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Neither boosted elvitegravir nor darunavir with emtricitabine/tenofovir disoproxil fumarate increase insulin resistance in healthy volunteers: results from the STRIBILD-IR study

Christoph D Spinner1,*,, Kristina E Kern1,, Alexander Zink2, Eva Wolf3, Annamaria Balogh3, Sebastian Noe1, Alexander Von Werder1, Christiane Schwerdtfeger1, Roland M Schmid1, Roman Iakoubov1

1Department of Medicine II, University Hospital Klinikum rechts der Isar, Munich, Germany
2Department of Dermatology and Allergology, University Hospital Klinikum rechts der Isar, Munich, Germany
3MUC RESEARCH, Munich, Germany

*Corresponding author e-mail: christoph.spinner@tum.de

These authors contributed equally to the manuscript

Citation: Antiviral Therapy 2016; 21:627-631
doi: 10.3851/IMP3049

Date accepted: 31 March 2016
Date published online: 06 April 2016

Copyright (c) 2016 International Medical Press, all rights reserved.

Abstract

Background: Insulin resistance (IR) was one of the first reported complications in HIV-positive patients who were receiving antiretroviral therapy (ART). However, the metabolic effects of newer fixed-dose ART combinations are unclear.

Methods: This Phase I prospective randomized open-label study evaluated the effects on IR in 30 healthy volunteers who were receiving newer fixed-dose combinations of tenofovir disoproxil fumarate, emtricitabine, elvitegravir and cobicistat (E/C/F/TDF, 10 patients) or the established ART regimens, such as tenofovir disoproxil fumarate/emtricitabine with lopinavir/ritonavir (F/TDF+LPV/r, 9 patients) or darunavir/ritonavir (F/TDF+DRV/r, 9 patients). IR was measured before and after the 14-day treatments using the hyperinsulinemic-euglycemic clamp technique, and changes in IR were evaluated using the mean glucose disposal rate that was normalized to body weight (MBW) and lipid metabolism.

Results: The groups exhibited similar pretreatment IR, although MBW was significantly lower after the 14-day F/TDF+LPV/r treatment compared with baseline (12.5 ±3.3 versus 9.2 ±1.8 mg glucose/min×kg; P=0.037). No significant IR changes were observed for E/C/F/TDF (11.2 ±3.2 versus 11.3 ±2.5) or F/TDF+DRV/r (11.6 ±2.5 versus 11.3 ±2.4). Compared with baseline, F/TDF+LPV/r and F/TDF+DRV/r treatments significantly increased day 14 triglyceride levels (62 [54–73] versus 119 [77–147] mg/dl, P=0.0109; 75 [56–95] versus 96 [93–128] mg/dl, P=0.009, respectively).

Conclusions: Short-term treatment using fixed-dose combinations of E/C/F/TDF or F/TDF+DRV/r did not affect IR, although IR significantly increased after treatment using F/TDF+LPV/r.

Introduction

Insulin resistance (IR) was one of the first reported metabolic complications in HIV-positive patients after antiretroviral therapy (ART) became commonly used in this population [1,2]. In addition, ART is associated with the incidences of IR and diabetes mellitus, which contribute to cardiovascular-related morbidity and mortality [1,3,4]. Thus, based on the increasing life expectancy of treated HIV-positive patients, attention has shifted to the long-term tolerability and safety of ART [1].

Both in vitro and in vivo studies have found that ritonavir-boosted lopinavir (LPV/r) is associated with adverse effects on insulin sensitivity [5,6], and this association is supported by studies that used the gold-standard hyperinsulinemic-euglycemic clamp (HEGC) technique [7]. However, no comparable adverse effects have been reported for newer nucleoside reverse transcriptase inhibitors (NRTIs), such as emtricitabine/tenofovir disoproxil fumarate (F/TDF) or abacavir. Furthermore, newer boosted HIV protease inhibitors (for example, atazanavir or darunavir) only exert marginal effects on IR [1]. Moreover, limited data exist regarding the metabolic effects of ART regimens that include fixed-dose combinations [5,6,8]. Although TDF has no reported negative effects on IR, it does have a general lipid-lowering effect [1,9], and boosted protease inhibitors are associated with unfavourable effects on lipid profiles [10,11].

