Cobicistat Versus Ritonavir as a Pharmacoenhancer of Atazanavir Plus Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-Naive HIV Type 1–Infected Patients: Week 48 Results

Gallant, Joel E.; Koenig, Ellen; Andrade-Villanueva, Jaime; Chetchotisakd, Ploenchan; DeJesus, Edwin; Antúnes, Francisco; Arastéh, Keikawus; Moyle, Graeme; Rizzardini, Giuliano; Fehr, Jan; Liu, Yapei; Zhong, Lijie; Callebaut, Christian; Szwarcberg, Javier; Rhee, Martin S; Cheng, Andrew

doi:10.1093/infdis/jit122

Cited by 105 publications

(127 citation statements)

References 22 publications

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“…On the other hand, similar lipid profiles were observed with atazanavir being boosted with ritonavir or cobicistat [68,69] NNRTIs have been found to increase TC and high-density lipoprotein-cholesterol (HDL-C), with an improvement of the TC/HDL ratio. In a recent study, efavirenz was associated with increases in TC, LDL-C, but not TC/HDL compared to atazanavir-ritonavir [70].…”

Section: Metabolic and Thrombotic Complications Associated With Cartmentioning

confidence: 64%

Risk of Cardiovascular Disease in an Aging HIV Population: Where Are We Now?

2015

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With more effective and widespread antiretroviral treatment, the overall incidence of AIDS- or HIV-related death has decreased dramatically. Consequently, as patients are aging, cardiovascular disease (CVD) has emerged as an important cause of morbidity and mortality in the HIV population. The incidence of CVD overall in HIV is relatively low, but it is approximately 1.5-2-fold higher than that seen in age-matched HIV-uninfected individuals. Multiple factors are believed to explain this excess in risk such as overrepresentation of traditional cardiovascular risk factors (particularly smoking), toxicities associated with cumulative exposure to some antiretroviral agents, together with persistent chronic inflammation, and immune activation associated with HIV infection. Tools are available to calculate an individual's predicted risk of CVD and should be incorporated in the regular follow-up of HIV-infected patients. Targeted interventions to reduce this risk must be recommended, including life-style changes and medical interventions that might include changes in antiretroviral therapy.

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Section: Metabolic and Thrombotic Complications Associated With Cartmentioning

confidence: 64%

Risk of Cardiovascular Disease in an Aging HIV Population: Where Are We Now?

2015

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“…GS-US-216-0105 [18] GS-US-216-0114 [19] GS-US-236-0104 [22] GS-US-236-0102 [23,24] GS-US-236-0103 [26,27] Phase II III II III III Cobi arm n = 50 344 48 348 versus 11 with eGFR ‡ 90 ml/min showed reduction of EVG AUC, C max and C tau by 25, 33 and 31% in subjects with severe renal impairment, although EVG plasma levels were still well above the protein-adjusted IC 95 , whereas Cobi AUC, C max and C tau were increased by 25, 22 and 13%, which were considered to be not clinically relevant. When measured with the Cockroft--Gault equation, the eGFR in the ‡ 90 group decreased by -8.40 ml/min at day 7 and by further -1.20 at day 14, whereas in the < 30 group it decreased by -10.50 at day 7 and by further -4.00 at day 14, with a difference of 4.90 ml/min increased damage in already impaired kidneys.…”

Section: Studymentioning

confidence: 99%

Cobicistat: a new opportunity in the treatment of HIV disease?

Capetti

Rizzardini

2014

Expert Opinion on Pharmacotherapy

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Cobi has shown good efficacy in HIV-infected treatment-naïve subjects, either in combination with ELV, within a quadruple drug, single tablet regimen, and in combination with atazanavir and darunavir. Coformulations containing cobi will mark the near future of antiretroviral therapy, therefore it will be necessary for physicians to become familiar with their management. In particular, the inhibition of creatinine secretion by the proximal renal tubule will require the acquisition of competences in estimating the real glomerular filtration rate, since studies with iohexol clearance have shown that the eGFR reduction is cosmetic. The long-term metabolic advantages of cobi versus ritonavir can be hypothesized, given the initial data from current trials.

