Neither Boosted Elvitegravir nor Darunavir with Emtricitabine/Tenofovir Disoproxil Fumarate Increase Insulin Resistance in Healthy Volunteers: Results from the STRIBILD-IR Study

Spinner, Christoph D.; Kern, Kristina E; Zink, Alexander; Wolf, Eva; Balogh, Annamaria; Noe, Sebastian; Werder, Alexander von; Schwerdtfeger, Christiane; Schmid, Roland M.; Iakoubov, Roman

doi:10.3851/imp3049

Cited by 10 publications

(11 citation statements)

References 21 publications

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“…Recent studies evaluated in young lean male controls the effect of lopinavir/r vs raltegravir and reported that lopinavir/r increased insulin resistance but not raltegravir [61]. As well, darunavir/r or elvitegravir boosted by cobicistat had no effect on insulin sensitivity by contrast to lopinavir/r [62]. However, these studies are far from the reallife situation of aging, often overweight and HIV-infected patients.…”

Section: Studies Of Art Effect On Insulin Sensitivity In Healthy Contmentioning

confidence: 99%

Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment

Lagathu

Béréziat

Gorwood

et al. 2019

Expert Opinion on Drug Safety

124

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Introduction: Efficient antiretroviral-treatment(ART) generally allows control of HIV infection. However, persons-living-with-HIV(PLWH), when ageing, present a high prevalence of metabolic diseases. Area covered: Altered adiposity, dyslipidemias, insulin resistance, diabetes and their consequences are prevalent in PLWH and could be partly related to ART. Expert opinion: At first, personal and lifestyle factors are involved in the onset of these complications. The persistence of HIV in tissue reservoirs could synergize with some ART and enhance metabolic disorders. Altered fat repartition, diagnosed as lipodystrophy, has been related to first-generation nucleoside-reverse-transcriptase-inhibitors(NRTIs) (stavudine zidovudine) and some protease inhibitors(PIs). Recently, use of some integraseinhibitors(INSTI) resulted in weight/fat gain, which represents a worrisome unresolved situation.Lipid parameters were affected by some first-generation NRTIs, non-NRTIs(efavirenz) but also PIs boosted by ritonavir, with increased total and LDL-cholesterol and triglycerides.Insulin resistance is common in aging PLWH, often associated with abdominal obesity.Diabetes incidence, high with first-generation-ART (zidovudine, stavudine, didanosine, indinavir) has declined with contemporary ART close to that of the general population.Metabolic syndrome, a dysmetabolic situation with central obesity and insulin resistance, and liver steatosis are common in PLWH and could indirectly result from ART-associated fat gain and insulin resistance. All these dysmetabolic situations increase the atherogenic cardiovascular risk.Before 2000, PLWH received first-generation ART, as nucleoside analogue reverse transcriptase inhibitors (thymidine NRTIs, stavudine, zidovudine, didanosine) and protease inhibitors (PI, indinavir, ritonavir, nelfinavir) responsible for marked adverse events on lipid and glucose metabolism and on adipose tissue. These ART were replaced by newer molecules presenting a markedly lower metabolic toxicity.However, some PLWH, previously treated with first-generation NRTIs, present long-lasting fat alterations with metabolic consequences [1]. Some contemporary ART as integrase inhibitors (INSTI), considered as metabolic-friendly, were recently associated with weight/fat gain. Therefore, there are remaining and evolving concerns regarding the effect of ART on metabolism and adipose tissue in PLWH.As a consequence of the metabolic effects of some ART, increased prevalence of cardiovascular diseases (CVD), particularly atherosclerotic CVD[2] and diabetes, has been reported, but differ according to the calendar years and the geographic area. It is important to consider the metabolic profile of each patients to adapt ART. If required, classical lipid and glucose-lowering medications are prescribed.

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Section: Studies Of Art Effect On Insulin Sensitivity In Healthy Contmentioning

confidence: 99%

Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment

Lagathu

Béréziat

Gorwood

et al. 2019

Expert Opinion on Drug Safety

124

View full text Add to dashboard Cite

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“…In analysing and quantifying potential changes in IR as an early factor for metabolic disease, the hyperinsulinemic-euglycaemic clamp (HEGC) is currently a golden standard [6]. Particularly, HIV protease inhibitors, namely (boosted) indinavir, saquinavir or lopinavir, as well as thymidine analogues, have been associated with increased IR; however, this is not the case in current ART approaches, as previously shown by our group and others [1,4,7]. Neither newer nucleoside reverse transcriptase inhibitors such as emtricitabine/tenofovir disoproxil fumarate (F/TDF), abacavir, fixed-dose combination of cobicistat-boosted elvitegravir/emtricitabine/tenofovir disoproxil fumarate, nor protease inhibitor ritonavir-boosted darunavir (DRV/r) combined with emtricitabine/tenofovir disoproxil fumarate significantly changed the IR in HIV-infected patients or healthy individuals [7,8].…”