No data are available regarding changes in IR among patients who are receiving F/TDF with elvitegravir/cobicistat (E/C/F/TDF), ritonavir-boosted lopinavir (F/TDF+LPV/r), or ritonavir-boosted darunavir (F/TDF+DRV/r). Therefore, this study aimed to compare F/TDF+LPV/r (as an established ART regimen with known probable adverse effects on IR) and newer combinations (F/TDF+DRV/r and fixed-dose E/C/F/TDF). These treatments were selected based on the German and European treatment guidelines at the time of this study’s initiation, and IR changes were evaluated using HEGC testing to provide clinically relevant data.

Methods

The Ethics Committee of the Technische Universität München approved this study (EudraCT: 2014-000359-98). The study complied with the Declaration of Helsinki, and all participants provided their written consent. This prospective open-label randomized Phase I study randomly assigned 30 healthy, HIV-negative, non-obese and non-smoking male volunteers to receive fixed-dose combinations of either E/C/F/TDF (Gilead Sciences, Foster City, CA, USA), F/TDF+LPV/r (Gilead Sciences; AbbVie, North Chicago, IL, USA), or F/TDF+DRV/r (Janssen-Cilag, New Brunswick, NJ, USA). Adherence was evaluated using pill counting and pharmacokinetic analysis of a single indicative ART component (elvitegravir, lopinavir, or darunavir, as appropriate) on days 7 and 14.

We measured IR using the HEGC technique before treatment and after 14 ±2 days of treatment, based on the established protocols of DeFronzo et al. [7] and Hung et al. [12]. Based on the ethical considerations and potential harm to healthy individuals, we used venous glucose sampling, as described by Nauck et al. [13]. The HEGC measurements were started at 7–8 AM after a 12-h overnight fast. Two catheters were inserted into the right and left antecubital veins, with one catheter used for glucose and insulin infusions, and the other catheter for blood sampling. A pre-HEGC blood sample was collected for laboratory testing of fasting glucose, potassium, C-peptide, insulin and lipid levels (total cholesterol, fasting triglycerides, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol and lipoprotein-a). Insulin (2 mIU/kg×min, Sanofi-Aventis, Frankfurt, Germany) was constantly infused over 2 h, and the glucose infusion (20% dextrose, Baxter, Unterschleissheim, Germany) was adjusted to achieve stable serum glucose levels (target: 90 ±5 mg/dl).

Serum glucose levels were measured every 5 min using the RapidPoint 400/405 System® (Siemens, Munich, Germany), and blood samples for insulin testing were collected every 20 min. C-peptide levels were measured at 60 min and 120 min to calculate the endogenous insulin secretion rate. After the first 60 min of the HEGC test, a steady-state insulin homeostasis was achieved, and was maintained for another 60 min before the test was finished. IR was evaluated using the mean glucose disposal rate that was normalized to body weight (MBW [mg glucose/min×kg]), body weight and steady-state insulin (MBW/I [mg glucose/min×kg×μIU]), or glucose (Mcr [dl/min×kg]), as previously described [7,12].

The samples were collected on ice using Monovettes® (Sarstedt, Nürmbrecht, Germany), and were immediately centrifuged at 20°C (3,000 rpm for 15 min). The supernatants were stored at -20°C. Glucose concentrations were measured instantly, without processing the sample, using the Siemens RapidPoint 400/405 System® . Insulin was measured using a double-antibody radioimmunoassay (LIASON Analyzer; DiaSorin, Dietzenbach, Germany) and C-peptide (Roche Cobas 8000; Roche, Mannheim, Germany).

