Effects of Switching From Efavirenz to Raltegravir on Endothelial Function, Bone Mineral Metabolism, Inflammation, and Renal Function

Gupta, Samir K.; Mi, Deming; Moe, Sharon M.; Dubé, Michael P.; Liu, Ziyue

doi:10.1097/qai.0b013e3182a97c39

Cited by 42 publications

(42 citation statements)

References 32 publications

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“…[20], [21] Whether these results directly translate into changes in subclinical markers of atherosclerosis is debatable, given that switching to RAL-based regimens failed to show improvement in flow-mediated dilation. [22] Moreover, studies examining both switching to and intensification of RAL-based ART have not demonstrated any further decrease in ultrasensitive HIV-RNA detection [23], [24], leaving it difficult to hypothesize how residual viremia would fit into the association between RAL and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Association of Residual Plasma Viremia and Intima-Media Thickness in Antiretroviral-Treated Patients with Controlled Human Immunodeficiency Virus Infection

Boyd¹,

Meynard²,

Morand‐Joubert³

et al. 2014

PLoS ONE

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BackgroundWhile residual plasma viremia is commonly observed in HIV-infected patients undergoing antiretroviral treatment (ART), little is known about its subclinical consequences.MethodsThis cross-sectional study included 47 male, never-smoking, non-diabetic patients with ≥4 years of ART and controlled HIV-replication (HIV-viral load, VL <20 copies/mL for ≥1 year). Residual HIV-VL was measured using an ultrasensitive assay (quantification limit: 1 copy/ml). Patients were categorized as having detectable (D; 1-20 copies/mL, n = 14) or undetectable (UD; <1 copies/mL, n = 33) HIV-VL. Linear regression was used to model the difference in total carotid intima-media thickness [c-IMT, measures averaged across common carotid artery (cca), bifurcation, and internal carotid artery] and cca-IMT alone across detection groups. Multivariable models were constructed for each endpoint in a forward-stepwise approach.ResultsNo significant differences were observed between viremia groups with respect to median ART-duration (9.6 years, IQR = 6.8–10.9), nadir CD4+T-cell (208/mm3, IQR = 143–378), and CD4+T-cell count (555/mm3, IQR = 458–707). Median adjusted inflammatory markers tended to be higher in patients with D- than UD-viremia, with differences in IL-10 being significant (p = 0.03). After adjustment on age, systolic blood pressure, and insulin resistance, mean cca-IMT was significantly lower in patients with undetectable (0.668 mm±0.010) versus detectable viremia (0.727 mm±0.015, p = 0.002). Cca-IMT was also independently associated with age and insulin resistance. Mean adjusted total c-IMT was no different between viremia groups (p = 0.2), however there was large variability in bifurcation c-IMT measurements.ConclusionsHigher cca-IMT was observed in patients with detectable, compared to undetectable, HIV-VL in never-smoking ART-controlled patients, suggesting that residual HIV viremia may be linked to atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Association of Residual Plasma Viremia and Intima-Media Thickness in Antiretroviral-Treated Patients with Controlled Human Immunodeficiency Virus Infection

Boyd¹,

Meynard²,

Morand‐Joubert³

et al. 2014

PLoS ONE

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“…4 However, mice without a retroviral background, including C57BL/6 mice, did not develop proteinuria or autoimmunity over this prolonged interval. In the RAL Switch trial, 3 elevations of both serum creatinine and plasma cystatin C were observed in patients. While this finding provided an impetus for our study, we did not find an elevation of cystatin C in RAL and DTG mice.…”

Section: Discussionmentioning

confidence: 99%

“…In a mouse retroviral model, treatment with RAL led to increased autoimmunity manifested by hemolytic anemia and proteinuria. 4 Given these findings, we sought to determine whether a two-week regimen of 1 Division of Nephrology, Indiana University School of Medicine, Indianapolis, USA 2 Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, USA 3 Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, USA high-dose integrase inhibitor administration had a direct nephrotoxic effect in C57BL/6 mice.…”

