Darunavir: A Review of Its Use in the Management of HIV-1 Infection

Deeks, Emma D.

doi:10.1007/s40265-013-0159-3

Cited by 71 publications

(45 citation statements)

References 91 publications

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“…In GS-US-216-0130 and ARTEMIS, patients received optimized background treatment (OBR) with two nucleoside (nucleotide) reverse transcriptase inhibitors (NRTIs); in ODIN, patients receiving OBR with at least two NRTIs. Consistent with the previous experience with darunavir showing that it has a high genetic barrier to resistance development [5], the rates of developing resistant HIV strains were low in treatment-naïve, as well as treatmentexperienced patients with baseline darunavir RAMs, in these trials [2,22,23].…”

Section: In Which Art-experienced Patients Is Darunavir/cobicistat Insupporting

confidence: 82%

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Darunavir/cobicistat fixed-dose single tablet (Rezolsta™): a guide to its use in HIV-1 infection in adults in the EU

Lyseng‐Williamson

2015

Drugs Ther Perspect

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Oral darunavir/cobicistat 800 mg/150 mg fixed-dose single tablets [Rezolsta TM (EU); Prezcobix TM (USA, Canada)] are indicated as a component of antiretroviral treatment of HIV-1 infection in treatment-naïve and treatment-experienced adults without known darunavir resistance-associated mutations. Treatment with cobicistator ritonavir-boosted regimens of the protease inhibitor darunavir have been shown to reduce viral load in these patient populations. Relative to the use of low-dose ritonavir to boost darunavir, the use of cobicistat reduces the potential for drug interactions involving enzymatic induction, provides bioequivalent exposure to darunavir, and has similar virological efficacy and tolerability profiles, and allows co-formulation of the agents in a single tablet.Adis evaluation of darunavir/cobicistat fixed-dose single tablet as a antiretroviral therapy in adults with HIV-1 infection What are its key clinical benefits?Convenient oral once-daily, single-tablet regimen that combines a protease inhibitor (darunavir) with a pharmacokinetic enhancer that selectively inhibits cytochrome P450 3A (cobicistat)Boosted darunavir provides marked and durable suppression of plasma HIV-1 RNA to \50 copies/mL in treatment-naïve and treatment-experienced patients without known darunavir resistance-associated mutationsRelative to boosting darunavir with low-dose ritonavir, boosting darunavir with cobicistat has a lower potential for drug interactions involving enzymatic induction, provides bioequivalent exposure to darunavir, and achieves similar virological efficacy Generally well tolerated; \4 % of patients discontinued treatment because of adverse eventsWhat are its key clinical limitations? Regular monitoring of hepatic function is requiredAlthough the potential for drug interactions is lower with cobicistat than with low-dose ritonavir, the concomitant use of darunavir/cobicistat and many other drugs is contraindicated, not recommended or requires caution

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Section: In Which Art-experienced Patients Is Darunavir/cobicistat Insupporting

confidence: 82%

“…The antiviral activity of darunavir, the most recent PI approved as a component of ART in patients with HIV-1 infection [4], is well established [5]. Darunavir provides a high genetic barrier to the emergence of resistance, as well as activity against HIV-1 strains no longer susceptible to some other PIs [6].…”

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confidence: 99%

Darunavir/cobicistat fixed-dose single tablet (Rezolsta™): a guide to its use in HIV-1 infection in adults in the EU

Lyseng‐Williamson

2015

Drugs Ther Perspect

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“…The phenotype showed a lesser 15-fold change in susceptibility to saquinavir; however, we chose darunavir over saquinavir, as there is broad experience with darunavir in salvage therapy in clinical trials and in clinical practice (11). With dolutegravir and darunavir, higher doses and blood concentrations can increase antiretroviral activity against HIV strains with intermediate resistance to these drugs (12, 13).…”

Section: Discussionmentioning

confidence: 99%

Tenofovir Alafenamide as Part of a Salvage Regimen in a Patient with Multi-Drug Resistant HIV and Tenofovir-DF-Associated Renal Tubulopathy

et al. 2015

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Brief Summary We describe a patient with two recent episodes of tenofovir disoproxil fumarate (TDF)-associated acute kidney injury and six-class drug-resistant HIV infection who achieved and maintained viral suppression without worsening kidney function on a regimen including tenofovir alafenamide (TAF) through 48 weeks of therapy. The safety and efficacy of TAF in patients with TDF-associated renal tubulopathy and multiple drug resistance HIV has not yet been described. TAF may represent a useful option to maximally suppress HIV in patients with these complications.

