1. McGill University AIDS Centre, Montreal, Canada
2. Russian Federal AIDS Centre, Moscow, Russia
3. Engelhardt Institute of Molecular Biology, Moscow, Russia

Background:
Phosphonovir (PZT) (3'-azido-2',3'-dideoxy thymidine-5'-H-phosphonate) is a phosphonated nucleoside analogue with anti HIV-1 activity. It is an inactive pro-drug of azidothymidine triphosphate (AZTTP) a known potent inhibitor of HIV-1 reverse transcriptase. In-vitro and, animal studies as well as an initial phase I clinical trial patients have shown it to be well tolerated at daily oral doses of 600 mg for up to 12 weeks. Pre-clinical and clinical data suggested a lower potential for hematologic side effects compared with AZT.

Objective:
To evaluate the nature time course and dose dependence of PZT related side effects in a dose escalating study.

Methods:
42 patients were recruited. Oral daily doses of 400 mg, 600 mg, 800 mg and 1,200 mg in bid or tid regimens were used. Patients were followed for clinical virologic, immunologic and hematologic parameters at baseline and at weeks 2, 4, 8 and 12.

Results:
In 36 patients who have completed the study to date, a dose response antiviral effect was noted. Furthermore, the 800 and 1,200mg doses had >.5 log10 reduction in HIV-1 RNA. Patients tolerated treatment well. None discontinued for adverse event or toxicity reasons. A transient decrease in HGB and WBC and neutrophils were noted at week 4 and resolved in subsequent visits. No Grade 3 or 4 hematologic toxicities were noted. During the 12 weeks platelet counts remained stable and the mean corpuscular volume (MCV) did not increase.

Conclusion:
PZT was well tolerated without significant laboratory, clinical or hematologic toxicity. It has similar anti HIV-1 effects to AZT yet differs in having fewer short term hematologic side effects. Its role in combination antiretroviral therapy remains to be determined.

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