PK of Tenofovir, Emtricitabine and Efavirenz in Healthy Volunteers
Condition: HIV Infection; HIV Infections
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of the study is to look at the levels of three HIV medications: tenofovir,
      emtricitabine, and efavirenz in blood after the drug intake has been stopped in order to
      understand how long these drugs persist in the blood. The study will specifically look at
      blood levels of these three drugs (taken as a 3-in-1 tablet) after taking them every day for
      14 days.

      This study is not randomised which means that all subjects will receive all study medications
      in the same order. You and the study doctor will know which study medications you are taking
      at all times during the study.
    

Detailed description: 
      The administration of combination antiretroviral therapy (cART) to HIV-infected patients has
      been associated with a dramatic reduction in AIDS-related morbidity and mortality [1-3].

      The key to successful HIV drug treatment is adhering to the prescribed combination every day
      [2]. The approval of Atripla® (tenofovir/emtricitabine/efavirenz co-formulated in a single
      tablet) provides HIV care providers with a "one tablet once a day" therapy, making adherence
      much easier for patients.

      However, in HIV therapy, successful adherence also means attention to intervals between doses
      or dietary restrictions. Ideally, to guarantee long-term virological response, HIV-infected
      patients should take their cART every day at the same time. However, cART is for life and
      doses can be forgotten or delayed.

      Importantly, the 24-week 'Five-on-Two-off' (FOTO) study results were presented in November
      2008; these showed that when HIV-infected patients stable (viral load < 50 copies/mL) on
      Atripla® were randomised to continue treatment daily or to stop taking it at weekends, no
      difference in maintenance of undetectable viral load was observed. Eighty percent in the
      control arm and 83% in the 'weekend off' arm had a viral load < 50 copies/mL [4]. This
      suggests that either the drugs' effects, or the drugs themselves, persist for a significant
      time following drug intake cessation. However, the persistence time and the inter-individual
      variability of this parameter for the components of Atripla® have not been clearly defined.

      A drug's persistence in plasma or in cells depends on its half life. Long half-life
      antiretroviral agents may allow for missed or delayed doses, if concentrations are maintained
      at therapeutic levels until the next dose is taken. NRTI are pro-drugs and must be activated
      by different phosphorilation steps to be effective against HIV. Intracellular triphosphate
      (TP) metabolites have been shown to be characterized by long half lives. However, data on
      drug persistence are limited and whether drug doses can be omitted and dosing delayed is
      unknown.

      Knowledge of the length of time the drug contained in the Atripla® formulation lasts would
      increase the confidence of doctors in this combination.

      Importantly, triple regimen persistence should be investigated in order to provide
      information on the permissiveness (of forgotten or delayed doses) of the whole regimen rather
      than one single agent. Due to the simplicity of administering Atripla®, a study investigating
      the pharmacokinetic "forgiveness" of tenofovir and emtricitabine (in plasma and
      intracellularly) and plasma efavirenz would be readily performed in healthy volunteers and
      would provide information on how to advise HIV infected patients on delayed and missed doses.

      Rationale for the pharmacogenomics analysis

      Pharmacogenetics holds promise in HIV treatment because of the complexity and potential
      toxicity of multi antiretroviral drug therapies that are prescribed for long periods. Thus
      far, few candidate genes have been examined for a limited number of allelic variants, but a
      number of confirmed associations have already emerged.

      From a public health perspective, as antiretroviral medications become increasingly available
      to racially and ethnically diverse populations worldwide, understanding the genetic
      structures of each population may allow us to anticipate the impact of adverse responses,
      even in groups that were not represented in drug registration trials.

      The existing literature on pharmacogenetic determinants of antiretroviral drug exposure, drug
      toxicity, as well as genetic markers associated with the rate of disease progression
      underline the recent advances which occurred in the past few years.

      However, it is expected that larger-scale comprehensive genome approaches will profoundly
      change the landscape of knowledge in the future. Additional studies are needed to assess the
      implications for long-term responses to antiretroviral agents.

      For this reason we plan to collect a single blood sample from each participant in our
      intensive pharmacokinetic studies, such as this one, in order to be able to investigate the
      association between genetic polymorphisms in drug disposition genes (such as those encoding
      for cytochrome P450 isoenzymes or transmembrane transporters) and drug exposure. A candidate
      gene approach will be utilised to examine loci of interest. This procedure will provide
      potentially important information on genetic influences on plasma drug concentrations and
      give insight into how to improve the management of HIV-infected patients by individualising
      therapy. These studies will not be powered for genetic associations but will enable us to
      build a data base of genotype-phenotype. Prospective genetic studies would need to be planned
      based on these preliminary data.
    

Intervention name(s): Atripla®
Intervention type(s): Drug
Intervention description(s): All subjects will be administered Atripla® (tenofovir 245 mg plus emtricitabine 200 mg plus efavirenz 600 mg), one tablet orally once daily for 14 days
Other intervention name(s): tenofovir = Viread®; emtricitabine = Emtriva® (formerly Coviracil); tenofovir + emtricitabine = Truvada®; efavirenz = Sustiva® and Stocrin®
Intervention MeSH terms: Tenofovir; Emtricitabine; Efavirenz; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment