1. Immune Deficiency Treatment Centre, McGill University, Montreal, Canada;
2. Russian Federal AIDS Centre, Moscow, Russia;
3. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

Background to study:
PZT (3'-azido-2', 3' dideoxythymidine-5'-H-phosponate) is a phosphonated nucleoside analog with demonstrated in vitro antiretroviral activity, a selectivity index similar to AZT and a longer retention time. Because of the possibility that this compound may have a favorable dosing and tolerance profile, as well as good anti-HIV potency, a phase one study was carried out.

Objectives:
To determine the safety, tolerability, magnitude and short term durability of the anti-viral activity.

Design:
A phase one open label, 12 week, dose escalating study. Eligibility criteria included no previous antiretroviral drug therapy and no active opportunistic infections. 42 patients were recruited and randomized to four treatment groups. (A) 200mg BID (B) 200 mg TID (C) 400mg BID and (D) 400mg TID. The drug was supplied in 200mg oral tablets. Thirty-one men, mean age 22-y.o. range (17-40 yrs), 11 women, mean age 27 y.o. range (18-59 yrs) were enrolled. All patients were asymptomatic at time of entry. Mean baseline at CD4 was 413 (range 65-1104) cells/mm3 in men, and 459 (range 160-1135) cells/mm3 in women.

Results:
Of the 29 patients analyzed to date, a dose response effect was noted as early as two weeks post therapy. The mean drop in HIV-RNA in Group A was -0.31 log10 copies/mL (range -0.13 to -0.63) and in Group B was -0.38 log10 copies/mL (range -0.21 to -0.66). In Group C -0.70 log10 copies/mL (range 0 to -1.73) and Group D -0.78 log10 copies/mL (range -0.27 to 1.97). This magnitude of antiviral effect was sustained in all groups throughout the study visits.

Conclusions:
No major toxicities were noted, all dosage levels were tolerated during the study period. The higher dosages had the most potent antiviral activity. Group C (400 mg BID dosing) showed equivalence to group D (400mg TID dosing). This compound warrants further clinical study in combination therapies with other and HIV agents.

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