Efficacy and Safety of Darunavir/Ritonavir at 48 Weeks in Treatment-naïve, HIV-1–infected Adolescents

Flynn, Patricia M.; Komar, Svitlana; Blanche, Stéphane; Giaquinto, Carlo; Noguera-Julián, Antoni; Welch, S; Lathouwers, Erkki; Casteele, Tom Van de; Kakuda, Thomas N.; Opsomer, Magda

doi:10.1097/inf.0000000000000308

Cited by 24 publications

(18 citation statements)

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“…No grade 3/4 or serious AEs, deaths, or discontinuations due to AEs occurred. The tolerability profile is consistent with earlier studies, with the most commonly reported AEs during the studies, headache and nausea, reported previously for studies of DRV, COBI, FTC, and TAF and in the ongoing phase 3 studies …”

Section: Discussionsupporting

confidence: 89%

“…Once‐daily boosted DRV 800 mg has demonstrated a high and durable virologic response in a range of patient populations and a high genetic barrier to the development of resistance . Current treatment guidelines include DRV/COBI combined with 2 nucleoside reverse transcriptase inhibitors, or administered as the D/C/F/TAF single‐tablet regimen, as a recommended treatment option for HIV‐1 treatment‐naive patients or recommended either when integrase inhibitors are not an option or in certain clinical situations…”

mentioning

confidence: 99%

“…Once-daily boosted DRV 800 mg has demonstrated a high and durable virologic response in a range of patient populations and a high genetic barrier to the development of resistance. [10][11][12][13][14] Current treatment guidelines include DRV/COBI combined with 2 nucleoside reverse transcriptase inhibitors, or administered as the D/C/F/TAF single-tablet regimen, as a recommended treatment option for HIV-1 treatmentnaive patients 15,16 or recommended either when integrase inhibitors are not an option or in certain clinical situations. 17,18 TAF is a prodrug predominantly hydrolyzed to tenofovir intracellularly by cathepsin A5, resulting in higher intracellular levels of the active moiety tenofovir diphosphate and 90% lower plasma tenofovir concentrations relative to tenofovir disoproxil fumarate (TDF).…”

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confidence: 99%

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Bioequivalence of the Once‐Daily Single‐Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability

Crauwels

Baugh

Landuyt

et al. 2018

Clinical Pharm in Drug Dev

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The effect of food on the bioavailability of the components of the once‐daily, single‐tablet human immunodeficiency virus (HIV) type 1 regimen containing darunavir (DRV 800 mg), cobicistat (COBI 150 mg), emtricitabine (FTC 200 mg), and tenofovir alafenamide (TAF 10 mg) (D/C/F/TAF) (NCT02475135) and the bioequivalence of D/C/F/TAF versus combined intake of the separate agents (NCT02578550) were evaluated. These were 2 phase 1, open‐label, randomized, 2‐period crossover studies (7‐day washout between treatments) in HIV‐negative healthy volunteers. Twenty‐four participants each received a single dose of D/C/F/TAF in fasted conditions (test) or after a standardized high‐fat breakfast (reference). Ninety‐six participants each received a single dose of D/C/F/TAF (test) or combined intake of a single DRV 800‐mg tablet, a COBI 150‐mg tablet, and an FTC/TAF 200/10‐mg tablet (reference), both after a standardized regular‐calorie, regular‐fat breakfast. Pharmacokinetic profiles for all D/C/F/TAF components, safety, and tolerability were assessed. Following D/C/F/TAF in fasted conditions, DRV peak concentration, area under the concentration‐time curve from time of administration until the last time point with a measurable concentration (AUC)last, and extrapolated to infinity (AUCinf) were lower by 45%, 34%, and 30%, respectively, compared with fed conditions, with no clinically relevant differences in COBI, FTC, or TAF exposures between fed and fasted conditions. In the bioequivalence study 90% confidence intervals of the geometric mean ratios of all main pharmacokinetic parameters were within the 80.00% to 125.00% bioequivalence limits for DRV, COBI, FTC, and TAF. No grade 3/4 adverse events (AEs), serious AEs, deaths, or discontinuations due to AEs occurred. D/C/F/TAF is bioequivalent to combined administration of the separate agents. Consistent with other (co)formulations of DRV, DRV exposure was lower in fasted than in fed conditions as evaluated when taken with food, so D/C/F/TAF should be taken with food.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

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confidence: 99%

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Bioequivalence of the Once‐Daily Single‐Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability

Crauwels

Baugh

Landuyt

et al. 2018

Clinical Pharm in Drug Dev

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“…[6][7][8][9][10][11][12][13][14] In addition, DRV/r is not recommended in children <3 years of age owing to toxicity concerns in animal studies, and ETR, a second-generation NNRTI, is not recommended in children <6 years of age owing to lack of safety and efficacy data. Until very recently, DTG was only recommended by the US Food and Drug Administration (FDA) for adolescents >12 years of age and >40 kg body weight.…”

