Changes in Insulin Sensitivity in Healthy Volunteers Taking Tenofovir Alafenamide (TAF)-Containing Antiretroviral Medication
Condition: Insulin Resistance
MeSH terms: Insulin Resistance
Study type: Interventional
Phase: Phase 1

Summary: 
      Investigation of possible changes in insulin sensitivity in healthy volunteers taking the
      following HIV treatment combinations: F/TAF (group 1) as compared to E/C/F/TAF (group 2) as
      compared to R/F/TAF (group 3). The measurement of insulin sensitivity will be performed in 30
      HIV-negative healthy non-obese (BMI 18-25) male volunteers before and after 14±2 days of
      treatment. The volunteers will be randomly assigned to one of the three groups. Changes in
      insulin sensitivity will be measured by golden standard hyperinsulinemic euglycemic clamp
      (HEGC) technique, using glucose and insulin infusion as diagnostic agents
    

Detailed description: 
      Nearly immediately following the characterization of HIV, the metabolic disturbances in
      HIV-positive patients, particularly changes in insulin sensitivity, were reported. The
      chronic inflammation due to metabolic changes caused by HIV-Infection on one hand and the
      antiretroviral therapy (ART) itself on the other hand were considered major contributors to
      pathological changes in insulin sensitivity in HIV-positive patients. There were two possible
      mechanisms discussed in the literature: Direct effects on insulin-associated cellular glucose
      uptake and indirect effects of changes in lipid metabolism, i.e. the lipotoxicity.
      Particularly, thymidine analogues, such as nucleoside reverse transcriptase inhibitors (NRTI)
      were strongly linked to lipotoxicity and depletion of mitochondric DNA, causing insulin
      resistance (IR) in HIV-positive patients and healthy volunteers, ultimately resulting in
      overt diabetes mellitus. Furthermore, protease inhibitors (PI) showed lipotoxicity, further
      increasing insulin resistance.

      The incidence of insulin resistance and, ultimately, diabetes mellitus in patients receiving
      ART increases over time, significantly contributing to cardiovascular morbidity and mortality
      in HIV-positive patients. Due to significant increases both in life expectation and duration
      of ART in HIV-patients, the early recognition of unfavorable metabolic changes (i. e. insulin
      resistance) gains in importance. Particularly, the considerations of long-term toxicity and
      safety of ART are receiving more and more attention. Unfortunately, the appropriate
      strategies for screening, surveillance and therapeutic consequences are not well established
      in HIV-positive patients.

      While the very well established HIV nucleoside reverse transcriptase inhibitor Tenofovir
      disaproxil fumarate (TDF) was associated with a favorable influence on lipids and with no
      known negative effects on insulin sensitivity, the new drug Tenofovir alafenamide (TAF) has
      not been analyzed in concern of changes in insulin sensitivity yet. As TAF has been recently
      submitted for approval by FDA and EMEA for treatment of HIV-positive patients, widespread use
      and potential replacement of TDF can be expected soon. Fixed dose combinations with
      Emtricitabine (F/TAF) or cobicistat-boosted elvitegravir (E/C/F/TAF) or rilpivirine (R/F/TAF)
      have been developed and will take part in ART settings. Unfortunately, only limited data
      exists on metabolic effects of TAF or TAF-containing fixed dose combination drugs,
      particularly concerning changes in lipid metabolism and insulin sensitivity in HIV-positive
      patients or healthy volunteers. For providing more safety data concerning changes in insulin
      sensitivity and associated effects on lipids more data should be provided.

      We intend to investigate the possible changes in insulin sensitivity, measured as described
      below by "hyperinsulinemic eugylcemic clamp" in healthy volunteers taking TAF/FTC (group 1)
      as compared to E/C/F/TAF (group 2) as compared to R/F/TAF (group 3). To our best of
      knowledge, there are currently no data available investigating changes in insulin sensitivity
      of TAF-containing ART-regiments.
    

Intervention name(s): F/TAF; E/C/F/TAF; R/F/TAF
Intervention type(s): Drug; Drug; Drug
Intervention description(s): antiretroviral therapy; antiretroviral therapy; antiretroviral therapy
Other intervention name(s): Descovy; Genvoya; Odefsey
Intervention MeSH terms: Emtricitabine tenofovir alafenamide; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Group 1: F/TAF ; oral; Dose: 25/200 mg; Frequency: QD Group 2: E/C/F/TAF; oral; Dose: 150/150/200/10 mg; Frequency: QD Group 3: R/F/TAF; oral; Dose: 25/200/25 mg; Frequency: QD
Masking: None (Open Label)
Primary purpose: Treatment