AN OPEN-LABEL DOSE-ESCALATION TRIAL OF ORAL DEHYDROEPIANDROSTERONE TOLERANCE AND PHARMACOKINETICS IN PATIENTS WITH HIV DISEASE

Dehydroepiandrosterone (DHEA) is a naturally occurring adrenal steroid reported to have immunomodulatory and antiviral activity in cellular and animal models as well as modest in vitro antiretroviral activity a gainst human immunodeficiency virus (HIV). A phase I dose-escalation s tudy was performed to evaluate the safety and pharmacokinetics of DHEA in subjects with symptomatic HIV disease and an absolute CD4 lymphocy te count between 250 and 600 cells/mul. Thirty-one subjects were evalu ated and monitored for safety and tolerance. The oral drug was adminis tered three times daily in doses ranging from 750 mg/day to 2,250 mg/d ay for 16 weeks. Some immunological and virological parameters were mo nitored as well. The drug was well tolerated and no dose-limiting side effects were noted. Dose proportionality was evidenced neither by the serum DHEA nor by DHEA-S time-concentration curves for the three dosi ng groups. However, the study cohort appeared to consist of two subpop ulations with markedly different bioavailability for a given DHEA dose . No sustained improvements in CD4 counts nor decreases in serum p24 a ntigen or beta-2 microglobulin levels were observed. However, serum ne opterin levels decreased transiently by 23-40% at week 8 compared with baseline in all dosing groups. DHEA was well tolerated by patients wi th mild symptomatic HIV disease; evaluation of this agent for efficacy in HIV disease would require randomized, controlled trials.