Single Dose Truvada in HIV-negative Men and Women (TAIL)
This open-label, non-blinded, pharmacokinetic (PK) study will assess both tenofovir and emtricitabine (components of Truvada) concentrations within genital tract of male and females after a single dose of Truvada®. Concentrations of the active drug will be measured in blood (women and men), cervicovaginal aspirates and vaginal tissue (women only), seminal fluid and rectal tissue (men only). Samples will be obtained at 24 hours (1 day), 48 hours (2 days), 5 days, 7 days, 10 days, and 14 days post-dose. Each subject will undergo 2 biopsy days, at least 72 hours apart. Additionally, tissue samples will be evaluated ex-vivo for HIV infectivity.
Pharmacokinetic Study in Healthy Volunteers
Drug: tenofovir + emtricitabine
|Study Design:||Observational Model: Cohort
Time Perspective: Prospective
|Official Title:||Extracellular and Intracellular TFV/FTC Residues After a Single Dose in HIV-Negative Men and Women: Implications for Pre-exposure HIV Prophylaxis Dosing of Truvada®|
- TFV, TFV-DP, FTC, FTC-TP in blood, CVF, cervical and vaginal and rectal tissue over 14 days [ Time Frame: 14 days ] [ Designated as safety issue: No ]The study aims to examine intra- and extracellular tenofovir and emtricitabine concentrations in various human compartments after a single dose, and to look at the potential for HIV infectivity in tissue samples from these compartments.
|Study Start Date:||October 2008|
|Study Completion Date:||May 2009|
|Primary Completion Date:||May 2009 (Final data collection date for primary outcome measure)|
Single dose of Truvada
Drug: tenofovir + emtricitabine
tenofovir 300mg + emtricitabine 200mg x one dose
Other Name: Truvada
An estimated 80% of HIV infections worldwide are acquired through sexual transmission.1 Viable methods of preventing the sexual transmission of HIV are urgently needed, especially in resource-poor countries. As these countries now have increased access to generic antiretroviral medications, oral administration of antiretroviral drugs as pre-exposure prophylaxis may serve as a feasible, minimally invasive mechanism of preventing the sexual transmission of HIV globally.
Antiretroviral prophylaxis with the combination of tenofovir and emtricitabine has recently been investigated by the U.S. Centers for Disease Control and Prevention in a series of studies with rhesus macaques. Researchers developed a rectal inoculation model using concentrations of Simian HIV (SIV) that were representative of HIV exposure in humans. With this model, researchers demonstrated that standard doses of tenofovir disoproxil fumarate delayed, or partially protected, animals from the acquisition of Simian HIV during a 14-week time period. In this same model, high dose tenofovir was fully protective from infection.2 However, it is unknown how concentrations in the macaque mucosal surfaces compare to that in humans. Notwithstanding, a number of clinical studies are currently investigating daily dosing of tenofovir or tenofovir with emtricitabine for pre-exposure prophylaxis.3
Since daily dosing of antiretrovirals for pre-exposure prophylaxis is not sustainable long-term, other coitally-dependent (episodic) dosing strategies are needed. However, the extent to which these drugs concentrate in tissues, and the duration of intracellular phosphate exposure after single doses, is currently unknown. This information is required to inform the potential of success with these dosing strategies.
At steady-state concentrations, the mean blood plasma half-life (t½) of tenofovir and emtricitabine are 15.9 hours and 10.7 hours, respectively. 4 However, the intracellular t½ of tenofovir diphosphate and emtricitabine triphosphate are >60 hours and 39 hours, respectively.5 The long intracellular t½ of the active forms of these drugs might hold advantages for episodic dosing. However, the long t½ might also hold disadvantages in terms of the development of viral resistance mutations. This phenomenon (the development of resistance after a single dose of a long t½ drug), has been previously seen with nevirapine given during delivery to HIV-infected women to prevent mother to child transmission of HIV.6 However, these women were chronically infected, rather than newly infected, as would be the case with populations exposed to prevention strategies.
The proposed study aims to augment the information gathered in previous studies by examining intracellular and extracellular tenofovir and emtricitabine drug concentrations in various human compartments after a single dose, and to describe the potential for HIV infectivity in selected tissue samples obtained from these compartments.
|United States, North Carolina|
|University of North Carolina|
|Chapel Hill, North Carolina, United States, 27599|
|Principal Investigator:||Angela DM Kashuba, PharmD||University of North Carolina|
|Principal Investigator:||Kristine B Patterson, MD||University of North Carolina|