Section: Introductionmentioning

confidence: 99%

A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice

Eadon

Zhang

Skaar

et al. 2015

Antivir Chem Chemother

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Background: The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration. We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of highdose integrase inhibitors. Methods: C57BL/6 mice were fed standard water (CTRL, n ¼ 6), raltegravir-containing water (40 mg/kg/day, n ¼ 6), or dolutegravir-containing water (2.7 mg/kg/day, n ¼ 6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen. Results: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p < 0.05) compared to control (raltegravir ¼ 0.25 mg/dl, dolutegravir ¼ 0.30 mg/dl versus CTRL ¼ 0.17 mg/dl). Blood urea nitrogen, cystatin C, and urine microalbumin were unchanged. Kidney injury molecule-1 tissue expression in raltegravir and dolutegravir groups was nonsignificantly elevated compared to control (1.2-fold compared to control). Renal histopathology by periodic acid-Schiff staining failed to reveal glomerular or tubular renal injury in any group. Conclusion: These studies are consistent with integrase inhibitors competitively inhibiting creatinine secretion. While no evidence of direct nephrotoxicity was observed after two weeks of high-dose drug administration, additional studies may be performed to understand whether these drugs lead to chronic nephropathy.

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“…Nell'ambito degli inibitori nucleosidici/nucleotidici della transcriptasi inversa (NRTI), i dati della letteratura hanno evidenziato generalmente una riduzione dei valori di trigliceridi, colesterolo totale ed LDL sostituendo stavudina, didanosina o zidovudina con tenofovir (preferibile) o abacavir (in alternativa, se il test HLA B*5701 è negativo) (24,25). Tra gli inibitori non nucleosidici della transcriptasi inversa (NNRTI), efavirenz è associato più spesso a dislipidemia e può essere sostituito, con effetti favorevoli sui parametri lipidici, da altri NNRTI (quali nevirapina, etravirina o rilpivirina) o da un inibitore dell'integrasi (raltegravir) (26)(27)(28)(29)(30). Gli inibitori della proteasi boosterati con ritonavir (PI/r) sono i farmaci più spesso associati a ipertrigliceridemia e/o ipercolesterolemia e gli studi di switch hanno dimostrato che si può ottenere un miglioramento significativo della dislipidemia sostituendo il PI/r con un altro PI a minor impatto sull'assetto lipidico (atazanavir, atazanavir/r, darunavir/r), con un NNRTI (nevirapina, etravirina, rilpivirina) o con un inibitore dell'integrasi (raltegravir, elvitegravir/cobicistat) (31-39).…”

Section: Gestione Del Rischio Cardiovascolare: Stile DI Vita E Terapiunclassified

Gestione del rischio cardiovascolare nel paziente HIV positivo

Calza¹

2017

JHA

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RiassuntoDopo l'introduzione della moderna terapia antiretrovirale di combinazione (cART), l'infezione da HIV è divenuta una malattia cronica con un notevole prolungamento dell'attesa media di vita dei pazienti HIV-positivi. Di conseguenza le comorbosità tra cui le malattie cardiovascolari, hanno acquisito un'importanza via via crescente in questa popolazione. Nei pazienti con infezione da HIV si osserva infatti un rischio di infarto miocardico acuto significativamente più elevato rispetto alla popolazione generale, ma il meccanismo patogenetico di questa malattia aterosclerotica accelerata è complesso e certamente multifattoriale. La comparsa più frequente della malattia coronarica può essere la conseguenza di una maggiore prevalenza dei fattori di rischio tradizionali (che sono più frequenti tra i soggetti HIV-positivi), ma anche della replicazione diretta del virus e dell'effetto cardiotossico a lungo termine di alcuni farmaci antiretrovirali. Inoltre, nonostante la persistente soppressione della viremia indotta dalla cART generalmente si associ ad una riduzione del rischio cardiovascolare, numerosi studi hanno evidenziato in questi pazienti una condizione di infiammazione e di immunoattivazione cronica, che può condurre al danno endoteliale ed alla malattia aterosclerotica. La corretta gestione del rischio cardiovascolare e la prevenzione della malattia coronarica rappresentano oggi una sfida di primaria importanza per tutti i clinici coinvolti nella cura dei pazienti con infezione da HIV.

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Effects of Switching From Efavirenz to Raltegravir on Endothelial Function, Bone Mineral Metabolism, Inflammation, and Renal Function

Cited by 42 publications

References 32 publications

Association of Residual Plasma Viremia and Intima-Media Thickness in Antiretroviral-Treated Patients with Controlled Human Immunodeficiency Virus Infection

Association of Residual Plasma Viremia and Intima-Media Thickness in Antiretroviral-Treated Patients with Controlled Human Immunodeficiency Virus Infection

A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice

Gestione del rischio cardiovascolare nel paziente HIV positivo

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