Single Dose Truvada in HIV-negative Men and Women
Condition: Pharmacokinetic Study in Healthy Volunteers
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): tenofovir + emtricitabine
Intervention type(s): Drug
Intervention description(s): tenofovir 300mg + emtricitabine 200mg x one dose
Other intervention name(s): Truvada
Intervention MeSH terms: Tenofovir; Emtricitabine
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Twelve adult (18 years or older) healthy volunteers will be recruited to participate in the
        study. A total of 6 men and 6 women will be enrolled. Subjects of all races and ethnicities
        may participate, provided they meet study inclusion/exclusion criteria.
      
Keywords: Truvada; tenofovir; emtricitabine; Pharmacokinetics; Healthy Volunteers