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Determining the Relative Efficacy of Tenofovir DF Using Frequent Measurements of HIV-1 RNA During a Short Course of Monotherapy in Antiretroviral Drug Naïve Individuals
M. Louie*1, C. Hogan1, A. Hurley1, B. Captan1, J. Flaherty2, P. Lamy2, A. Balagtas2, D. F. Coakley2, C. Chung1, D. Ho1, and M. Markowitz1
1Aaron Diamond AIDS Res. Ctr., Rockefeller Univ., New York, NY and 2Gilead Sci., Inc., Foster City, CA
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Background: The antiviral potency of new drugs is difficult to assess. Tenofovir DF is a novel nucleotide RTI developed to treat HIV-1 infection. To assess its inherent potency we determined the slopes of the initial phase of decay of plasma HIV-1 RNA after starting Tenofovir DF monotherapy. The slope of HIV-1 RNA decay is a function of the decay constant of the actively infected virus producing CD4+ T cell (delta) and the efficacy (epsilon) of the antiviral agent being applied. As delta is a constant in comparable populations, we found the ratio of initial decay slopes to determine the relative antiviral efficacy of one drug(s) vs another. We have previously determined mean initial decay slopes of -0.99 for potent HAART containing Kaletra, EFV, tenofovir DF, and 3TC and -0.34 for ritonavir monotherapy.
Methods: 10 chronically HIV-1-infected antiretroviral naïve individuals were hospitalized for initiation of tenofovir DF 300 mg, 1 tablet once daily as monotherapy, and frequent monitoring of HIV-1 RNA levels every 6 hours for 72 hours. After discharge patients were seen daily till day 10, then on days 12, 14, and 21.
Results: 10 subjects, (9 males) mean age 34.2 yrs, including 5 African Americans, 2 Hispanics, 2 Caucasians, and 1 Asian presented with mean CD4+ T cells counts of 559 ± 330 cells/mm3 (range: 280-1414) and mean HIV-1 RNA levels of log 4.3 ± 0.5 (range: 3.7-5.0). Maximal reductions in HIV-1 RNA levels during the 3 weeks of therapy were 1.5 log10 on average (range: 0.7- 2.0). Individual first phase decay slopes of plasma HIV-1 RNA ranged from -0.24 to -0.59. The mean and median values were -0.39 and -0.40, respectively. Assuming that delta is a constant across the 3 studies, then tenofovir DF has a relative efficacy (epsilon) of 1.1 when compared to ritonavir monotherapy and 0.39 when compared to the potent HAART detailed above. Mean CD4+ T-cell counts increased 63 cells/mm3 at day 21.
Conclusions: Based on determinations of relative efficacy, tenofovir DF has robust antiretroviral activity with potency comparable to ritonavir monotherapy.
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