Insulin Resistance Clinical Trial
Official title:
Changes in Insulin Sensitivity in Healthy Volunteers Taking Tenofovir Alafenamide (TAF)-Containing Antiretroviral Medication: The TAF-IR Study
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
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.
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