AIDS THERAPIES IN ANIMAL RETROVIRUS MODELS

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We examined the long-term effects of treatment of rhesus monkeys with 30 mg/kg/day (R)-9-(2-phosphonylmethoxypropyl) adenine (PMPA) administered by subcutaneous injection beginning 14 days after intravenous infection with SIV. A very strong antiviral effect was observed in 3 of 5 monkeys. After only 7 days of treatment the virus burden in plasma had decreased an average of 3.4 logs, from a mean of 7 x 106 to 2 x 103 SIV RNA copies per ml, corresponding to a decrease of 99.8%. After 28 days of treatment, the levels of plasma RNA had decreased further below the quantifiable range (<1 x 103) and remained low or undetectable for the duration of treatment. A much weaker antiviral effect was observed in 2 other monkeys which after 7 days of treatment had decreases of only 1.2 logs, from a mean of 1.6 x 107 to 1 x 106 RNA copies per ml, corresponding to a decrease of 93.7%. After 28 days of treatment, these 2 monkeys had decreases of 2.1 logs to a mean of 1.6 x 105 copies per ml and values ranged from 1.6 x 104 to 1 x 106 (average = 3.03 x 105) for the duration of treatment. After 330 days of treatment all 5 monkeys had varying degrees of osteopenia and 4 of 5 had decreased levels of serum phophorus and increased alkaline phosphatase. Osteopenia continued to progress and serum phosphorus remained low. After 14 months of treatment with 30 mg/kg/day pharmacokinetic evaluation revealed that in the long-term treated group the Cmax was 1.8 times normal, the AUC was 2.1 times normal, the t1/2 was 1.7 times normal, and the clearance rate was 51% of normal. Treatment was stopped in 3 of the monkeys after 448 to 469 days. Serum phosphorus levels increased rapidly toward normal levels, beginning 13-21 days after cessation. One monkey had maintained high levels of plasma viral RNA throughout treatment and the RNA level only increased 0.6 log, from 6.4 x 104 to 2.6 x 105 copies/ml, beginning 63 days after cessation. However, the percentage of CD4+ cells decreased progressively from 19% to 6% beginning 91 days after treatment was stopped. Another monkey showed a marked progressive increase in plasma viral RNA beginning 42 days after cessation, and the percentage of CD4+ cells plunged from 36% to 15% beginning 84 days after cessation. Proviral DNA, which had been undetectable in PBMC, became consistently detectable after 112 days. The third monkey showed only a small transient increase in plasma viral RNA 56 days after cessation, along with a slight transient decrease in CD4+ cells. Serial radiologic examinations indicated that bone density began to increase towards