{"id":28333,"date":"2015-06-01T09:23:46","date_gmt":"2015-06-01T09:23:46","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=28333"},"modified":"2015-06-11T11:36:43","modified_gmt":"2015-06-11T11:36:43","slug":"elvitegravir-in-children-and-adolescents","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/28333","title":{"rendered":"Elvitegravir in children and adolescents"},"content":{"rendered":"

\"CROI<\/a>Polly Clayden, HIV i-Base<\/strong><\/p>\n

Three posters at CROI 2015 showed new paediatric elvitegravir (EVG) data. The posters described preliminary safety in the 6 to 12 year old age group, and safety, efficacy, pharmacokinetics (PK) and resistance in 12 to 18 year olds receiving EVG in fixed dose combinations (FDCs).<\/strong> [1, 2, 3]<\/p>\n

EVG 150 mg is approved for adults as a component of the once-daily FDC containing cobicistat (COBI, C), emtricitabine (F) and tenofovir disoproxil fumarate (TDF), or when co-administered with a ritonavir-boosted protease inhibitor.<\/p>\n

EVG has also been co-formulated with tenofovir alafenamide fumarate (TAF) in E\/C\/F\/TAF, the FDC that is currently under regulatory review in the US and EU.<\/p>\n

EVG 85 mg is used in combination with ritonavir-boosted atazanavir or lopinavir because of increased EVG plasma concentrations due to UGT enzyme inhibition. Previous studies have confirmed use of the ritonavir or COBI-boosted adult dose in 12 to 18 year olds. [4]<\/p>\n

Elvitegravir in children aged six to less than 12 years<\/h2>\n

GS-US-183-0160 is an ongoing, phase 2\/3 open label, study with an age de-escalation design (oldest to youngest) evaluating the safety and PK of EVG in treatment experienced infants, children and adolescents 4 weeks to <18 years of age.<\/p>\n

PK and preliminary safety data from 6 to <12 year olds (Cohort 2) were presented.<\/p>\n

Sixteen participants were enrolled: median age 9 years (range 6 \u2013 11); 14 had viral load <50 copies and 2 >1000 copies mL and baseline, their mean CD4 count was 811 cells\/mm3.<\/p>\n

Participants received EVG (adult or paediatric formulation) once daily added to their background regimen including either lopinavir\/r or atazanavir\/r. Data were available for 14 (57% male, 14% Asian, 71% black and 14% white).<\/p>\n

Participants weighing >30 kg received the adult EVG 85 mg dose (n=6) and those weighing 17 to <30 kg received 50 mg (n=8).<\/p>\n

The investigators compared PK parameters to exposures in adults from EVG plus boosted protease inhibitor phase 3 trials.<\/p>\n

This comparison revealed geometric mean ratios (GMR) of 136%, 147%, and 129% vs adult exposure for AUCtau, Cmax and Ctrough respectively.<\/p>\n

Mean EVG Ctrough was approximately 11-fold above the in vitro protein-binding adjusted IC95 (44.5 ng\/mL); all participants’ Ctroughs were above the IC95.<\/p>\n

These data are consistent with the range of exposures seen in the 12 to <18 years age group.<\/p>\n

The investigators suggested that EVG appeared to be safe and well tolerated, based on limited data in a small number of participants.<\/p>\n

E\/C\/F\/TAF PK in adolescents<\/h2>\n

Treatment-naive 12 to 18 year olds (n=50), with viral load >1000 copies\/mL, CD4 >100 cells\/mm3 and eGFR >90 mL\/min\/1.73m2 received E\/C\/F\/TAF once daily, in a phase 2\/3, single arm, open label, two part trial.<\/p>\n

Steady-state PK parameters of EVG, COBI, FTC, TAF and tenofovir (TFV) were compared to adult exposures by GMR with equivalence boundary of 70% to 143% for the 90% confidence interval. The trial evaluated adverse events, laboratory tests, and the proportion of subjects with viral load <400 and <50 copies\/mL.<\/p>\n

There were 48 participants (24 Part A\/24 Part B) with a median age of 15 years (range 12 \u2013 17), median weight of 52 kg, 58% female, 88% Black and 12% Asian; 21% with viral load >100,000 copies\/mL, median CD4 count 452 cells\/mm3, and median eGFR 158 mL\/min\/1.73m2.<\/p>\n

