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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