A Randomized, Double-Blind Comparison of Coformulated Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF vs Ritonavir-Boosted Atazanavir Plus Coformulated Emtricitabine and Tenofovir DF for Initial Treatment of HIV-1 Infection

Rockstroh, Jürgen K.; DeJesus, Edwin; Henry, Keith; Molina, Jean Michel; Gathe, Joseph; Ramanathan, S.; Wei, Xuelian; Plummer, Andrew; Abram, Michael E.; Cheng, Andrew; Fordyce, Marshall W.; Szwarcberg, Javier

doi:10.1097/qai.0b013e318286415c

Cited by 113 publications

(75 citation statements)

References 8 publications

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“…At 96 weeks, the change in cholesterol was greater in the elvitegravir/cobicistat/emtricitabine/tenofovir group, whereas there was no significant change from baseline for fasting LDL and HDL. By contrast, the change from baseline for fasting triglycerides was increased more in the ritonavir-boosted atazanavir and emtricitabine/tenofovir group (97). More studies are needed to elucidate the effect of elvitegravir/cobicistat/emtricitabine/tenofovir on lipid homeostasis.…”

Section: Multi-class Drug Combinationsmentioning

confidence: 85%

MECHANISMS IN ENDOCRINOLOGY: Metabolic and body composition effects of newer antiretrovirals in HIV-infected patients

Srinivasa

Grinspoon

2014

European Journal of Endocrinology

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In the absence of a cure, HIV-infected patients are being successfully treated with antiretroviral therapies (ART) and living longer. Indeed, an increasing number of HIV-infected patients are living beyond the age of 50 years, and in that regard, the use of ART has transformed HIV into a chronic medical condition. As more HIV-infected patients are virologically controlled and living longer, the trajectory of disease morbidity has shifted, however, primarily from opportunistic infections and immune dysfunction to metabolic complications. Evidence suggests that HIV-infected patients acquire significant metabolic risks, including lipodystrophic changes, subclinical atherosclerosis, and insulin resistance. The etiology of these metabolic complications specifically in HIV-infected patients is not entirely clear but may be related to a complex interaction between long-term consequences of infection and HIV itself, chronic use of antiretrovirals, and underlying inflammatory processes. Previous classes of ART, such as protease inhibitors (PIs) and reverse transcriptase inhibitors, have been implicated in altering fat redistribution and lipid and glucose homeostasis. Advances in drug development have introduced newer ART with strategies to target novel mechanisms of action and improve patient adherence with multi-class drug combinations. In this review, we will focus on these newer classes of ART, including selected entry inhibitors, integrase inhibitors, and multi-class drug combinations, and two newer PIs, and the potential of these newer agents to cause metabolic complications in HIV-infected patients. Taken together, further reduction of morbidity in HIV-infected patients will require increasing awareness of the deleterious metabolic complications of ART with subsequent management to mitigate these risks.

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Section: Multi-class Drug Combinationsmentioning

confidence: 85%

MECHANISMS IN ENDOCRINOLOGY: Metabolic and body composition effects of newer antiretrovirals in HIV-infected patients

Srinivasa

Grinspoon

2014

European Journal of Endocrinology

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“…The virological efficacy of RPV has been demonstrated in naïve patients in different studies [48, 49] (Table 2). The pooled data of the early capture HIV cohort study (ECHO) and [treatment of HIV RPV vs. EFV trials (THRIVE)] indicated RPV as non-inferior to EFV both at 48 and 96 weeks.…”

Section: Introductionmentioning

confidence: 99%

Single-Tablet Regimens in HIV Therapy

Astuti

Maggiolo

2014

Infect Dis Ther

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Combined antiretroviral therapy (cART) has evolved considerably over the past decades leading to a better control of human immunodeficiency virus replication. Recently, regimens have evolved so as to simplify dosing frequency and reduce pill burden to improve adherence. Several national and international guidelines suggest antiretroviral (ARV) regimen simplification as a method of improving adherence. Decreased cART adherence has been associated with both patient-related factors and regimen-related factors. Adherence rates are statistically higher when simpler, once-daily (OD) regimens are combined with smaller daily regimen pill burdens. The avoidance of selective non-adherence, where a patient takes part of a regimen but not the full regimen, is a further potential benefit offered by single-tablet regimens (STRs). Simplification of cART has been associated with a better quality of life (QoL). Although tempered by other factors, better adherence, higher QoL and patients’ preferences are all key points which might combine to assure long-lasting efficacy and durability of cART. All studies underlined the favorable tolerability profile of newer STRs. Three STRs are currently available. Tenofovir (TDF) plus emtricitabine (FTC)/efavirenz (EFV) was the first OD complete ARV regimen available as a STR. TDF plus FTC/rilpivirine is a second-generation STR. The most recently approved STR, TDF plus FTC/cobicistat/elvitegravir, is the first non-nucleoside reverse transcriptase inhibitor-based STR. All of them have shown excellent efficacy; safety and tolerability have been improved by more recent formulations. Several other STRs are anticipated both combining completely different drugs, abacavir (ABC) plus lamivudine (3TC)/dolutegravir, utilizing innovative formulations of older drugs, tenofovir alafenamide fumarate, or taking advance of bioequivalent drugs, lamivudine (3TC) plus ABC/EFV. The future challenge would be to develop completely alternative STRs (including for example protease inhibitors or new molecules) to extend the advantages of simplicity to heavily pre-treated individuals.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0024-z) contains supplementary material, which is available to authorized users.

