PK of Tenofovir, Emtricitabine and Efavirenz in Healthy Volunteers

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.