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Tenofovir Disoproxil Fumarate (TDF) Pharmacokinetics (PK) with Daily Dosing in

the First Week of Life (HPTN 057) Karin Nielsen-Saines*, Mark Mirochnick, Newton Kumwenda, Esau Joao, Regis Kreitchmann, Jorge Pinto, Breno Santos,

Teresa Parsons, Taha Taha, Lynne Mofenson, Paul Sato, Brian Kearney, and Mary Glenn Fowler for the

HPTN 057 Protocol Team

Washington, D.C.

July 23, 2012

HPTN 057

TUAB0201

Background Alternatives to perinatal single dose NVP are needed

for HIV PMTCT purposes. Tenofovir (TFV):

• Is highly effective in protecting newborn macaques against SIV infection with no major toxicity and no development of resistance

• Is available as a pro-drug (tenofovir disoproxil fumarate - TDF) in an oral tablet for maternal dosing and powder for oral suspension for infants

Can we develop a simple TDF regimen for use in place of NVP in pregnant women during labor and in the newborn? 2

HPTN 057

Study Design and Objectives HPTN 057: A prospective, phase I study of the PK

and safety of TDF administered to HIV infected pregnant women in labor and to their infants. Primary objectives: To evaluate the

pharmacokinetics, safety and tolerance of intrapartum/neonatal TDF in HIV-infected women and their infants.

Secondary objectives: To evaluate the effect of single dose TDF on maternal HIV-1 RNA levels, evaluate viral resistance to TDF in women and infants, determine infection status of infants & measure TDF concentration in amniotic fluid and breast milk following maternal exposure.

HPTN 057

PK target and sites PK Goal: Maintain infant TDF concentration

throughout the first week of life above 50 ng/mL, the mean trough TDF concentration in adults receiving chronic dosing with TDF.

Study sites: Malawi and Brazil Malawi College of Medicine, Blantyre, Malawi Univ. Federal de Minas Gerais, Belo Horizonte, Brazil Irmandade Santa Casa da Misericordia, Porto Alegre, Brazil Hospital Nossa Senhora da Conceiçao, Porto Alegre, Brazil Hospital dos Servidores do Estado, Rio de Janeiro, Brazil

Study Strategy: Maternal/infant TDF dosing in addition to local PMTCT standard of care.

HPTN 057

Study cohorts (n = 122 mother-infant pairs enrolled)

Cohort n Maternal TDF Dosing (in labor) Infant TDF Dosing

1 30 600 mg x1 None

2 20 None 4 mg/kg within 12 hours of birth, day 3 and day 5

3 30 900 mg x1 6 mg/kg within 12 hours of birth, day 3 and day 5

4 30 600 mg x 1 6 mg/kg daily x 1 week

HPTN 057

Patient Characteristics cohort 4 33 Mother/infant pairs enrolled/followed for 12 mo

• 16 in Malawi, 17 in Brazil Route of Delivery:

• 21 vaginal, 12 cesarean section Median maternal delivery weight (kg):

• 66 kg, range: 49 - 115 kg Median time between maternal dose and

delivery: 4.5 hrs, range: (0.6-11.4) hrs Median birth weight: 3.1 kg, range: 2.1 – 4.2 kg

HPTN 057

Cord Blood and Maternal Delivery TDF Concentrations

Cord Blood 61 ng/mL (69.3%)Cord Blood TDF > 50 ng/mL 24/31 (77%)

Maternal Delivery Concentration 108 ng/mL (76.1%)

Cord Blood/Maternal Delivery Ratio 0.55 (64.0%)

0

100

200

300

400

500

600

700

0.00 2.00 4.00 6.00 8.00 10.00 12.00

TFV

(ng/

mL)

Time after Dose (hr)

Maternal Delivery and Cord Blood TDF Concentration

Cord Blood

Maternal Delivery

50 ng/mL

0.00

1.00

2.00

0.00 2.00 4.00 6.00 8.00 10.00 12.00

TFV

(ng/

mL)

Time after Dose (hr)

Cord Blood/Maternal TDF Concentration Delivery Ratio

Geo mean (CV%) or #/n (%)

