safety and efficacy of maraviroc in ccr5-tropic hiv-1-infected children aged 2 to
TRANSCRIPT
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 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
Country Investigator/institution Country Investigator/institution
Brazil Marinella Della Negra, Instituto de Infectologia Emilio Ribas, São Paulo
Thailand Kulkanya Chokephaibulkit, Siriraj Hospital, Mahidol University, Bangkok noi, Bangkok
Italy Carlo Giaquinto, Clinica Pediatrica, Centro AIDS Pediatrico, Padova
Virat Sirisanthana, Chiang Mai University, Muang, Chiang Mai
Portugal José Gonçalo Marques, Centro Hospitalar de Lisboa Norte, EPE, Hospital Santa Maria, Lisboa
Pope Kosalaraksa, Khon Kaen University, Muang, Khon Kaen
Flora Candeias, Hospital D. Estefânia -Serviço de Imunologia, Lisboa
Jintanat Ananworanich, The HIV Netherlands Australia Thailand Research Collaboration, The Thai Red Cross AIDS Research Centre, Bangkok
Maria João Virtuoso, Hospital Distrital de Faro, EPE, Faro
USA Carina Adriana Rodriguez, University of South Florida, Children's Research Institute, St Petersburg, FL
Puerto Rico
Midnela Acevedo-Flores, San Juan Research Hospital, Puerto Rico Medical Center, Rio Piedras
Antonio Carlos Arrieta, Children's Hospital of Orange County, Orange County, CA
South Africa
Ismail Haroon Mitha, Benmed Clinic, Benoni, Gauteng
Suzanne Renee Lavoie, Virginia Commonwealth University, Richmond, VA
Jan Fourie, Dr. J Fourie Medical Centre, Dundee, KwaZulu Natal
Joseph August Church, Children's Hospital Los Angeles, Los Angeles, CA
Muthuhadini Patience Mawela, University of Limpopo, Pretoria, Gauteng
Stephen Cole Eppes, Alfred I. DuPont Hospital for Children, Wilmington, DE
Lizelle Keet, Iatros International, Westdene, Bloemfontein
Charles Debeaux Mitchell, University of Miami Miller School of Medicine, Miami, FL
Spain Claudia Fortuny, Hospital Sant Joan de Deu, Barcelona
Natella Yurievna Rakhmanina, Children's National Medical Center - Infectious Disease, Washington, D.C.
Daniel Blazquez Gamero, Hospital Universitario 12 de Octubre,
Study A4001031: participating sites (23 sites from 8 countries)
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 meeting1. 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
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
Screening Day 1
Baseline
Cohort 1: ≥2–<6 years (liquid)
Cohort 2: ≥6–<12 years (tablet)
Cohort 3: ≥6–<12 years (liquid)
Cohort 4: ≥12–<18 years (tablet)
End of study
Weeks4–6
weeks 48 weeks 240 weeks (5 years)
S1 Follow-up5 years after initial MVC exposure
On or off MVC
S2
S2
Screening
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
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 nature1. 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
MVC doses by BSA on entry and OBT
BSA, m2Dose in absence of potent
CYP3A4 inhibitors/inducers
Dose with potentCYP3A4 inhibitors
Dose with CYP3A4 inducers (in absence of
potent CYP3A4 inhibitors)
<0.22 40 mg BID 10 mg BID 40 mg BID
0.220.43 100 mg BID 25 mg BID 100 mg BID
0.440.72 200 mg BID 50 mg BID 200 mg BID
0.731.19 300 mg BID 75 mg BID 300 mg BID
1.201.30 300 mg BID 100 mg BID 375 mg BID
1.311.73 300 mg BID 125 mg BID 450 mg BID
>1.73 300 mg BID 150 mg BID 600 mg BID
Subject baseline characteristics (N=94)
Cohort 1(N=13)
Cohort 2(N=27)
Cohort 3(N=12)
Cohort 4(N=42)
Sex, males/females 9/4 13/14 6/6 16/26Race, White/Black/Asian/Other 1/8/2/2 5/18/3/1 1/11/0/0 9/26/6/1
Body surface area, m2 (median [range])
0.7 (0.5 – 0.7)
1.0 (0.6–1.4)
0.9 (0.6–1.6)
1.3 (0.9–1.8)
Age, years(median [range])
3.0 (2.0–5.0)
10.0 (6.0–11.0)
9.0 (6.0–11.0)
14.0 (12.0–17.0)
Median baseline plasma HIV-1 RNA (log10, copies/mL [range])
4.6 (3.9–5.6)
4.3 (3.2–5.5)
4.7 (3.5–5.3)
4.4 (2.9–5.9)
Median baseline CD4 counts (μ/L [range])
894.5 (131.5–1768.5)
467.8 (5.5–1120.5)
414.0 (192.5–1341.0)
371.0 (29.0–847.5)
Median duration of study treatment (days) [range]
226(45 – 1321)
526(92 – 1316)
240(2 – 1373)
261(14 – 1234)
7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia
