The difference in the proportion of patients who achieved and maintained HIV-1 RNA < 400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label study. In addition, 80% and 70% of patients in the VIREAD + EMTRIVA group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA < 50 copies/mL. The mean increase from baseline in CD4 cell count was 190 cells/mm³ in the VIREAD + EMTRIVA group and 158 cells/mm³ in the zidovudine/lamivudine group.

Through 48 weeks, 7 patients in the VIREAD + EMTRIVA group and 5 patients in the zidovudine/lamivudine group experienced a new CDC Class C event.

Treatment-Experienced Patients

Study 907: VIREAD + Standard Background Therapy (SBT) Compared to Placebo + SBT

Study 907 was a 24-week, double-blind placebo-controlled multicenter study of VIREAD added to a stable background regimen of antiretroviral agents in 550 treatment-experienced patients. After 24 weeks of blinded study treatment, all patients continuing on study were offered open-label VIREAD for an additional 24 weeks. Patients had a mean baseline CD4 cell count of 427 cells/mm³(range 23–1385), median baseline plasma HIV-1 RNA of 2340 (range 50-75,000) copies/mL, and mean duration of prior HIV-1 treatment was 5.4 years. Mean age of the patients was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic.

Changes from baseline in log₁₀ copies/mL plasma HIV-1 RNA levels over time up to Week 48 are presented below in Figure 1.

Figure 1: Mean Change from Baseline in Plasma HIV-1 RNA (log₁₀ copies/mL) Through Week 48: Study 907 (All Available Data)^†

The percent of patients with HIV-1 RNA < 400 copies/mL and outcomes of patients through 48 weeks are summarized in Table 8.

Table 8: Outcomes of Randomized Treatment (Study 907)

At 24 weeks of therapy, there was a higher proportion of patients in the VIREAD arm compared to the placebo arm with HIV-1 RNA < 50 copies/mL (19% and 1%, respectively). Mean change in absolute CD4 counts by Week 24 was +11 cells/mm³ for the VIREAD group and -5 cells/mm³ for the placebo group. Mean change in absolute CD4 counts by Week 48 was +4 cells/mm³ for the VIREAD group.

Through Week 24, one patient in the VIREAD group and no patients in the placebo arm experienced a new CDC Class C event.

Animal Toxicology

Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6 fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

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