mentioning

confidence: 98%

Effects of antiretroviral combination therapies F/TAF, E/C/F/TAF and R/F/TAF on insulin resistance in healthy volunteers: The TAF-IR Study

et al. 2017

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Background Increased insulin resistance (IR), associated with specific antiretroviral drugs or drug classes, is an established risk factor for type 2 diabetes in HIV patients, ultimately increasing morbidity and mortality. To date, data on the risk of IR in tenofovir alafenamide (TAF)-based protocols are unavailable. Methods This prospective randomized, open-label study evaluated the effects of IR on 30 healthy volunteers receiving fixed-dose combinations (FDCs) of emtricit-abine/tenofovir alafenamide (F/TAF), elvitegravir/cobi-cistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or rilpivirine/emtricitabine/tenofovir alafenamide (R/F/TAF). IR was measured before and after 14-day treatments using the hyperinsulinemic-euglycaemic clamp technique (HEGC). Changes in IR in each group were evaluated using the mean glucose disposal rate, normalized with body weight (MBW [mg glucose/(minxkg)]). Results A total of 30 subjects underwent randomization: one subject in the F/TAF arm withdrew consent after randomization and one in the R/F/TAF arm had to be excluded because of technical failure during HEGC, resulting in 28 subjects in the per-protocol population (F/TAF, n=9 subjects; E/C/F/TAF, n=10 subjects; R/F/TAF n=9 subjects). No significant differences were detected on the baseline characteristics. IR did not differ among the groups before treatment. None of the studied anti-retroviral combinations resulted in a significant change in IR after 14 days compared with baseline values, as measured by MBW (F/TAF, 11.42 ±3.04 mean [±sd] versus 11.43 ±3.23, P=0.49; E/C/F/TAF, 10.04 ±2.49 versus 10.95 ±4.26, P=0.30; R/F/TAF, 11.03 ±1.96 versus 13.01 ±4.11, P=0.13). Conclusions Short-term treatment for F/TAF, E/C/F/TAF or R/F/TAF did not increase IR in healthy male volunteers.

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“…Individually, efavirenz-based treatment is associated with a 21% insulin resistance prevalence, although this risk was reduced in patients treated with NRTIs rather than protease inhibitors [34] , suggesting that efavirenz per se , may not be the driving factor. Emtricidabine treatment has not been associated with insulin resistance and importantly, emtricidabine and tenofovir fail to impair insulin resistance in healthy individuals [35] . Overall these reports, along with our current findings, suggest that a complex interaction between the combined components of ART treatment and HFD-feeding impairs regulation of energy balance and glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance

Pepin¹,

Padgett²,

McDowell³

et al. 2018

Molecular Metabolism

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ObjectiveBreakthroughs in HIV treatment, especially combination antiretroviral therapy (ART), have massively reduced AIDS-associated mortality. However, ART administration amplifies the risk of non-AIDS defining illnesses including obesity, diabetes, and cardiovascular disease, collectively known as metabolic syndrome. Initial reports suggest that ART-associated risk of metabolic syndrome correlates with socioeconomic status, a multifaceted finding that encompasses income, race, education, and diet. Therefore, determination of causal relationships is extremely challenging due to the complex interplay between viral infection, ART, and the many environmental factors.MethodsIn the current study, we employed a mouse model to specifically examine interactions between ART and diet that impacts energy balance and glucose metabolism. Previous studies have shown that high-fat feeding induces persistent low-grade systemic and adipose tissue inflammation contributing to insulin resistance and metabolic dysregulation via adipose-infiltrating macrophages. Studies herein test the hypothesis that ART potentiates the inflammatory effects of a high-fat diet (HFD). C57Bl/6J mice on a HFD or standard chow containing ART or vehicle, were subjected to functional metabolic testing, RNA-sequencing of epididymal white adipose tissue (eWAT), and array-based kinomic analysis of eWAT-infiltrating macrophages.ResultsART-treated mice on a HFD displayed increased fat mass accumulation, impaired glucose tolerance, and potentiated insulin resistance. Gene set enrichment and kinomic array analyses revealed a pro-inflammatory transcriptional signature depicting granulocyte migration and activation.ConclusionThe current study reveals a HFD-ART interaction that increases inflammatory transcriptional pathways and impairs glucose metabolism, energy balance, and metabolic dysfunction.

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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

Abstract: 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.

Cited by 10 publications

References 21 publications

Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment

Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment

Effects of antiretroviral combination therapies F/TAF, E/C/F/TAF and R/F/TAF on insulin resistance in healthy volunteers: The TAF-IR Study

Antiretroviral therapy potentiates high-fat diet induced obesity and glucose intolerance

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