{"id":15536,"date":"2011-08-01T11:07:13","date_gmt":"2011-08-01T11:07:13","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=15536"},"modified":"2011-08-01T11:07:13","modified_gmt":"2011-08-01T11:07:13","slug":"paediatric-antiretroviral-pipeline-darunavir-and-raltegravir","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/15536","title":{"rendered":"Paediatric antiretroviral pipeline: darunavir and raltegravir"},"content":{"rendered":"

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

Two posters at CROI 2011 presented pharmacokinetic (PK), efficacy and safety data of paediatric formulations of antiretroviral drugs. [1, 2]<\/p>\n

Darunavir <\/strong><\/h2>\n

ARIEL (TMC114-C228) is a 48-week, open-label, single-arm, phase II trial evaluating PK, safety and efficacy of darunavir\/ritonavir (DRV\/r) plus an optimised background regimen (OBR) in HIV-positive treatment-experienced children. Avy Violari and colleagues reported interim (24 week) data from ARIEL.<\/p>\n

Children aged 3 to <6 years, weighing 10 to <20kg, with viral load >1000 copies\/mL and <3 DRV resistance-associated mutations (RAM) at screening, received DRV. The formulation used in this study is a high concentrate oral suspension (100 mg\/mL) – initially dosed at 20 mg\/kg BID plus ritonavir (RTV) 2.6 to 3.2mg\/kg BID with an OBR (>2 active NRTI) – over 48 weeks.<\/p>\n

After a PK analysis at week 2, the DRV dose was amended to 25mg\/kg BID children weighing 10 to 15kg and 375mg BID fixed for those weighing 15 to <20 kg (following Data Safety Monitoring Board recommendations).<\/p>\n

A total of 27 patients – 55.6% male and mean age 4.6 years at screening – with DRV\/r + an OBR. At baseline, the children\u0092s median viral load was 4.51 log copies\/mL, median CD4 count was 927 cells\/mm3, and median CD4 percentage was 27.7% cells\/mm3. The children had a median of 0 primary PI mutations at baseline and 4 PI RAM, 1 NRTI RAM, and 1 NNRTI RAM.<\/p>\n

The majority of children, 23 (85.2%) experienced at least one adverse event (AE). One child discontinued treatment (due to grade 2 vomiting, believed to be associated with ritonavir). Most side effectss were grade 1-2. Grade 3-4 and serious side effects were reported in 18.5% and 11.1% of patients, respectively but none was considered treatment-related. Most commonly reported adverse events (occurring in over 10% of patients) were diarrhea, vomiting, pyrexia, nasopharyngitis, rhinitis, upper respiratory tract infection, hypokalemia, cough, acidosis, and alkalosis.<\/p>\n

One child had a grade 3 laboratory abnormality \u0096 neutropenia – but this was present since baseline and not considered to be related to treatment.<\/p>\n

There was a steady increase in response from week 2 to 24. By week 24, 55.6% of the children met the primary efficacy endpoint of viral load <50 copies\/mL (ITT-TLOVR). The mean increase in CD4 at week 24 was 109 cells\/mm3.<\/p>\n

Two children had DRV RAMs at baseline but both were <50 cells\/mL at week 24. Eleven children (40.7%) were considered virological failures. None of the six children with paired baseline\/endpoint genotype samples developed PI or NRTI RAMS.<\/p>\n

Raltegravir<\/strong><\/h2>\n

P1066 is an open-label study of raltegravir (RAL) in treatment experienced HIV-positive children and adolescents. Sharon Nachman and colleagues reported PK, and week 12 and 24 efficacy and safety data for treatment-experienced children aged 2 to 5 years receiving the RAL chewable tablet formulation.<\/p>\n

In this dose finding study, intensive PK was initially performed on 4 children and once PK targets were met, 8 more were enrolled. Inclusion criteria included viral load >1000 copies\/mL, prior ART experience but na\ued65 to integrase inhibitors. A RAL chewable tablet 6 mg\/kg twice daily was added to the existing\u00a0 regimen, intensive PK samples were taken between days 5 and 12. Once the dose was selected, an additional 9 children were enrolled to assess longer-term safety and efficacy.<\/p>\n

PK parameters were evaluated and a dose was selected using an AUC12h target (range 14 to 25uM*h) based on available PK data with a C12h target to exceed the protein-adjusted IC95 of RAL against wild type virus. The investigators compared PK parameters to existing data from 6 to 18 year old children and adolescents receiving the adult formulation and 6 to 11 year old children receiving RAL chewable tablet. Of the 12 children, 67% were female, they were a mean, age of 3 years old, viral load 4.14 log10 copies\/mL, CD4%, 33% cells\/mm3, CD4 count, 1505 cells\/mm3, and weight, 14.3 kg. They received a mean RAL dose of 6.24 mg\/kg (0.67).<\/p>\n

The geometric mean AUC12 was 8.8hr*mg\/L, 18uM*h; C12h 32ng\/mL, 71nM; Cmax 4329ng\/mL, 9.7uM; CL\/F 10.5L\/hr and %CV 77%.A 6mg\/kg BID dose (maximum 300mg) was selected.<\/p>\n

At week 24, by ITT analysis, 62% (95% CI, 53-92) of children (n=21) were <400 copies\/mL and 52% (95% CI, 30-74) <50 copies\/mL. CD4 gain from baseline was a median of 4.1% (95% CI 2.0-9.9) and 218 (95% CI 39-290) cells\/mm3.<\/p>\n

No child discontinued RAL due to AEs in this study. One child had grade 3 ALT (2 events), grade >3 AST and ungraded elevated GGT (5 events), considered possible treatment related. Three children had grade >3 neutropenia (7 events) but this was not judged to be treatment related. Other non-treatment related events were: grade 3 bronchopneumonia, grade 3 hydrogen ion concentration, ungraded lactic acidosis, decreased blood glucose, acute gastro enteritis and impetigo.<\/p>\n

References<\/p>\n

1. \tViolari A et al. ARIEL: 24-week safety and efficacy of DRV\/r in treatment-experienced 3- to <6-year-old patients. 18th CROI, 27 February\u00962 March 2011, Boston. Poster abstract 713<\/a>.<\/p>\n

2. \tNachman S et al. Interim results from IMPAACT P1066: RAL oral chewable tablet formulation for 2- to 5-year-olds. 18th CROI, 27 February\u00962 March 2011, Boston. Poster abstract 715<\/a>.<\/p>\n","protected":false},"excerpt":{"rendered":"

Polly Clayden, HIV i-Base Two posters at CROI 2011 presented pharmacokinetic (PK), efficacy and safety data of paediatric formulations of antiretroviral drugs. [1, 2] Darunavir ARIEL (TMC114-C228) is a 48-week, open-label, single-arm, phase II trial evaluating PK, safety and efficacy …<\/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],"tags":[65],"class_list":["post-15536","post","type-post","status-publish","format-standard","hentry","category-conference-reports","category-antiretrovirals","category-paediatric-care","tag-croi-2011"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/15536","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=15536"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/15536\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=15536"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=15536"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=15536"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}