Darunavir–cobicistat–emtricitabine–tenofovir alafenamide: safety and efficacy of a protease inhibitor in the modern era

Abstract

A fixed-dose combination consisting of darunavir (Drv), cobicistat (Cobi), emtricitabine (2′,3′-dideoxy-5-fluoro-3′-thiacytidine [FTC]), and tenofovir alafenamide (Taf) has been recently approved by the European Medicines Agency for the treatment of HIV infection, and is the first ever protease-inhibitor-based single-tablet regimen. This article provides a detailed description of its pharmacokinetic, efficacy, and safety profile. The pharmacokinetics of single compounds were analyzed, with a special focus on contrasts between Drv/Cobi and Drv/ritonavir (Rtv). When comparing Cobi and Rtv, multiple interactions must be taken into account: in comparison to Rtv, Cobi is a more selective CYP3A4 inhibitor and has no clinical effect on other isoenzymes inhibited by Rtv (eg, 2C8 and 2C9). Moreover, unlike Cobi, Rtv shows in vivo induction activity on some CYP isoenzymes (eg, 1A2, 2C19, 2C8, 2C9, and 2B6), glucuronyltransferases (eg, UGT1A4), and Pgp. Drv-Cobi-FTC-Taf has recently been demonstrated to be of equal efficacy to Drv-Rtv and other protease inhibitors in both experienced (EMERALD study) and naïve (AMBER study) patients. Moreover, kidney and bone safety profiles have been shown to be good, as has central nervous system tolerance. Total cholesterol:low-density-lipoprotein cholesterol and total cholesterol:high-density-lipoprotein cholesterol ratios are generally high in Drv-Cobi-FTC-Taf vs Rtv-Drv-FTC + tenofovir disoproxil fumarate. An unlikely role of Drv in influencing cardiovascular risk in HIV infection has also been reported. Kidney safety profile is influenced by Cobi, with an increase in creatinine plasma concentration of 0.05–0.1 mg/dL and a parallel glomerular filtration-rate reduction of 10 mL/min within the first 4 weeks after Cobi introduction, which remains stable during treatment. Bone and central nervous system safety profiles were found to be good in randomized clinical trials of both experienced and naïve patients. The efficacy and safety of Drv/Cobi/FTC/Taf are comparable to other drug regimens recommended for HIV treatment.

COVID-19, cytokines, inflammation, and spices: How are they related?

“…Darunavir is a potent HIV protease inhibitor [ 112 ]. Cobicistat is an effective booster that enhances the pharmacokinetics of the anti-retroviral drugs and is hence often co-administered with darunavir [ 172 ]. A pilot study ( NCT04252274 ) showed that Darunavir/cobicistat in COVID-19 patients is well-tolerated.…”

Co-crystals, Salts or Mixtures of Both? The Case of Tenofovir Alafenamide Fumarates

“…Interestingly, according to the FDA data, TAF is marketed as a hemifumarate [21]. In addition, TAF received approval by the FDA for the treatment of HIV infection as a fixed dose combination with: cobicistat, elvitegravir and emtricitabine (Genvoya ® ) in November 2015 [22][23][24]; emtricitabine and rilpivirine hydrochloride (Odefsey ® ) in March 2016 [25]; emtricitabine (Descovy ® ) in April 2016 [26]; bictegravir sodium and emtricitabine (Biktarvy ® ) in February 2018; and cobicistat, darunavir and emtricitabine (Symtuza ® ) in July 2018 [27][28][29]. TAF exhibited an improved antiviral activity and safety profile related to renal and bone toxicity [30][31][32].…”

Positioning of darunavir/cobicistat-containing antiretroviral regimens in real life: results from a large multicentre observational prospective cohort (SCOLTA)

“…Despite this, the total discontinuation rate was unexpectedly high, with 29% of the study population who stopped DRV/c, often for reasons other than adverse events, namely treatment simplifications, proactive switches or drug interactions. Those data could potentially be different with the arrival of the new single tablet formulation of DRV/c and tenofovir alafenamide (TAF), that could bring to lower rate of simplification thanks to the advantage of a single-pill regimen and the excellent safety profile of its TAF component [10, 12, 27]. On the other hand, the ageing of the HIV infected population and the desire of minimizing the possible metabolic effects of ART could be another important reason for proactive PI withdrawal from the regimen [28].…”