Pharmacokinetics, Safety, and 48-Week Efficacy of Oral Raltegravir in HIV-1-Infected Children Aged 2 Through 18 Years

Nachman, Sharon; Nan, Zheng; Acosta, Edward P.; Teppler, Hedy; Homony, Brenda; Graham, Bobbie; Fenton, Terence; Xu, Xia; Wenning, Larissa; Spector, Stephen A.; Frenkel, Lisa M.; Alvero, Carmelita; Worrell, Carol; Handelsman, Edward; Wiznia, Andrew

doi:10.1093/cid/cit696

Cited by 56 publications

(66 citation statements)

References 9 publications

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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 [3] An unpublished systematic review presented in 2015 assessing second-and third-line ART options for children and adolescents concluded that there is insufficient evidence to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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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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“…IMPAACT (International Maternal, Pediatric, Adolescent AIDS Clinical Trials) P1066 is a phase I/II multicenter open-label trial assessing the pharmacokinetics, safety, tolerability, and efficacy of raltegravir in HIV-infected children [15]. In the initial report, subjects were enrolled into three distinct cohorts based upon age and the formulation of raltegravir (Table 1).…”

Section: Raltegravir Use In Childrenmentioning

confidence: 99%

“…As a class, integrase inhibitors have a potentially higher threshold for developing resistance than other antiretroviral agents, as well as a lower risk of cross-resistance given their unique mechanism of action [10][11][12]. These drugs as a whole have demonstrated utility in salvage regimens in both children and adults and as initial therapy in adults [13][14][15][16][17]. They provide rapid control of viral replication and have a favorable adverse effect profile overall [10-12, 17, 18].…”

Section: Introductionmentioning

confidence: 99%

Use of Integrase Inhibitors in HIV-Infected Children and Adolescents

Dehority

Abadi

Wiznia

et al. 2015

Drugs

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Resistance to antiretroviral drugs is an increasingly prevalent challenge affecting both the adult and pediatric HIV-infected populations. Though data on the safety, pharmacokinetics, and efficacy of newer antiretroviral agents in children typically lags behind adult data, newer agents are becoming available for use in HIV-infected children who are failing to respond to or are experiencing toxicities with traditional antiretroviral regimens. Integrase strand transfer inhibitors are one such new class of antiretrovirals. Raltegravir has been US Food and Drug Administration (FDA) approved for use in patients over the age of 4 weeks. Elvitegravir is a second member of this class, and has the potential for use in children but does not yet have a Pediatric FDA indication. Dolutegravir, a second-generation integrase inhibitor, is approved for those older than 12 years. This review summarizes the use of integrase inhibitors in children and adolescents, and highlights the results of recent clinical trials.

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“…Raltegravir is available in 25 mg and 100 mg chewable tablets. Pediatric patients 912 years of age or weighing 925 kg should be given the adult dose of 400 mg twice daily [54]. & Elvitegravir is available only as a fixed dose combination, which is not FDA-approved nor recommended for pediatric patients under 18 years.…”

Section: Pediatric Considerationsmentioning

confidence: 99%