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Safety and efficacy of maraviroc in CCR5-tropic HIV-1-infected children aged 2 to <18 years

Safety and efficacy of maraviroc in CCR5-tropic HIV-1-infected children aged 2 to <18 years. C Giaquinto , 1 L Keet, 2 C Fortuny, 3 A Fang, 4 M Vourvahis, 4 L McFadyen, 5 SR Valluri, 4 G Mukwaya, 4 J Heera 6.

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Safety and efficacy of maraviroc in CCR5-tropic HIV-1-infected children aged 2 to <18 years

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  1. Safety and efficacy of maraviroc in CCR5-tropic HIV-1-infected children aged 2 to <18 years C Giaquinto,1 L Keet,2 C Fortuny,3 A Fang,4 M Vourvahis,4L McFadyen,5 SR Valluri,4 G Mukwaya,4 J Heera6 1Clinica Pediatrica, Centro AIDS Pediatrico, Padova, Italy; 2Department Pediatrics, University of the Free State, Bloemfontein, South Africa; 3Hospital Sant Joan de Deu, Barcelona, Spain; 4Pfizer Inc, New York, NY, USA; 5Pfizer Inc, Sandwich, Kent, UK; 6Pfizer Inc, Groton, CT, USA 7th IAS Conference on HIV Pathogenesis, Treatment and PreventionJune 30-July 3, 2013; Kuala Lumpur, Malaysia

  2. Study A4001031: participating sites (23 sites from 8 countries)

  3. Introduction • Maraviroc (MVC) is a selective CCR5 antagonist and is the first of this class of oral agents approved for treatment of CCR5-tropic HIV-1 in adults • Preliminary data from 31 children have previously been presented at IAS 2011 • Here we present updated safety and efficacy findings from 94 subjects who received at least one dose of study medication with a data cut-off of March 12, 2013 • Efficacy data is reported until Week 48 • All safety data is included as of the cut-off date of March 12, 2013 • Pharmacokinetic (PK) and dose-finding data from Stage 1 are presented in poster MOPE044,1 also at this meeting 1. Vourvahis et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract #MOPE044. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

  4. Study A4001031: Ongoing, open-label, two-stage, age-stratified, non-comparative study to evaluate PK, safety, and efficacy of MVC with optimized background therapy (OBT) in treatment-experienced children and adolescents infected with CCR5-tropic HIV-1 Cohort 1: ≥2–<6 years (liquid) Cohort 2: ≥6–<12 years (tablet) Baseline Cohort 3: ≥6–<12 years (liquid) Screening Day 1 End of study Cohort 4: ≥12–<18 years (tablet) 4–6 weeks 240 weeks (5 years) Weeks 48 weeks Screening S1 Follow-up 5 years after initial MVC exposure On or off MVC S2 S2 S1, Stage 1: intensive PK for dose finding (4-12 weeks): Minimum of 12 (cohort 1) and 10 children (in each of cohorts 2-4) to complete stage 1, prior to entering stage 2. S2, Stage 2: safety/efficacy. Following the minimum numbers being reached for stage 1, all new patients then directly enter stage 2 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

  5. Methods • Subjects infected with CCR5-tropic HIV-1 (as detected by Phenotypic assay, ESTA) were enrolled into one of four age/formulation cohorts • Eligibility criteria included: • HIV-1 RNA >1000 copies/mL at screening • On stable or no pre-study antiretroviral (ARV) regimen for >4 weeks prior to screening visit • Previous experience/intolerance >6 months (sequential or cumulative) with at least two ARV drug classes • OBT choice was guided by resistance test results and consisted of ≥3 ARVs in addition to MVC • MVC dose based on body surface area and co-medications1 • Safety, viral load and CD4 counts were evaluated at all study visits • Statistical analyses are descriptive in nature 1. Vourvahis et al. IAS 2013; Kuala Lumpur, Malaysia. Abstract #MOPE044. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

  6. MVC doses by BSA on entry and OBT

  7. Subject baseline characteristics (N=94) 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

  8. Study disposition through Week 4875/94 children were followed up for 48 weeks (26 discontinued MVC; 49 still on treatment) Screened(N=262) Screen failure (N=164) Viral load <1000 copies/mL (n=40) PSGT was non-reportable (n=4) Not CCR5-tropic (n=71) Tropism not reportable (n=36) Other (n=13) In screening (N=4) Enrolled(N=94) Cohort 2 (N=27) Cohort 3 (N=12) Cohort 4 (N=42) Cohort 1 (N=13) 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

