[NATAP] New Study of Low-Dose Hydrxyurea

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New Study of Low-Dose Hydrxyurea

“Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic ('virostatic') mechanisms'

The authors conclude: “…… The identification of the optimal daily dose of 600 mg hydroxyurea should mitigate the concerns over mitochondrial toxicity and blunted CD4 cell increase….. reducing the hydroxyurea dose from 1200 to 600 mg decreased toxicity without loss of antiviral efficacy, measured as viral load reduction and CD4 T cell count increase, in HIV-1-infected patients…..â€

AIDS: Volume 19(11) 22 July 2005

Lori, Francoa; Foli, a; Groff, Antonellaa; Lova, Lucaa; Whitman, Luciaa; Bakare, Nyashaa; Pollard, Bb; Lisziewicz, nnaa

From the aResearch Institute for Genetic and Human Therapy, IRCCS Policlinico S. Matteo, Pavia, Italy and Washington, DC, USA

b Medical Center, University of California, Sacramento, California, USA.

Introduction

The mechanism of antiviral action of the hydroxyurea-didanosine regimen is based on the capacity of hydroxyurea to deplete intracellular components required for viral replication, namely deoxynucleotides [1,2], particularly deoxyadenosine trisphosphate (Didanosine competitor) [3], thus enabling it to act synergistically with didanosine. The hydroxyurea-didanosine combination offers a favorable resistance profile, as hydroxyurea targets a cellular enzyme that, unlike viral enzymes (e.g., reverse transcriptase), is not prone to mutation/resistance, and it has been shown to compensate for resistance to didanosine, explaining the long-term antiviral efficacy observed with this combination [4]. Both hydroxyurea and didanosine have a favorable antiviral profiles compared with other drugs in cells that are believed to represent the latent pools of replication-competent virus [5-7], such as resting/quiescent T cells, macrophages and dendritic cells [2,8].

The cytostatic and cytotoxic properties of hydroxyurea have been exploited for over 40 years for the treatment of myeloproliferative disorders [9,10], and might have implications in the HIV field. Treatment of CD4 T lymphocytes with hydroxyurea, in fact, renders them quiescent and refractory to productive HIV infection [1,2] (as HIV is mainly replicating in proliferating T lymphocytes [5-7]) and also increases beta-chemokines, inhibiting R5 HIV-1 [11]. Suppression of immune activation by cytostatic drugs such as hydroxyurea could complement antiretroviral treatment, because chronic immune activation plays a predominant role in the immune pathogenesis of AIDS [12,13].

Hydroxyurea blunts the CD4 cell count increase seen during antiretroviral therapy [14-17], and this has raised concerns regarding its potential use in a disease characterized by loss of CD4 T cells. Additional toxicity concerns were raised by the AIDS Clinical Trials Group (ACTG) 5025 study investigating a combination of didanosine, stavudine and indinavir with or without addition of hydroxyurea (1200 mg daily). The hydroxyurea-containing study arm showed a higher frequency of treatment failure and possibly pancreatic toxicity [18] and clinicians have become hesitant to use hydroxyurea for treatment of HIV-1 infection. Therefore, hydroxyurea remains an investigational new drug for HIV indication and it is not registered for clinical use in HIV-1 infection. However, a recent review on the risks of pancreatitis regarding 20 ACTG studies from 1989 to 1999, which involved over 8000 patients, concluded that although didanosine, stavudine, and indinavir combination bears the highest rate of incidence of pancreatitis, this is independent of the addition of hydroxyurea [19]. The study also concluded that hydroxyurea does not increase the risk of pancreatitis compared to didanosine alone [19].

Moreover, none of the clinical investigations with hydroxyurea in over 500 HIV-infected patients preceding the ACTG 5025 study, namely the RIGHT 411 trial [14], the ACTG 307 study [15], the Swiss HIV Cohort Study [16] and the BMS 055 study [17], had reported cases of pancreatitis, but all showed superior efficacy of the hydroxyurea-containing arms. Since the 1200 mg daily dose of hydroxyurea used in the ACTG 5025 study was higher than in the preceding trials, it could be hypothesized that lowering the dose of hydroxyurea could decrease toxicity. The present study examines the in vitro effects of varying the dosage of hydroxyurea in terms of cytostatic and antiviral effects.

Abstract

Background: The hydroxyurea-didanosine combination has been shown to limit immune activation (a major pathogenic component of HIV/AIDS) and suppress viral load by both antiviral and cytostatic ('virostatic') activities. Virostatics action represent a novel approach to attack HIV/AIDS from multiple directions; however, the use of these drugs is limited by the lack of understanding of their dose-dependent mechanism of action and by fear of pancreatic toxicity, even though a large review of ACTG studies has shown that hydroxyurea does not increase the incidence of pancreatitis.

Methods: In vitro cytostatic and cytotoxic activity, inhibition of viral replication and immune activation by pharmacologically attainable plasma concentrations of hydroxyurea (10-100 _mol/l) and didanosine (1-5 _mol/l) were analyzed by cell proliferation, viability, apoptosis and infection assays using peripheral blood mononuclear cells. In vivo, 600, 900 and 1200 mg daily doses of hydroxyurea in combination with standard doses of didanosine and stavudine were studied in 115 randomized chronically infected patients.

Results: A cytostatic low (10 _mol/l) concentration of hydroxyurea inhibited cell proliferation and HIV replication in vitro. A gradual switch from cytostatic to cytotoxic effects was observed by increasing hydroxyurea concentration to 50-100 _mol/l, predicting that lower doses of hydroxyurea would be less toxic and more potent in vivo. The clinical results confirmed that 600 mg hydroxyurea was better tolerated, had fewer side effects and was more potent in suppressing HIV replication than the higher doses