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“…Ritonavir (RTV), initially used simply as an active drug, is now used at low dosages (100 mg once [QD] or twice daily [BID]) as a booster in PI-based regimens; this is due to the drug's inhibitory activity on various cytochrome P450 isoenzymes (5). However, the toxicity of this drug (6), which led to its transition from an antiviral drug (high dosage, 600 mg twice daily) to a pharmacoenhancer (low dosage), has led to the introduction of alternative booster molecules, e.g., cobicistat (COBI) (7)(8)(9).…”

mentioning

confidence: 99%

“…To date, the low dosage of RTV when administered as a booster is considered to be completely ineffective in preventing viral replication, while the choice of other CYP3A4-specific inhibitors seems to be a noninferior and safer alternative (8,9). However, previous studies conducted with RTV have not focused enough on its accumulation rate in peripheral blood mononuclear cells (PBMCs) or on its intrinsic antiviral properties.…”

mentioning

confidence: 99%

Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

Nicolò

Simiele

Calcagno

et al. 2014

Antimicrob Agents Chemother

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Protease inhibitors are largely used for the treatment of HIV infection in combination with other antiretroviral drugs. Their improved pharmacokinetic profiles can be achieved through the concomitant administration of low doses of ritonavir (RTV), a protease inhibitor currently used as a booster, increasing the exposure of companion drugs. Since ritonavir-boosted regimens are associated with long-term adverse events, cobicistat, a CYP3A4 inhibitor without antiviral activity, has been developed. Recently, high intracellular concentrations of ritonavir in lymphocytes and monocytes were reported even when ritonavir was administered at low doses, so we aimed to compare its theoretical antiviral activity with those of the associated protease inhibitors. Intracellular concentrations of ritonavir and different protease inhibitors were determined through the same method. Inhibitory constants were obtained from the literature. The study enrolled 103 patients receiving different boosted protease inhibitors, darunavir-ritonavir 600 and 100 mg twice daily and 800 and 100 mg once daily (n ‫؍‬ 22 and 4, respectively), atazanavir-ritonavir 300 and 100 mg once daily (n ‫؍‬ 40), lopinavir-ritonavir 400 and 100 mg twice daily (n ‫؍‬ 21), or tipranavir-ritonavir 500 and 200 mg twice daily (n ‫؍‬ 16). According to the observed concentrations, we calculated the ratios between the intracellular concentrations of ritonavir and those of the companion protease inhibitor and between the theoretical viral protease reaction speeds with each drug, with and without ritonavir. The median ratios were 4.04 and 0.63 for darunavir-ritonavir twice daily, 2.49 and 0.74 for darunavir-ritonavir once daily, 0.42 and 0.74 for atazanavir-ritonavir, 0.57 and 0.95 for lopinavir-ritonavir, and 0.19 and 0.84 for tipranavir-ritonavir, respectively. Therefore, the antiviral effect of ritonavir was less than that of the concomitant protease inhibitors but, importantly, mostly with darunavir. Thus, further in vitro and in vivo studies of the RTV antiviral effect are warranted. Infection with HIV is a worldwide health problem, with an estimated burden of 34 million infected patients. With the introduction of highly active antiretroviral therapy (HAART), it has been possible to manage infections and prevent the occurrence of AIDS and HIV-related complications (1, 2). HAART is based on the coadministration of drugs that target several important HIV enzymes or cell coreceptors, including reverse transcriptase, integrase, protease, and CCR5. Currently, protease inhibitor (PI)-based regimens are often adopted for HIV treatment (3, 4). Ritonavir (RTV), initially used simply as an active drug, is now used at low dosages (100 mg once [QD] or twice daily [BID]) as a booster in PI-based regimens; this is due to the drug's inhibitory activity on various cytochrome P450 isoenzymes (5). However, the toxicity of this drug (6), which led to its transition from an antiviral drug (high dosage, 600 mg twice daily) to a pharmacoenhancer (low dosage), has led to the introduction o...

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Cobicistat Versus Ritonavir as a Pharmacoenhancer of Atazanavir Plus Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-Naive HIV Type 1–Infected Patients: Week 48 Results

Abstract: COBI was noninferior to RTV in combination with ATV plus FTC/TDF at week 48. Both regimens achieved high rates of virologic success. Safety and tolerability profiles of the 2 regimens were comparable. Once-daily COBI is a safe and effective pharmacoenhancer of the protease inhibitor ATV.

Cited by 105 publications

References 22 publications

Risk of Cardiovascular Disease in an Aging HIV Population: Where Are We Now?

Risk of Cardiovascular Disease in an Aging HIV Population: Where Are We Now?

Cobicistat: a new opportunity in the treatment of HIV disease?

Intracellular Antiviral Activity of Low-Dose Ritonavir in Boosted Protease Inhibitor Regimens

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