  9. Study disposition through Week 4875/94 children were followed up for 48 weeks (26 discontinued MVC; 49 still on treatment) Screened(N=262) Screen failure (N=164) Viral load <1000 copies/mL (n=40) PSGT was non-reportable (n=4) Not CCR5-tropic (n=71) Tropism not reportable (n=36) Other (n=13) In screening (N=4) Enrolled(N=94) Cohort 2 (N=27) Cohort 3 (N=12) Cohort 4 (N=42) Cohort 1 (N=13) • DC prior to Week 48 (n=4) • Virological failures (n=3) • Other* (n=1) • DC prior to Week 48 (n=3) • Virological failures (n=2) • Other* (n=1) • DC prior to Week 48 (n=18) • Virological failures (n=11) • Adverse events (n=1) • Other* (n=6) • DC prior to Week 48 (n=1) • Other* (n=1) *Other includes discontinuation (DC) due to withdrawal of consent, non-compliance, lost to follow-up; all virological failures had confirmed poor compliance with study medication; 3 virological failures had non-R5 tropism at failure

  10. Study disposition through Week 4875/94 children were followed up for 48 weeks (26 discontinued MVC; 49 still on treatment) Screened(N=262) Screen failure (N=164) Viral load <1000 copies/mL (n=40) PSGT was non-reportable (n=4) Not CCR5-tropic (n=71) Tropism not reportable (n=36) Other (n=13) In screening (N=4) Enrolled(N=94) Cohort 2 (N=27) Cohort 3 (N=12) Cohort 4 (N=42) Cohort 1 (N=13) • DC prior to Week 48 (n=4) • Virological failures (n=3) • Other* (n=1) • DC prior to Week 48 (n=3) • Virological failures (n=2) • Other* (n=1) • DC prior to Week 48 (n=18) • Virological failures (n=11) • Adverse events (n=1) • Other* (n=6) • DC prior to Week 48 (n=1) • Other* (n=1) Ongoing Pre-Week 48 (n=4) Ongoing Pre-Week 48 (n=4) Ongoing Pre-Week 48 (n=4) Ongoing Pre-Week 48 (n=7) Completed Week 48 (n=20) Completed Week 48 (n=19) Completed Week 48 (n=5) Completed Week 48 (n=5) *Other includes discontinuation (DC) due to withdrawal of consent, non-compliance, lost to follow-up; all virological failures had confirmed poor compliance with study medication; 3 virological failures had non-R5 tropism at failure

  11. Percentage of subjects with HIV-1 RNA <400 copies/mL at 24 (N=84) and 48 weeks (N=75)* 67% at 24 weeks and 52% at 48 weeks had VL < 400c/mL 22/26 7/10 4/6 15/23 5/8 6/10 21/38 % of subjects with HIV-1 RNA <400 copies/mL 15/38 *Efficacy was evaluated using the missing/discontinuation = failure approach Numerator=Number of responding subjects Denominator=Includes all subjects who completed week 48 or discontinued prior to week 48 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

  12. Percentage of subjects with HIV-1 RNA <48 copies/mL at 24 (N=84) and 48 weeks (N=75)* 46% at 24 weeks and 40% at 48 weeks had VL < 48 c/mL 6/10 14/26 3/6 4/8 % of subjects with HIV-1 RNA <48 copies/mL 17/38 10/23 13/38 2/10 *Efficacy was evaluated using the missing/discontinuation = failure approach Numerator=Number of responding subjects Denominator=Includes all subjects who completed week 48 or discontinued prior to week 48 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

  13. Median CD4% at baseline, Week 24, and Week 48 CD4% n = 11 6 4 26 23 15 11 9 5 36 23 19 Cohort 1 Cohort 2 Cohort 3 Cohort 4 n = children with available CD4 data at Week 24 and Week 48 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

  14. Summary of all-causality adverse events* • *All data included as of the cut-off date of March 12, 2013 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

  15. Adverse events (>Grade 2) in each cohort, n (grade) None of these events were attributed to maraviroc by the study investigators 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

  16. Conclusions • These data suggest that in HIV-1-infected, treatment-experienced children aged 2 − <18 years, MVC (administered twice-daily) in addition to OBT was: • Generally well-tolerated • Effective at 48 wks, with 52% and 40% of subjects achieving HIV-1 RNA < 400 copies/mL and < 48 copies/mL, respectively • Virological failure was associated with non adherence and was more frequent in adolescents (Cohort 4) • Enrolment is continuing with collection of additional data, including OBT resistance, out to 5 years 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

  17. Acknowledgments • We would like to thank all study participants, care-givers, DMC members, and investigators • This ongoing study is being conducted by Pfizer Inc and is funded by ViiVHealthcare • Editorial support was provided by Complete Medical Communications and was funded by ViiVHealthcare 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia

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