Data that did not fulfil the normality assumption (based on the Shapiro-Wilk W-test for normality) were analysed using non-parametric tests (that is, the Kruskal–Wallis test or Mann–Whitney U test). Intra-group changes in IR were evaluated using paired t-tests or Wilcoxon signed-rank tests, as appropriate. Only non-parametric tests were used to evaluate serum lipid levels. The data were expressed as mean ±sd or median (IQR), as appropriate.

Results

Among the 38 screened volunteers, we enrolled 31 patients during the recruitment period. One volunteer withdrew his consent before the randomization, and two patients were excluded from the analyses for medical (diagnosed with hypothyroidism after the randomization) or technical (insulin pump failure) reasons. Thus, the E/C/F/TDF group included 10 patients, the F/TDF+LPV/r group included 9 patients, and the F/TDF+DRV/r group included 9 patients. All groups exhibited similar baseline characteristics (Table 1). The treatments were well tolerated and detectable plasma levels of the drugs in the patients confirmed 100% adherence on days 7 and 14. No serious adverse events were observed during the study period.

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Table 1.  Patient baseline characteristics
Table 1. Patient baseline characteristics

E/C/F/TDF, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate; F/TDF+LPV/r, emtricitabine/tenofovir disoproxil fumarate in combination with ritonavir-boosted lopinavir; F/TDF+DRV/r, emtricitabine/tenofovir disoproxil fumarate in combination with ritonavir-boosted darunavir.

The three groups exhibited similar baseline IR values (Table 2; Figure 1), based on the MBW (E/C/F/TDF: 11.2 ±3.2; F/TDF+LPV/r: 12.5 ±3.3; F/TDF+DRV/r: 11.6 ±2.5 mg glucose/min×kg), MBW/I and MCR data. Neither E/C/F/TDF nor F/TDF+DRV/r significantly affected IR from baseline to day 14. However, F/TDF+LPV/r treatment significantly increased IR from baseline to day 14, based on the MBW (12.5 ±3.3 versus 9.2 ±1.8 mg glucose/min×kg, P=0.037), MBW/I (0.10 ±0.02 versus 0.07 ±0.02 mg glucose/min×kg×μIU, P=0.0336) and MCR data (0.14 ±0.04 versus 0.10 ±0.02 dl/min×kg, P=0.039).

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Table 2.  Changes in insulin resistance after 14 days of antiretroviral treatment
Table 2. Changes in insulin resistance after 14 days of antiretroviral treatment

a The statistical analyses were performed using paired t-tests. E/C/F/TDF, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate; F/TDF+LPV/r, emtricitabine/tenofovir disoproxil fumarate in combination with ritonavir-boosted lopinavir; F/TDF+DRV/r, emtricitabine/tenofovir disoproxil fumarate in combination with ritonavir-boosted darunavir; MBW, mean glucose disposal rate normalized to weight; MBW/I, mean glucose disposal rate normalized to weight and steady-state insulin concentration; MCR, mean glucose disposal rate normalized to weight and steady-state glucose concentration.

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Figure 1.
Figure 1. Mean insulin sensitivity as expressed using the mean insulin glucose disposal rate that was normalized to body weight on days 1 and 14

Data are shown as mean ±se. E/C/F/TDF, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate; F/TDF+DRV/r, emtricitabine/tenofovir disoproxil fumarate in combination with ritonavir-boosted darunavir; F/TDF+LPV/r, emtricitabine/tenofovir disoproxil fumarate in combination with ritonavir-boosted lopinavir; MBW, mean glucose disposal rate normalized to weight; NS, not significant.

The three groups exhibited comparable pretreatment triglyceride levels. Significant post-treatment increases in triglyceride levels (versus baseline) were observed in the F/TDF+LPV/r arm and the F/TDF+DRV/r arm, but not in the E/C/F/TDF arm. The total cholesterol and LDL cholesterol levels did not significantly change in any group (Table 3).

