MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Background: Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. Objective: MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. Methods and Findings: We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Conclusions: Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. Trial Registration: ClinicalTrials.gov NCT00592124

Differential Effects of Tipranavir plus Ritonavir on Atorvastatin or Rosuvastatin Pharmacokinetics in Healthy Volunteers▿

To identify pharmacokinetic (PK) drug-drug interactions between tipranavir-ritonavir (TPV/r) and rosuvastatin and atorvastatin, we conducted two prospective, open-label, single-arm, two-period studies. The geometric mean (GM) ratio was 1.37 (90% confidence interval [CI], 1.15 to 1.62) for the area under the concentration-time curve (AUC) for rosuvastatin and 2.23 (90% CI, 1.83 to 2.72) for the maximum concentration of drug in serum (Cmax) for rosuvastatin with TPV/r at steady state versus alone. The GM ratio was 9.36 (90% CI, 8.02 to 10.94) for the AUC of atorvastatin and 8.61 (90% CI, 7.25 to 10.21) for the Cmax of atorvastatin with TPV/r at steady state versus alone. Tipranavir PK parameters were not affected by single-dose rosuvastatin or atorvastatin. Mild gastrointestinal intolerance, headache, and mild reversible liver enzyme elevations (grade 1 and 2) were the most commonly reported adverse drug reactions. Based on these interactions, we recommend low initial doses of rosuvastatin (5 mg) and atorvastatin (10 mg), with careful clinical monitoring of rosuvastatin- or atorvastatin-related adverse events when combined with TPV/r

A randomized trial of two-drug versus three-drug tenofovir-containing maintenance regimens in virologically controlled HIV-1 patients.

International audienceOBJECTIVES: To assess simplified maintenance regimens containing dual antiretroviral drugs in patients with controlled human immunodeficiency virus type 1 infection. METHODS: A non-inferiority, randomized, multicentre, open-label trial was performed in 24 AIDS clinical centres in France randomizing 143 patients [treated for >or=6 months, plasma viral load (pVL) <50 copies/mL, no prior history of treatment failure] to receive a two-drug regimen [tenofovir disoproxil fumarate (tenofovir DF) and efavirenz] or to maintain a three-drug treatment (tenofovir DF, lamivudine and efavirenz). The main outcome measure was the success rate (percentage of patients with pVL <50 copies/mL without treatment modifications) at week 48. RESULTS: Success rates for the intention-to-treat analysis were 97.2% (70/72) versus 81.7% (58/71) in the three-drug versus two-drug maintenance regimen groups, respectively [difference, 15.5%; upper limit of one-sided 95% confidence interval (CI), 23.7%], and 100% (70/70) versus 90% (54/60) for the per protocol analysis, respectively (difference, 10%; upper limit of one-sided 95% CI, 16.4%), with a non-inferiority margin set at 14%. Three patients from the two-drug group experienced virological failure with selection of efavirenz-associated mutations. Overall, CD4 counts were significantly increased from baseline (median, +24 cells/mm(3); P = 0.007). Four patients discontinued study treatment due to adverse events in the two-drug group and none in the three-drug group. No significant changes in creatinine clearance or phosphataemia were reported. Overall, levels of triglycerides, total and high-density lipoprotein cholesterol were improved; low-density lipoprotein cholesterol was improved only in the three-drug group. CONCLUSIONS: The non-inferiority of the two-drug versus the three-drug regimen was not demonstrated. Lipid parameters improved after switching from twice-daily highly active antiretroviral therapy (HAART) to once-daily tenofovir-based HAART