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“…In addition, the high barrier to genetic resistance, as well as the tolerability, safety profile, and potency of DRV when it is administered in combination with a low dose of either RTV (DRV/r) or COBI (DRV/c), has made these fixed-dose combinations important options for the treatment of HIV-infected patients (20)(21)(22).…”

mentioning

confidence: 99%

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

Roberts

Khoo

Owen

et al. 2017

Antimicrob Agents Chemother

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Treatment of HIV-infected patients coinfected with Mycobacterium tuberculosis is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB) drugs. The aim of this study was to quantify the effect of cobicistat (COBI) or ritonavir (RTV) in modulating DDIs between darunavir (DRV) and rifampin (RIF) in a human hepatocyte-based in vitro model. Human primary hepatocyte cultures were incubated with RIF alone or in combination with either COBI or RTV for 3 days, followed by coincubation with DRV for 1 h. The resultant DRV concentrations were quantified by high-performance liquid chromatography with UV detection, and the apparent intrinsic clearance (CL int.app. ) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CL int.app. in a concentrationdependent manner. Linear regression analysis showed that log 10 RTV and log 10 COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CL int.app. , where ␤ was equal to Ϫ234 (95% confidence interval [CI] ϭ Ϫ275 to Ϫ193; P Ͻ 0.0001) and Ϫ73 (95% CI ϭ Ϫ89 to Ϫ57; P Ͻ 0.0001), respectively. RTV was more effective in lowering 10 M RIF-induced elevations in DRV CL int.app. (half-maximal [50%] inhibitory concentration [IC 50 ] ϭ 0.025 M) than COBI (IC 50 ϭ 0.223 M). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CL int.app. , with RTV being more potent than COBI. These data provide the first in vitro experimental insight into DDIs between RIF and COBI-boosted or RTV-boosted DRV and will be useful to inform physiologically based pharmacokinetic (PBPK) models to aid in optimizing dosing regimens for the treatment of patients coinfected with HIV and M. tuberculosis. KEYWORDS antiretroviral agents, cobicistat, darunavir, drug-drug interaction, human immunodeficiency virus, in vitro, rifampin, ritonavirA pproximately 25% of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected patients worldwide are coinfected with Mycobacterium tuberculosis (1, 2) (referred to here as HIV-tuberculosis [TB] patients), with such coinfections accounting for 390,000 deaths in 2014 (3). The clinical management of HIV-TB patients presents significant challenges, especially in resource-limited settings (2, 4), where virological failure or intolerance to first-line antiretroviral therapy requires the use of HIV protease inhibitors (PIs) (5). PIs largely undergo phase I metabolism by cytochrome P450 3A4 (CYP3A4) and are also substrates of P-glycoprotein (P-GP; ABCB1) (6). Consequently, PIs are commonly administered in combination with pharmacokinetic (PK) boosters, such as ritonavir (RTV) or cobicistat (COBI), which act by inhibiting CYP3A4-mediated PI metabolism and P-GP-mediated PI efflux, thereby improving the PK profile of PIs by prolonging PI half-life and increasing PI bioavailability (7-9).Rifampin (RIF) is an essential component of short-course anti-TB treatment regimens (2, 10); however, RIF is also a potent...

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Darunavir: A Review of Its Use in the Management of HIV-1 Infection

Cited by 71 publications

References 91 publications

Darunavir/cobicistat fixed-dose single tablet (Rezolsta™): a guide to its use in HIV-1 infection in adults in the EU

Darunavir/cobicistat fixed-dose single tablet (Rezolsta™): a guide to its use in HIV-1 infection in adults in the EU

Tenofovir Alafenamide as Part of a Salvage Regimen in a Patient with Multi-Drug Resistant HIV and Tenofovir-DF-Associated Renal Tubulopathy

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

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