Prophylactic Efficacy and Bone Toxicity Associated with Phosphonoformate Therapy against Retrovirus Infection

Abstract

Phosphonoformate (PFA) is a simple pyrophosphate analogue which is a topical and parenteral treatment for human herpes virus infections and is currently undergoing evaluation for treatment of human immunodeficiency virus (HIV) and cytomegalovirus infections associated with (AIDS). In this study, antiretroviral activity of PFA was demonstrated by two separate treatment regimens. In the first, an inoculum of feline leukaemia virus (FeLV) in plasma from viraemic cats was treated with 1024 μM PFA prior to intravenous inoculation into susceptible animals. Three of four cats given the PFA treated inoculum were protected from viraemia by the PFA treatment, while 2 of 2 challenge controls receiving sham treated inoculum and 6 of 6 untreated challenge controls became viraemic. In the second regimen, a long-term continuous intravenous infusion of PFA (1000 mg kg⁻¹ day⁻¹) was administered to 6 young cats beginning 1–2 days prior to and extending 4 weeks following intravenous inoculation with FeLV. Five of the six PFA-treated cats also received heparin intravenously and acetyl salicylic acid (aspirin) orally to reduce risk of thrombosis. Six cats (heparin controls) received only heparin and aspirin and were inoculated with FeLV in an identical manner. Six cats served as untreated challenge controls. Four of 6 PFA-treated cats were protected from FeLV antigenaemia. In contrast, all 6 heparin-control animals and all 6 challenge-control animals became persistently viraemic as evidenced by continuous expression of FeLV p27 antigen. All challenged cats including the 4 protected by PFA treatment developed antibody to FeLV, indicating that PFA did not prevent primary virus infection. Significant toxic effects of PFA treatment were reduced weight-gain and rickets-like bone lesions in the cats receiving the 4 week treatment. Additionally, decreased serum alkaline phosphatase, phosphorus, and calcitriol concentrations, presumably related to the bone lesions, were observed. Results of this study suggest that the antiviral effect of PFA involves an immediate and direct mechanism targeted at cell-free virus and that long-term continuous intravenous infusion of PFA has significant anti-retroviral activity in vivo.