Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents

Blanche, Stéphane; Bologna, Rosa; Cahn, Pedro; Rugină, Sorin; Flynn, Patricia M.; Fortuny, Clàudia; Vis, Peter; Sekar, Vanitha; Baelen, B. Van; Dierynck, Inge; Spinosa‐Guzman, Sabrina

doi:10.1097/qad.0b013e328330abaa

Cited by 54 publications

(65 citation statements)

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“…3,4 Twicedaily darunavir/ritonavir is also indicated for use in combination with other antiretrovirals in treatment-experienced pediatric patients at least 3 years of age, 5 based on the findings of the phase 2 DELPHI (Darunavir EvaLuation in Pediatric, HIV-Infected, treatment-experienced patients; TMC114-C212; NCT00355524) and ARIEL (dArunavir in tReatment experIenced pEdiatric popuLation; TMC114-TiDP29-C228; NCT00919854) trials. 6,7 In the DELPHI trial, weight-adjusted darunavir/ritonavir twice daily, combined with other antiretrovirals, demonstrated a favorable safety/tolerability profile and a significant virologic response in treatment-experienced children and adolescents (6 to <18 years). 6 Weight-adjusted darunavir/ritonavir twice daily also showed good efficacy with no new safety concerns in treatment-experienced pediatric patients 3 to <6 years of age (ARIEL).…”

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confidence: 98%

“…6,7 In the DELPHI trial, weight-adjusted darunavir/ritonavir twice daily, combined with other antiretrovirals, demonstrated a favorable safety/tolerability profile and a significant virologic response in treatment-experienced children and adolescents (6 to <18 years). 6 Weight-adjusted darunavir/ritonavir twice daily also showed good efficacy with no new safety concerns in treatment-experienced pediatric patients 3 to <6 years of age (ARIEL). 7 Although darunavir/ritonavir is indicated for use in treatment-experienced pediatric patients, the efficacy and safety of once-daily darunavir/ritonavir in treatment-naïve pediatric patients has not been established.…”

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confidence: 98%

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

Flynn

Komar²,

Blanche

et al. 2014

Pediatric Infectious Disease Journal

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confidence: 98%

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confidence: 98%

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

Flynn

Komar²,

Blanche

et al. 2014

Pediatric Infectious Disease Journal

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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%

“…[6] Other than phase 2 trials under controlled conditions, two other retrospective studies involving treatment-experienced adolescents in Spain receiving RALor ETR-based regimens in combination with other ARVs have found comparable safety and efficacy outcomes. [7,8,[10][11][12] Although GRT is a prerequisite for accessing these medications in the SA public sector, specific indications for resistance testing are not included in the 2014 national guidelines, and access to GRT has not been uniform in the SA public sector. Before 2015, GRT was generally only available to patients with private medical insurance or through research studies or donor-funded access programmes in the public sector.…”

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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“…Studies of children and adolescents with experience of ART have shown safety and tolerability of DRV/r in these younger populations (8,9). DRV/r has been widely recommended as a salvage therapy for children older than 3 y and adolescents with high levels of treatment experience and ART resistance (9).…”

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Genotype-guided antiretroviral regimens in children with multidrug-resistant HIV-1 infection

et al. 2016

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Background: Genotyping tests were developed to attenuate the impact of viral resistance. Information about the efficacy in genotype base antiretroviral therapy in children is rare and even more in low-and middle-income countries. Methods: Sixteen children with antiretroviral therapy (ART) failure and triple-class drug-resistant viruses were included in this study. Protease and retrotranscriptase genotypes were available for all patients. Switch of ART regimen was guided by genotyping data. The primary end point was virological suppression (<50 copies/ml) and immunological improvement after 48 wk of treatment with the new ART regimen. results: The median age of the patients was 14.5 y (interquartile range (IQR) 11-16.5). Median HIV-1 RNA viral load was 4.2 log 10 (IQR: 3.4-4.8). The primary end point was found in 11 children (69%), and 13 children (81%) had an HIV-1 RNA viral load <200 copies/ml. Median (IQR) for the baseline CD4 + cell count was 382 cells/μl (281-686 cells/μl), whereas after 48 wk of treatment with the new ART regimen, it was 640 cells/μl (361-936 cells/μl) (P < 0.001). conclusion: Darunavir/ritonavir, raltegravir, and etravirine were well tolerated in the present pediatric population. These drugs provide good options for children exposed to extensive ART. Regimens guided by genotyping data were effective for children who had ART failure and multidrug-resistant HIV-1 infection.i nfants and children who were infected perinatally are now surviving to adulthood with lifelong HIV infection and longterm exposure to combined antiretroviral therapy (ART) (1). Data from the United Kingdom Collaborative HIV Pediatric Study cohort demonstrated that over one-third of children had experienced virological treatment failure and were on a second or subsequent line of therapy at the time of their transition to adult care (2). In the pediatric setting, virological treatment failure occurs most frequently because of poor adherence to ART, and whenever viral replication is inefficiently controlled, virological treatment failure occurs more quickly, allowing the selection of HIV-1 quasispecies resistant to antiretroviral (ARV) drugs (3).Many innate and external factors have been associated with HIV drug resistance mutations in children, such as being infected perinatally, and extremely high viral load during the first steps of the infection, which can take longer to suppress than that in older children or adults, even when they are on fully active ART regimens (4).Interpretation of resistance tests in this context can be complex, particularly in the presence of expanding options for ARV drugs, and treatment decisions should be made with the support of pharmacists and clinicians who have expertise in the field (5).Currently, more than 20 different ARV drugs with six different classes of action have been approved for use in children or adolescents with HIV infection worldwide; most of them are used in Mexico (6).A good level of adherence is particularly difficult during adolescence, especially with a complex regimen ...

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Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents

Abstract: In treatment-experienced children and adolescents, DRV/r showed comparable exposure to adults with appropriate dose selection, favorable safety and tolerability, improved body weight and significant virologic response. DRV/r is a valuable therapeutic option for this population.

Cited by 54 publications

References 6 publications

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

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

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

Genotype-guided antiretroviral regimens in children with multidrug-resistant HIV-1 infection

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