Proposed Clinical Trial: Effect of Prostratin on Latent Viral Reservoirs.

Stephen Brown, MD, Marjan Hezareh Ph.D. AIDS ReSearch Alliance, 621 A N San Vicente Blvd, West Hollywood, CA 90069 (USA).

Background: Prostratin, a non-tumor promoting phorbol ester has been used in traditional Samoan medicine for treatment of viral hepatitis. Prostratin, in addition to anti-HIV activity via downregulation of CD4 and CXCR4 receptors, exhibits potent activation of HIV replication and expression in latently infected cell lines, several in vitro models of latency and PBMC’s from suppressed patients. Current toxicological studies are being conducted to allow submission of an IND for phase I studies. Material and Methods: Currently prostratin is undergoing preclinical toxicology under the auspices of the NIH Inter-Institute Program for the Development of AIDS Related Therapeutics, (IIP-DART). Additional standard IND toxicology is the next development step. Preliminary toxicological results are presented below along with an outline of a proposed phase I trial design and endpoints, i.e., a “template” to examine reservoir depleting strategies and compounds. Results: Single dose range finding studies in rats indicates a dose dependent reversible hepatotoxicity with a maximum tolerated dose between 0.2 and 0.4 mg/kg. The maximum tolerated dose (via IV bolus) in Rhesus Macaques is estimated at between 0.4 and 0.6 mg/kg. Repeat dosing at 0.4mg/kg was tolerated with reversible toxicity. Human micromosomal experiments indicate time dependant loss of parent compound with a single metabolite representing less than 17% of total amount, and rapid distribution of the drug. Urinary excretion was less that 5%. Oral bioavailability is estimated at 28%. Simulations of various activation levels reveal that prostratin, used as a single agent, would require multiple cycles of administration to achieve a detectable 3 log decrease in latent virus. Additional dosing to determine whether toxicity is related to a “Cmax” effect or exposure are planned. These studies will help determine the optimal dosing schedule, i.e., single maximum dose vs multiple smaller daily doses per cycle. Clinical Trial Design and Endpoints: The initial clinical trial design will attempt to determine the maximum tolerated dose of prostratin, and the time to return to baseline of any toxicities seen. The initial endpoints will be determinations of activation markers, “blips” in plasma or tissue (gut) viral RNA and changes in proviral DNA in plasma, tissue and HIV co-culture assays. Conclusion: Clinical attempts to target viral reservoirs face challenges in designing interventions which can measure if changes in planned endpoints can reasonably be measured, whether any changes measured are clinically significant and whether such interventions warrant the potential risks to patients. Most likely, several targeting modalities will need to be combined to be successful.