Section: Researchmentioning

confidence: 99%

Characteristics and early outcomes of children and adolescents treated with darunavir/ritonavir-, raltegravir- or etravirine-containing antiretroviral therapy in the Western Cape Province of South Africa

Nuttall

Pillay

2018

S Afr Med J

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RESEARCHBy 2012, the estimated number of children (0 -14 years of age) receiving antiretroviral therapy (ART) in South Africa (SA) was 140 541, representing an estimated 63% of those requiring treatment. [1,2] As increasing numbers of children are started on first-and second-line ART, the demand for third-line regimens in children and adolescents with treatment failure is likely to increase. It is estimated that currently <1% of people on ART globally are receiving third-line regimens, and it is unknown what proportion of these are children. [3] An unpublished systematic review presented in 2015 assessing second-and third-line ART options for children and adolescents concluded that there is insufficient evidence to directly evaluate alternative second-and third-line ART options for children, and that current recommendations are still based on inference from adult trials.[4] The World Health Organization (WHO) recommends that national programmes should develop policies for third-line ART that should incorporate integrase strand transfer inhibitors (INSTIs), second-generation protease inhibitors (PIs) and secondgeneration non-nucleoside reverse transcriptase inhibitors (NNRTIs) with minimal risk of cross-resistance to previously used regimens. Recommended third-line ART regimens in the WHO 2016 guidelines [5] are: (i) darunavir/ritonavir (DRV/r) plus dolutegravir (DTG) (or raltegravir (RAL)) with or without one to two nucleoside reverse transcriptase inhibitors (NRTIs); (ii) DRV/r plus two NRTIs with or without one NNRTI; or (iii) RAL (or DTG) plus two NRTIs, depending on the preceding first-and second-line ART regimens.Although safety and efficacy of DRV/r, etravirine (ETR) and RAL have been reported in specific age groups of ART-naive and ARTexperienced children and adolescents, there is a paucity of data on treatment-experienced children from resource-constrained settings receiving these drugs as part of routine care. [6][7][8][9][10][11][12][13][14] In addition, DRV/r is not recommended in children <3 years of age owing to toxicity concerns in animal studies, and ETR, a second-generation NNRTI, is not recommended in children <6 years of age owing to lack of safety and efficacy data. Until very recently, DTG was only recommended by the US Food and Drug Administration (FDA) for adolescents >12 years of age and >40 kg body weight.[15] The FDA has recently approved DTG from 6 to <12 years and ≥30 kg in a dose of 35 mg once daily, but suitable formulations that allow for administration of this dose are not yet registered in SA.[16] In SA, DTG has only been approved from 18 years of age. ObjectiveTo describe the characteristics and early outcomes of treatmentexperienced children and adolescents (<20 years of age) in the Western Cape Province of SA who initiated an ART regimen that included one or more of DRV/r, RAL and ETR. Background. There is an increasing need for third-line treatment regimens in HIV-infected children with antiretroviral treatment (ART) failure. Data are limited on darunavir/ritonavir (DRV/r)-, r...

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“…Recent data on DRV in a once-daily regimen in ART-naive adolescents, support consideration in first-line therapy. [36] DRV is approved for children >6 years of age with 300 mg, 150 mg and 75 mg tablets registered in SA. There is some concern about DRV in children <3 years of age, as infant rats experienced seizures and a high death rate when exposed to the drug.…”

Section: Drugs Recently Licensed For Sa Childrenmentioning

confidence: 99%

Antiretroviral therapy for the management of HIV in children

2014

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Guidance on the indications for starting antiretroviral therapy (ART) and the preferred initial drugs has evolved substantially over the past 15 years. These changes were the result of a better understanding of the rate of disease progression and the high early morbidity and mortality. There is now a better appreciation of the long-term implications of early therapy and how to sequence the available drugs.

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Efficacy and Safety of Darunavir/Ritonavir at 48 Weeks in Treatment-naïve, HIV-1–infected Adolescents

Abstract: Over 48 weeks, once-daily darunavir/ritonavir 800/100 mg plus NRTIs was effective and well-tolerated for treatment of HIV-1-infected, antiretroviral-naïve adolescents (≥12 to <18 years). These findings support use of once-daily darunavir/ritonavir 800/100 mg in this population.

Cited by 24 publications

References 20 publications

Bioequivalence of the Once‐Daily Single‐Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability

Bioequivalence of the Once‐Daily Single‐Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability

Characteristics and early outcomes of children and adolescents treated with darunavir/ritonavir-, raltegravir- or etravirine-containing antiretroviral therapy in the Western Cape Province of South Africa

Antiretroviral therapy for the management of HIV in children

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