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Table 3.  Changes in lipid metabolism parameters after 14 days of antiretroviral treatment
Table 3. Changes in lipid metabolism parameters after 14 days of antiretroviral treatment

a The statistical analyses were performed using paired t-tests or Wilcoxon signed-rank tests, as appropriate. E/C/F/TDF, elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate; F/TDF+LPV/r, emtricitabine/tenofovir disoproxil fumarate in combination with ritonavir-boosted lopinavir; F/TDF+DRV/r, emtricitabine/tenofovir disoproxil fumarate in combination with ritonavir-boosted darunavir; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Discussion

We observed a significant increase in IR, as measured using MBW, after 14 days of treatment using F/TDF+LPV/r, which supports the findings of a previous study [1]. However, we did not find any evidence of IR changes in patients who received the F/TDF+DRV/r or the boosted HIV integrase fixed-dose E/C/F/TDF combinations. Significant changes in lipid metabolism were detected in all three treatment groups, and especially after the LPV/r- and DRV/r-containing treatments.

Although the mechanisms for IR in HIV-infected individuals with and without ART are not fully understood, two possible mechanisms are discussed in the literature. These are the direct effects on insulin-associated glucose uptake and the indirect effects of lipotoxicity [1]. Thymidine analogues, such as NRTIs, have been strongly linked to lipotoxicity and the depletion of mitochondrial DNA, which causes IR in HIV-positive patients and healthy volunteers, and ultimately results in overt diabetes mellitus. Furthermore, the first-generation HIV protease inhibitors induced lipotoxicity, which further increased the resulting IR [2,3,14,15].

Although unfavourable effects of thymidine analogue NRTI combinations, such as zidovudine/lamivudine/abacavir, have been previously described [16], there are conflicting data regarding changes in IR because of thymidine analogue NRTIs [17]. The published data suggest that F/TDF does not negatively affect IR [18], although no HEGC data are available for the E/C/F/TDF or F/TDF+DRV/r combinations. Therefore, we evaluated the effects of E/C/F/TDF, F/TDF+DRV/r and F/TDF+LPV/r; neither E/C/F/TDF nor F/TDF exerted unfavourable effects on IR in healthy volunteers after short-term exposures.

Interestingly, we observed short-term increases in triglyceride levels among our healthy volunteers after treatment using F/TDF+DRV/r or F/TDF+LPV/r. These findings agree with those of previous studies that found increases in triglyceride levels after treatment using F/TDF+DRV/r [11,19,20]. By contrast, the E/C/F/TDF regimen did not negatively affect triglyceride levels, although it did reduce HDL cholesterol levels.

Given the fact that patients’ lives are saved by ART, long-term drug safety is becoming an increasingly important consideration, especially regarding the drug’s metabolic safety and tolerability. The present study clearly revealed that E/C/F/TDF and F/TDF+DRV/r did not negatively affect IR in HIV-negative healthy volunteers. However, as we expected, F/TDF+LPV/r significantly affected IR, triglyceride levels and HDL cholesterol metabolism, which indicates that it has relatively unfavourable effects for long-term treatment. Nevertheless, the present study only evaluated a small number of healthy, male and non-obese volunteers. Therefore, further studies of HIV-positive men and women are needed to validate our findings after long-term treatment. Moreover, common comorbidities in HIV-positive patients should be considered, as they might significantly affect the metabolic profiles of the ART combinations.

In conclusion, we found that E/C/F/TDF did not exert short-term negative effects on glucose and lipid metabolisms. However, larger studies of HIV-positive men and women are needed to determine the long-term effects of these treatments.

Acknowledgements

This study was supported by Gilead Sciences and Technische Universität München.

Disclosure statement

CDS has received grants for travel and participation in advisory boards or speaker’s honoraria from AbbVie, Astellas, Bristol–Myers Squibb, Gilead, Janssen-Cilag, MSD and ViiV Healthcare. CDS has also received grants for investigator-sponsored studies from Gilead Sciences, Janssen-Cilag and ViiV Healthcare. AZ has received travel grants from AbbVie, Bristol–Myers Squibb, Gilead Sciences and MSD. All other authors declare no competing interests.

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