Study disposition through Week 4875/94 children were followed up for 48 weeks (26 discontinued MVC; 49 still on treatment)
Cohort 1 (N=13)
Cohort 2 (N=27)
Cohort 3 (N=12)
Cohort 4 (N=42)
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)
7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia
*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
Cohort 1 (N=13)
Cohort 2 (N=27)
Cohort 3 (N=12)
Cohort 4 (N=42)
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)
Screened(N=262)
DC prior to Week 48 (n=1)• Other* (n=1)
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)
Study disposition through Week 4875/94 children were followed up for 48 weeks (26 discontinued MVC; 49 still on treatment)
Cohort 1 (N=13)
Cohort 2 (N=27)
Cohort 3 (N=12)
Cohort 4 (N=42)
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)
Completed Week 48 (n=5)
Completed Week 48 (n=19)
Completed Week 48 (n=5)
Completed Week 48 (n=20)
Screened(N=262)
DC prior to Week 48 (n=1)• Other* (n=1)
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)
Ongoing Pre-Week 48 (n=7)
Ongoing Pre-Week 48 (n=4)
Ongoing Pre-Week 48 (n=4)
Ongoing Pre-Week 48 (n=4)
*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
Study disposition through Week 4875/94 children were followed up for 48 weeks (26 discontinued MVC; 49 still on treatment)
Percentage of subjects with HIV-1 RNA <400 copies/mL at 24 (N=84) and 48 weeks (N=75)*
*Efficacy was evaluated using the missing/discontinuation = failure approachNumerator=Number of responding subjectsDenominator=Includes all subjects who completed week 48 or discontinued prior to week 48
0102030405060708090
100
Cohort 1 Cohort 2 Cohort 3 Cohort 4
Week 24Week 48
7/104/6
22/26
15/236/10 5/8
21/38
15/38
% o
f sub
ject
s w
ith H
IV-1
RN
A <4
00 c
opie
s/m
L67% at 24 weeks and 52% at 48 weeks had VL < 400c/mL
7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia
Percentage of subjects with HIV-1 RNA <48 copies/mL at 24 (N=84) and 48 weeks (N=75)*
0102030405060708090
100
Cohort 1 Cohort 2 Cohort 3 Cohort 4
Week 24Week 48
2/10
3/6 14/26
10/23
6/104/8
17/38
13/38
% o
f sub
ject
s w
ith H
IV-1
RN
A <4
8 co
pies
/mL
*Efficacy was evaluated using the missing/discontinuation = failure approachNumerator=Number of responding subjectsDenominator=Includes all subjects who completed week 48 or discontinued prior to week 48
46% at 24 weeks and 40% at 48 weeks had VL < 48 c/mL
7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia
Median CD4% at baseline, Week 24, and Week 48
11
CD4%
6 4 26 23 15 11 9 5 36 23 19
n = children with available CD4 data at Week 24 and Week 48
n =
Cohort 1 Cohort 2 Cohort 3 Cohort 4
7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia
Summary of all-causality adverse events*Subjects n (%)
With adverse events 60 (63.8) Serious adverse events 16 (17) Grade 3 or 4 adverse events 10 (10.6) Death 0
Discontinued due to adverse events 3 (3.2)Most frequently reported (>10%) adverse events by system organ class, n (%)
Gastrointestinal disorders 34 (36.2)Infection and infestations 46 (48.9)Nervous system disorders 13 (13.8)Reproductive system and breast disorders 12 (12.8)Skin and subcutaneous tissue disorders 11 (11.7)
*All data included as of the cut-off date of March 12, 20137th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia
Adverse events (>Grade 2) in each cohort, n (grade)
Cohort 1(N=13)
Cohort 2(N=27)
Cohort 3(N=12)
Cohort 4(N=42)
Gastritis (1, G3) Pneumonia (1, G3) TB drug-induced liver injury (1, G4)
Vomiting (1, G3) Pneumonia (1, G3)
Otitis media (1, G3) H1N1 influenza (1, G3)
Transaminases increased (1, G4)
Hepatic enzyme abnormal (1, G3)
Bipolar disorder (1, G3)
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
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
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 ViiV Healthcare
• Editorial support was provided by Complete Medical Communications and was funded by ViiV Healthcare
7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30-July 3, 2013; Kuala Lumpur, Malaysia