M Cotton, H Cassim , N Pavía-Ruz , L Ross, S Ford, N Givens, K Cheng, J Sievers

19th International AIDS ConferenceJuly 22-27, 2012; Washington, DC

Pharmacokinetics, Safety and Antiviral Activity of Fosamprenavir/Ritonavir-Containing Regimens in HIV-Infected 4 Weeks to <2-Year-Old Children 48-Week Data From Study APV20002M Cotton, H Cassim, N Pavía-Ruz, L Ross, S Ford, N Givens, K Cheng, J Sievers

TUAB0202


Lisa Ross, Susan Ford, Naomi Givens, Katharine Cheng, and Jörg Sievers are employees of GlaxoSmithKline.

APV20002 is sponsored by ViiV Healthcare UK Limited and ViiV Healthcare Company.GlaxoSmithKline is responsible for implementing and managing all aspects of this study.


Background• Several protease inhibitor (PI) therapies are

approved for use in children– 6 are available in liquid formulation (USA)– 3 are approved in children <2 years of age (USA)

• Need for increased treatment options for very young children

• APV20002: PK, safety and antiviral activity of fosamprenavir (FPV)/ritonavir (RTV) BID in PI-naive and PI-experienced HIV-1–infected children 4 weeks to <2 years of age


APV20002 Study Design• Phase II, open-label, 2-cohort, multicentre

• Primary endpoints include:– Steady-state plasma amprenavir (APV) PK– AEs and laboratory abnormalities– Discontinuations due to AEs

• No formal statistical hypothesis testing

SDV

<2 yearsPI-naive/exp.HIV RNA ≥400

c/mL

4 weeks to <6 monthsFPV/RTV 45/10 mg/kg

BID6 months to <2 yearsFPV/RTV 45/7 mg/kg BID

Wk 2/88-12 hour PK

Wk 24 Wk 48


Baseline CharacteristicsITT[E] Population

4 Weeks to <6 months(n=26)

6 Months to <2 years(n=28)

Total(N=54)

Age, median (range), months 3 (2, 5) 13 (6, 24) 6 (2, 24)Sex, n (%)

Male 13 (50) 10 (36) 23 (43) Ethnicity, n (%)

Hispanic or Latino 0 9 (32) 9 (17)Race, n (%)

Black - - 44 (81)White/Caucasian - - 2 (4)Other (American Indian) - - 8 (15)

Median plasma HIV-1 RNA log10 c/mL (IQR)

5.80 (5.17, 6.30)

5.51 (4.81, 5.76)

5.60 (5.00, 6.15)

Median CD4+ cells/mm3 (IQR) 1378 (950, 1690)

1120 (874, 1828)

1235 (937, 1795)

Median % CD4+ cells (IQR) 27 (20, 36)

25 (18, 31)

26 (18, 34)


Prior NRTI, NNRTI and PI Therapy

PI-naive(n=49)n (%)

PI-experienced(n=5) n (%)

Any antiretroviral therapy, n (%) 33 (67) 5 (100)No. of NRTIs taken, n (%)

1 28 (57) 02 2 (4) 5 (100)3 1 (2) 0

Median duration of all prior NRTI exposure (IQR), weeks

1 (1, 4) 39 (16, 64)

No. of NNRTIs taken, n (%)1 30 (61) 1 (20)

Median duration of all prior NNRTI exposure (IQR), weeks

0.1 (0.1, 0.1) 0.1 (0.1, 0.1)

No. of PIs taken, n (%)1 0 4 (80)2 0 1 (20)

Median duration of all prior PI exposure (IQR), weeks 0 39 (16, 64)


Exposure to FPV/RTV BID• As of the data cutoff date for this 48-week analysis

(5 July 2011):– Median exposure to FPV was 640 days

(range 8-1093)– 78% were exposed for >48 weeks– 50% were exposed for >96 weeks

• Ongoing study: 21 subjects remain enrolled


Plasma APV AUC(0-)

Plasma APV AUC(0-) by FPV Dose following FPV/RTV BID

FPV Dose (mg/kg) + RTV

20 30 40 50 60 70

Pla

sma

AP

V A

UC

(0- ) (h

. g/m

L)

0

50

100

150

200

250

Subjects 4weeks to <6monthsSubjects 6months to <2 yearsHistorical adult min,maxHistorical adult median (37h.g/mL)

