerated, associated with fewer adverse events, and more potent by all efficacy parameters, including the primary end point (76 versus 60% patients with viremia<400 copies/ml at week 24 for the 600-mg and 800- to 900-mg dose groups, respectively; p=0.027), the mean area under the curve (60.3 versus 65.8; p=0.016), and the mean log10 decrease (-1.95 versus -0.77; p=0.001). Patients receiving 600 mg of hydroxyurea daily also had the highest CD4+ cell count, CD4+/CD8+ cell ratio, and lowest CD8+ cell count and percentage (p=0.035). The RIGHT 702 trial provides an explanation for the increased toxicity and decreased efficacy of hydroxyurea when it was used at high dosage (1200 mg daily). At the optimal dosage of 600 mg daily, hydroxyurea, in combination with didanosine, deserves reevaluation for the long-term management of HIV/AIDS worldwide, because of its excellent resistance profile, durability, and affordability.

Virostatics: A New Class of Anti-HIV Drugs

“…In order to prove the hypothesis and to clarify which component was responsible for the elevated pancreatic toxicity, Foli et al assessed the in vitro effects of hydroxyurea and didanosine concentrations For these reasons RIGHT 702, a phase I/II randomized, open-label, dose regimen study with 115 HIV-1 infected patients was designed to determine the best total daily dose and the best dosing interval of hydroxyurea, in combination with didanosine and stavudine. This study demonstrated that hydroxyurea when administered at a low dose (600mg total daily) is safer and more efficacious than higher doses (800-900mg and 1,200mg) for the treatment of HIV [44]. 400mg QD didanosine administered as an enteric coated capsule in combination with the lowest hydroxyurea dose (600mg hydroxyurea) was the best tolerated, had fewer side effects and was the most potent by all efficacy parameters analyzed, including the proportion of patients with viremia <400 copies/ml at week 24 (primary endpoint), mean area under the curve (AUC), mean log 10 decrease, increase in CD4 and decrease in CD8 count.…”

Strategies to improve efficacy and safety of a novel class of antiviral hyper‐activation‐limiting therapeutic agents: the VS411 model HIV/AIDS

“…Through the flexibility of the VS411 formulation, it is possible to reduce the dose of HU in order to potentially limit toxicities. A reduction in HU dosage is supported by the results of the RIGHT 702 study which demonstrated that a lower HU dose of 600 mg daily achieved better antiretroviral activity than did higher doses of 800–1200 mg, together with a better CD4+ cell count increase and fewer adverse effects (Lori et al ., 2005b). This was consistent with the in vitro observation that decreasing HU concentrations are associated with the transition from cytotoxic (50–100 µM) to cytostatic (10 µM) effects (Lori et al ., 2005a), indicating that lowering HU doses may be an option in combination with ddI.…”

“…For HU, the relationship between dosage and toxicity has already been established (Lori et al ., 2005b), although a clear relation between the maximal plasma concentration ( C max ) and adverse events has not been proven. HU is generally well tolerated.…”

Hydroxyurea for the Treatment of Psoriasis with an Emphasis on HIV-Infected Psoriasis Patients: A Review

“…There was a study that showed that a dose of 600mg daily was better tolerated and most effective in improving HIV status. 22 Dosing for psoriasis in the general population usually was 1.0–1.5g/day. However, if hydroxyurea therapy is initiated, our recommendation is a low dose of hydroxyurea 500mg daily, which can be slowly titrated up to minimize hematologic adverse events in a HIV-infected individual.…”