• Safety
  The two pivotal studies of the safety and efficacy of TDF, Studies 902 and 907, were conducted in individuals with 4.6 and 5.4 years, respectively, of prior antiretroviral therapy. Study 902 enrolled 189 HIV-infected subjects with viral loads of 400-100,000 copies/ml on stable antiretroviral therapy consisting of <4 drugs for >8 weeks. They were randomized 2:2:2:1 to receive one of three daily doses of TDF(75mg, 150 mg or 300 mg) or placebo in addition to their existing antiretroviral treatment regimen for 48 weeks. At week 24, all subjects receiving placebo were switched the TDF 300mg daily arm. After the end of the 48-week blinded study, 135 subjects rolled over into an open label extension phase and received 300 mg of TDF daily.

  Study 907 enrolled 552 subjects with viral loads of 400-10,000 copies/mL on stable antiretroviral therapy for at least eight weeks prior to entering the study. Subjects were randomized (2:1) to receive TDF 300mg once daily, or placebo, in addition to their existing antiretroviral therapy. After 24 weeks, all subjects had the option of receiving TDF for the remainder of the 48-week study period; 170 subjects who received placebo rolled over to receive treatment with TDF.

• For the first 24 weeks of Study 907, rates of drug discontinuation, of serious adverse events (SAEs), and of Grade 3 or 4 laboratory abnormalities in the 368 subjects who received TDF 300 mg daily were all comparable to those for placebo. Two SAEs in Study 902 were considered by the investigator to be possibly related to TDF: liver failure in one subject in the TDF 75 mg group and acute pancreatitis in a subject in the TDF 300 mg group. During this study, there was also one suicide, which was judged by the investigator not to be related to TDF. As of September 28, 2001, over 4 900 patients worldwide have enrolled in the TDF Expanded Access Program (EAP) which opened to accrual in March 2001. Globally, SAEs have been reported in 122 (2%) patients and all individual events were reported in < 1% patients.

• Since osteomalacia (softening of the bones due to demineralization) was observed in rats and dogs dosed at doses equivalent to 6- to 10-fold greater than human exposure and in juvenile monkeys at 12 to 50-fold greater than human exposure, close monitoring for bone toxicity in humans was done in Studies 902 and 907. There was no evidence of bone abnormalities. All fractures seen were due to high impact trauma and the rate of fractures for TDF 300mg daily was 1.9 per 100 patient-years compared with 3.0 per 100 patient-years for placebo.

• Because of the nephrotoxicity of adefovir, another nucleotide RTI, and because there was evidence of nephrotoxicity in newborn and juvenile monkeys dosed with TFV equivalent to 12- to 50-fold greater than human therapeutic doses, individuals with renal impairment were excluded from Studies 902 and 907. In addition, subjects were closely monitored for evidence of renal toxicity. No nephrotoxicity was seen and changes in serum creatinine and phosphate were similar to those seen in the placebo arm.

DAVG₂₄ by intent-to-treat (ITT) analysis among the 54 subjects treated with TDF 300 mg in Study 902 was -0.58 log10 copies/ml while for placebo it was +0.02 log10 (p<0.001). For Study 907, it was -0.59 log10 copies/ml for the TDF arm and -0.01 log10 in the placebo group (p<0.0001). In Study 907, 45% (155/346) of subjects treated with TDF achieved viral load reductions to <400 copies/ml at 24 weeks, compared with 13% (23/172) in the placebo group (p<0.0001). Reduction in viral load to <50 copies/ml was achieved by 22% (76/346) of subjects in the TDF group compared to 1% (2/172) in the placebo group (p<0.0001). DAVG₂₄ for both non-Caucasians (35% study population) and women (15%) was -0.6 log₁₀ by ITT analysis of 907. DAVG₄₈ for subjects who received TDF 300 mg in Study 902 was -0.62 log10 copies/ml.

TDF has demonstrated good efficacy against drug resistant HIV. Subjects in Study 902 with virus resistant to AZT, NNRTIs, or PIs experienced DAVG₂₄ of -0.52 to -0.61 log₁₀ copies/ml. Individuals with HIV exhibiting >10-fold change in susceptibility to AZT had DAVG of -0.58 log₁₀ copies/ml. DAVG₂₄ was -0.65 and -0.48 log₁₀ cells/ml, respectively, for subjects in 907 with and without the M184V mutation on TDF 300 mg and -0.20 and +0.28 log₁₀, respectively, for those on placebo.