HPTN 057

Infant TDF PK Results

Predose (ng/mL)

% with Predose >50 ng/mL

Tmax(hr)

Cmax(ng/mL)

AUC(ng*hr/mL)

t½ (hr)

Initial Dose 29 (6.7%) 45% 6.9

(54.8%)288

(49.9%)3939.4 (37.6%)

13.2(80.1%)

Dose 4 146(84.5%) 100% 2.3

(99.2%)336

(40.5%)4714.1 (37.4%)

14.5(45.0%)

Dose 7 79(77.2%) 84% 3.4

(84.6%)221

(66.1%)3061

(49.0%)14.6

(96.1%)

Geo mean (CV%) or %

Infant TFV Concentration (Geo mean +/- SE)

0.0

50.0

100.0

150.0

200.0

250.0

300.0

350.0

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180

Time After Birth (hrs)

TFV

(ng/

mL)

HPTN 057

Amniotic fluid concentrations of TDF Amniotic fluid was

obtained from women who underwent elective C-section for obstetrical reasons.

24 paired amniotic fluid -serum specimens were obtained from 3 of the study cohorts. The drug achieved effective amniotic fluid concentrations in the majority of subjects, with highest levels 3 - 6 hrs post-dosing. 9

HPTN 057

Amniotic Fluid and Maternal Delivery TFV Conc vs Time After Dosing

0100200300400500600700800

0 1 2 3 4 5 6 7 8 9 10 11 12

Time After Dosing (hours)

TFV

(ng/

mL)

AmnioticFluid Conc Maternal Delivery Conc

Geo mean 168 ng/ml, coeff variation: 72%

Safety of TDF All mothers and infants tolerated TDF well. Mild/moderate abnormal laboratory results according

to the DAIDS Toxicity Tables were common but appeared representative of local site background values in HIV infected women and their newborns.

No severe or life-threatening adverse events or deaths were assessed by the Protocol Safety Review Team as possibly, probably, or definitely related to TDF.

An HPTN Study Monitoring Committee reviewed safety and toxicity and noted no safety concerns.

1 of 33 infants (3%) in cohort 4 was found to be HIV-infected . HIV PCR was + at birth (in utero infection). In total 5 of 122 infants were infected in 057 (4.1%)

HPTN 057

Summary/ ConclusionsThis regimen of a single maternal TDF dose of

600 mg during labor and a daily TDF dose of 6 mg/kg to the infant during the 1st week of life: Was safe and well tolerated. Achieved cord blood TDF concentrations

above 50 ng/mL target in most infants. Maintained infant TDF concentrations above

50 ng/mL during the first week of life.

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HPTN 057

• Mothers and children who enrolled in the study.• Pharmaceutical :Gilead Sciences: James Rooney, Brian Kearney

• Study Sponsors: NIAID: Paul Sato and Sheryl Zwerski Eunice Kennedy Shriver NICHD: Lynne Mofenson, George Siberry

•DAIDS Pharmaceutical Branch: Ana Martinez, Scharla Estep, Eva Purcell (in memoriam)

•Study Coordination: FHI: Kathleen George, Melissa Allen

•Scharp: Lynda Emel, Elizabeth Brown, Molly Swenson• Institutions and Investigators: • Boston University: Mark Mirochnick • UCLA: Karin Nielsen, Yvonne Bryson• Johns Hopkins University, Baltimore: Taha Taha• Malawi College of Medicine, Blantyre: Newton Kumwenda, George Kafulafula (in memoriam),

Robin Broadhead• Federal University of Minas Gerais, Belo Horizonte: Jorge Pinto, Fabiana Kakehasi• Irmandade Santa Casa de Misericordia, Porto Alegre: Regis Kreitchmann, Debora Coelho• Hospital dos Servidores, Rio de Janeiro: Esau C. Joao, M. Leticia Santos Cruz, Leon Sidi• Hospital Nossa Senhora da Conceicao, Porto Alegre: Breno Santos, Rita Lira, Rosana Fonseca• CDC: Mary Glenn Fowler• HPTN Central Lab: Paul Richardson, Susan Eshelman• HPTN PK network: Teresa Parsons

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Acknowledgments…. HPTN 057