Current approaches to treatment of HIV infection include nucleoside
analogues and protease inhibitors. Despite the improved activity of
combination therapy over monotherapies as measured by effects on
surrogate markers or disease progression, the immunologic and clinical
impact of such therapies is incomplete and transient. Development of
in vitro resistance has been demonstrated in HIV isolates from treated
patients. Therefore the identification of novel drugs with improved
activity, tolerability, and resistance profiles for treating patients
with HIV infection are still needed.
PMPA is a nucleotide analogue with in vitro activity against HIV-1,
HIV-2, and Hepatitis B virus. The active intracellular metabolite, PMPA
diphosphate (PMPApp), inhibits HIV-1 reverse transcriptase at
concentrations about 200-fold lower than that needed to inhibit DNA
polymerase alpha. The in vivo half-life of PNWApp in peripheral blood
mononuclear cells and lymph nodes from monkeys injected with one dose
of PMPA was greater than 24 hours.
The objective of this proposed study are to (a) elevate the safety of
single and multiple doses of PMPA Prodrug when administered orally to
HIV-nfected subjects (b) to evaluate the pharmacokinetics of single and
multiple doses of PMPA Prodrug as demonstrated by effects on CD4 count
and HIV RNA.
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