In the TDF arm of Study 907, the DAVG24 for CD4 cells was an increase of 12.6 cells/ml compared with a decrease of 10.6 cells/ml in the placebo arm (p=0.0008).

Following single oral doses of TDF 300 mg with food in HIV-infected subjects, mean peak TFV plasma levels were 362 ng/mL, respectively. After dosing fasted subjects with TDF 300mg once daily until steady state, the Cmax was 350-380ng/ml, the Cmin was 50-70 ng/ml and the AUC0-24 was 2 500-3 000 ng.h/ml. When dosed with food, the Cmax was 300ng/ml and the AUC was 3300 ng.hr/ml. The volume of distribution was 600-800 ml/kg. and the serum half-life (T_½) 12-18 hours. The intracellular (IC) T_½ of PMPApp was 15-50 hours in resting cells and 10 hours in dividing cells. The PK in uninfected volunteers is similar to that in HIV-infected subjects.

Drug interactions between TFV and agents from all three licensed classes of antiretrovirals have been conducted. Among the NRTIs, interactions with 3TC and ddI, which are both excreted primarily by the kidneys, were studied. The NNRTI, EFV, and the PIs, IDV and LPV/rtv, were also studied. All studies were randomized, multiple-dose, open-label, 3-way cross over Phase I studies.

There was no clinically relevant effect of 3TC 150 mg BID on the PK of TDF 300 mg QD. 3TC absorption was delayed increasing T_max by 0.9 hr and decreasing C_max 24%. There was no significant change in 3TC exposure as measured by AUC_(o-t). There was no clinically relevant effect of ddI (Videx™) 400 mg (250 mg if weight <60 mg) QD taken 1 hour prior to TDF on the PK of TDF 300 mg QD. The C_max of ddI was increased by 28% and the AUC_(o-t) was increased by 44%.

The PK parameters for TDF 300 mg QD were not affected by administration with IDV 800 mg Q8H. The IDV C_max was slightly reduced when IDV was administered with TDF, but the AUC_(o-t) was unchanged. TDF AUC_(o-t) and C_max were approximately 30% higher when TDF 300 mg QD was given with LPV/r 400/100 mg BID. Co-administration with TDF resulted in 15% lower LPV AUC_(o-t) and Cmax and 11% lower Cmin. The decrease in Cmin was not statistically significant.

The PK of TDF 300 mg QD was not affected by administration with EFV 600 mg QD. Neither was the PK of EFV affected by administration with TDF.

• Study 903: To evaluate the potential role of tenofovir DF in treatment-naïve subjects, Gilead initiated a randomized, double-blind, multi-center, Phase III clinical trial in June 2000. This trial is designed to compare the safety and tolerability of two treatment regimens, TDF, efavirenz and lamivudine (3TC) versus stavudine (d4T), efavirenz and lamivudine. It was fully enrolled in January 2001 with 601 treatment-naíve subjects.

• Study 910: Open-label rollover of Studies 902 and 907. N=575.

• Expanded Access Program: In January 2001, after protracted discussions with the community, Gilead initiated an expanded access program (EAP) for individuals >18 years of age who required TDF to construct a viable treatment regimen and had failed treatment with at least two PIs or one PI and one NNRTI. Individuals were required to have a viral load of >10,000 copies/ml (by PCR) and CD4 count <100 cells/ml. Additionally, individuals with CD4 count between 100 and 200 cells/ml, and documented evidence of an AIDS-defining opportunistic infection within the past 90 days were eligible. Individuals were also eligible for the EAP if they had completed a clinical trial including TDF and desired continued access to the medication. Individuals receive TDF 300 mg once daily. In April 2001, after some start up difficulties, Gilead announced that the company had broadened the entry criteria for its US EAP to provide TDF to individuals who had failed prior antiretroviral therapy, regardless of their CD4 cell count or viral load. To date, nearly 5000 individuals have enrolled in TDF EAPs in the United States, Canada, Europe the United Kingdom.

• Pediatric Studies: A pediatric formulation of TDF is in development and Gilead has said that they expect it to be ready early in 2002. The study of TDF in infants and children was deferred pending the outcome of bone toxicology studies in animals.