The investigators found TAF, TFV, EVG, COBI, and FTC PK parameters in adolescents consistent with those associated with safety and efficacy in adults. TFV exposure by AUCtau was >90% lower from E\/C\/F\/TAF than E\/C\/F\/TDF as is seen in adult PK. All participants had EVG Ctau above the protein binding adjusted IC95 of 44.5 ng\/mL.<\/p>\n

Lack of resistance in adolescents on EVG-based FDCs at 24 week<\/h2>\n

Data from week 24 interim analyses that included 21 treatment-naive adolescents on E\/C\/F\/TDF and 23 on E\/C\/F\/TAF \u2013 from two ongoing single-arm studies of these FDCs, conducted in the US, Thailand, Uganda and South Africa \u2013 was also shown.<\/p>\n

Most participants receiving the TDF FDC had HIV subtype C (47.6%, 10\/21) or B (38.1%, 8\/21) and the remainder had subtype AE (14.3%, 3\/21). Most of the group receiving the TAF FDC had subtype A1 (56.5%, 13\/23) and smaller proportions had subtype AE (17.4%, 4\/23), B (17.4%, 4\/23), D (4.3%, 1\/23), or complex mixtures (4.3%, 1\/23). The investigators noted that distribution of subtypes reflected geography: A1, Uganda; AE, Thailand; B, USA; C, South Africa.<\/p>\n

The majority of adolescents receiving both FDCs had viral load <50 copies at 24 weeks: 85.7% (18\/21) on E\/C\/F\/TDF and 91.3% (21\/23) on E\/C\/F\/TAF.<\/p>\n

Genotyping was performed at baseline in all participants at study entry to confirm sensitivity to FTC and tenofovir; screening genotyping to confirm sensitivity to EVG was only done in those receiving the TAF.<\/p>\n

At baseline 14.3% of the participants receiving the TDF FDC had NNRTI-associated resistance mutations and 95.2% had secondary PI-associated mutations. Of those receiving the TAF FDC, 17.4% had NRTI-associated, 21.7% had secondary INSTI-associated, 8.7% had NNRTI-associated, and 100% had secondary PI-associated resistance mutations.<\/p>\n

There was no correlation between pre-existing NNRTI, NRTI, secondary PI and secondary INSTI resistance mutations and virologic success at 24 weeks. No emergent resistance was detected in participants receiving E\/C\/F\/TDF of E\/C\/F\/TAF in these interim analyses.<\/p>\n

References:<\/p>\n

Unless otherwise stated, all references to the programme and abstracts to the 22nd Conference on Retroviruses and Opportunistic Infections, 23-26 February 2015, Seattle.<\/p>\n

    \n
  1. Custodio JM et al. Safety and pharmacokinetics of elvitegravir in HIV-1 infected pediatric subjects. Poster abstract 951.
    \n    http:\/\/www.croiconference.org\/sessions\/safety-and-pharmacokinetics-elvitegravir-hiv-1-infected-pediatric-subjects<\/a><\/li>\n
  2. Kizito H et al. Week-24 data from a phase 3 clinical trial of E\/C\/F\/TAF in HIV-infected adolescents. Poster abstract 953.
    \n    http:\/\/www.croiconference.org\/sessions\/week-24-data-phase-3-clinical-trial-ecftaf-hiv-infected-adolescents<\/a><\/li>\n
  3. Porter DP et al. Lack of emergent resistance in HIV-1-infected adolescents on elvitegravir-based STRs. Poster abstract 952.
    \n    http:\/\/www.croiconference.org\/sessions\/lack-emergent-resistance-hiv-1-infected-adolescents-elvitegravir-based-strs<\/a><\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    Polly Clayden, HIV i-Base Three posters at CROI 2015 showed new paediatric elvitegravir (EVG) data. The posters described preliminary safety in the 6 to 12 year old age group, and safety, efficacy, pharmacokinetics (PK) and resistance in 12 to 18 …<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4,3,32,34],"tags":[203],"class_list":["post-28333","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-antiretrovirals","category-paediatric-care","category-pk-and-drug-interactions","tag-croi-2015"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/28333","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=28333"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/28333\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=28333"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=28333"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=28333"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}