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“…In a 48-week head-to-head comparison with the fixed-dose combination of TDF, emtricitabine, and efavirenz (5) or TDF and emtricitabine combined with RTV-boosted atazanavir (7), a noninferior efficacy and differentiated safety profile for TDF-FTC-EVG-COBI was observed. Recent data from the 96-week analyses of both trials established the longer-term robust and durable efficacy of this regimen (6,9). Minor elevation in serum creatinine attributed to the direct inhibitory effect of COBI on renal organic cation transporters has been noted in clinical studies with the TDF-FTC-EVG-COBI regimen (5,7,18).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Effect of Cobicistat on theIn VitroRenal Transport and Cytotoxicity Potential of Tenofovir

Stray

Bam

Birkuš

et al. 2013

Antimicrob Agents Chemother

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A once-daily single-tablet antiretroviral regimen containing tenofovir (TFV) disoproxil fumarate, emtricitabine (FTC), elvitegravir (EVG), and cobicistat (COBI) is an approved combination for the treatment of patients infected with HIV. COBI and TFV have been reported to interact with distinct transporters in renal proximal tubules; while TFV is renally eliminated by a combination of glomerular filtration and tubular secretion via anion transporters OAT1, OAT3, and MRP4, COBI inhibits renal cation transporters, particularly MATE1, resulting in a measurable decrease in the tubular secretion of creatinine. To investigate the potential for a renal drug-drug interaction between TFV and COBI in vitro, the uptake of TFV in the presence and absence of COBI was determined in fresh human renal cortex tissue and in cells expressing the relevant renal transporters. At concentrations exceeding clinical protein-unbound plasma levels, COBI did not significantly inhibit the transport of TFV by the anion transporters OAT1, OAT3, and MRP4 (50% inhibitory concentrations [IC 50 s] of >15, 6.6, and 8.5 M, respectively). Conversely, TFV had little or no effect on the cation transporters OCT2 and MATE1 (IC 50 > 100 M). Consistent with studies using individual transporters, no increase in the accumulation of TFV in freshly isolated human renal cortex tissue or renal proximal tubule cells (RPTECs) was observed in the presence of COBI. Finally, COBI alone or in combination with FTC and EVG did not affect the sensitivity to TFV of cultured primary RPTECs or cells coexpressing OAT1 and MRP4. These results illustrate that COBI and TFV interact primarily with distinct renal transporters and indicate a low potential for pharmacokinetic renal drug-drug interaction. STRIBILD, an antiretroviral single-tablet regimen, consists of two nucleoside/nucleotide HIV reverse transcriptase inhibitors, tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine, combined with the integrase strand transfer inhibitor elvitegravir and the pharmacokinetic enhancer cobicistat (COBI), which effectively blocks the CYP450-mediated metabolic clearance of elvitegravir (1-4). Once-daily treatment with this regimen showed noninferior and durable efficacy and safety in treatmentnaive HIV-infected patients when compared head-to-head with either efavirenz (5, 6)-or atazanavir (7-9)-containing once-daily treatment regimens. A small, early, and nonprogressive increase in the levels of serum creatinine due to a COBI-mediated blockade of creatinine active tubular secretion without an effect on glomerular filtration or overall renal function has been observed during clinical trials (10).The orally administered prodrug TDF is unstable in plasma and is rapidly hydrolyzed, releasing the parent nucleotide TFV. TFV is renally eliminated by a combination of glomerular filtration and active tubular secretion via renal transporters (11-15). TFV is taken up into proximal tubules by renal organic anion transporter 1 (OAT1) and OAT3, and its luminal efflux is mediated by ABC efflux pum...

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A Randomized, Double-Blind Comparison of Coformulated Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF vs Ritonavir-Boosted Atazanavir Plus Coformulated Emtricitabine and Tenofovir DF for Initial Treatment of HIV-1 Infection

Cited by 113 publications

References 8 publications

MECHANISMS IN ENDOCRINOLOGY: Metabolic and body composition effects of newer antiretrovirals in HIV-infected patients

MECHANISMS IN ENDOCRINOLOGY: Metabolic and body composition effects of newer antiretrovirals in HIV-infected patients

Single-Tablet Regimens in HIV Therapy

Evaluation of the Effect of Cobicistat on theIn VitroRenal Transport and Cytotoxicity Potential of Tenofovir

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