Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic ('virostatic') mechanisms.
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 micromol/l) and didanosine (1-5 micromol/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 micromol/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 micromol/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.


CONCLUSIONS
A bimodal, dose-dependent, cytostatic-cytotoxic switch is an immune-based mechanism explaining the apparent paradox that lowering the dose of hydroxyurea to 600 mg daily induces maximal antiviral suppression in HIV-infected patients.
Lori
Franco
F
Research Institute for Genetic and Human Therapy, IRCCS Policlinico S. Matteo, Pavia, Italy and Washington, DC 2007, USA.
Foli
Andrea
A
Groff
Antonella
A
Lova
Luca
L
Whitman
Lucia
L
Bakare
Nyasha
N
Pollard
Richard B
RB
Lisziewicz
Julianna
J
D019380:Anti-HIV Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016049:Didanosine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage* / Q000009:adverse effects; D020714:Maximum Tolerated Dose; D019384:Nucleic Acid Synthesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D010182:Pancreatic Diseases / Q000139:chemically induced; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D004338:Drug Combinations; D019384:Nucleic Acid Synthesis Inhibitors; D016049:Didanosine; D006918:Hydroxyurea