Group

FPV/RTV

(mg/kg)

Paeds vs adults

GMR (90% CI)4 wk to <6 mo

45/10 0.720 (0.542, 0.957)

6 mo to <2 y

45/7 0.744 (0.568, 0.975)


Plasma APV C

Plasma APV C by FPV Dose following FPV/RTV BID

FPV Dose (mg/kg) + RTV20 30 40 50 60 70

Pla

sma

AP

V C

g/

mL)

0

2

4

6

8

10

12Subjects 4weeks to <6monthsSubjects 6months to <2yearsHistorical adult min,maxHistorical adult median (2.2g/mL)

GroupFPV/RTV(mg/kg)

Paeds vs adults

GMR (90% CI)4 wk to <6 mo

45/10 0.397 (0.298, 0.528)

6 mo to <2 y

45/7 1.00 (0.833, 1.21)


0

20

40

60

80

100

0 12 24 36 48

Prop

ortio

n of

subj

ects

(%)

Study week

6m - <2y, <400 c/mL4w - <6m, <400 c/mL6m - <2y, <50 c/mL4w - <6m, <50 c/mL

Virologic Response and CD4+ Cell Percentage

• Median increase in CD4+ cell percentages at Week 48 was 5% in both cohorts

71%64%58%

Snapshot analysis (MSD=F)


Virologic Failures• Overall, 9 subjects met analysis plan–

defined virologic failure criteria • Virus from 3/9 had treatment-emergent

resistance mutations• Full resistance profile in Poster MOPE0401

1. Ross et al. IAC 2012; Washington, DC. Abstract MOPE040.


Adverse Events Safety Population• Most common AEs overall were diarrhoea (54%),

gastroenteritis (36%), and upper respiratory tract infection (36%)

• Drug-related Grade 2-4 AEs:N=59n (%) Grade

Subjects reporting at least one drug-related Grade 2-4 AE 12 (20)Blood cholesterol increaseda 6 (10) All 2Gastroenteritis 2 (3) 2 and 4Febrile convulsion 1 (2) 3Hepatomegaly 1 (2) 2Hyperlipidaemia 1 (2) 2Thrombocytopenia 1 (2) 3Transaminases increased 1 (2) 3a Includes one AE reported as “blood cholesterol.”


Adverse Events (cont) Safety Population• 3 discontinuations due to treatment-emergent AEs:

– Septicaemia, gastroenteritis, pulmonary tuberculosis• Overall, 22 subjects experienced serious AEs (SAEs)• 3 events were considered drug-related:

– Gastroenteritis n=1 (2%)– Febrile convulsion n=1 (2%)– Transaminases increased n=1 (2%)

• 3 subjects died following SAEs:– 24-month-old male: acute abdominal disorder– 19-month-old female: Grade 4 septicaemia– 2-month-old male: “muti” traditional medicine (herbal) poisoning

and Grade 4 drug-related gastroenteritis


Treatment-Emergent Grade 3/4 Laboratory Abnormalities—DAIDS 2004Observed AnalysisClinical chemistry N

Grade 3n (%)

Grade 4n (%)

Grade 3/4n (%)

All parameters 51 9 (18) 1 (2) 10 (20)ALT 51 3 (6) 0 3 (6)Alkaline phosphatase 51 3 (6) 1 (2) 4 (8)Creatine kinase 51 3 (6) 0 3 (6)

Haematology N Grade 3 Grade 4 Grade 3/4All parameters 51 5 (10) 1 (2) 6 (12)Neutropenia 51 4 (8) 1 (2) 5 (10)Haemoglobin 51 1 (2) 0 1 (2)


Conclusions• Data support use of FPV/RTV in this young

population:– Plasma APV exposures in infants aged 6 months to

<2 years comparable to those from regimens approved in adults

– Lower APV Cτ in infants <6 months of age but similar antiviral response in the two age groups

– Overall safety profile similar to that observed in older children and adults

• Another option for treatment with a PI in children in the US


AcknowledgementsWe would like to thank all investigators, study personnel and patients who participated in this trial.

Documents

M Cotton, H Cassim , N Pavía-Ruz , L Ross, S Ford, N Givens, K Cheng, J Sievers