HPTN 057 is a prospective phase I trial of the PK and safety of tenofovir disoproxil fumarate (TDF) in HIV-positive pregnant women in labour and their neonates.
The trial was designed when the question of alternative strategies to intrapartum/neonatal single dose nevirapine was still considered relevant.1
The study had four cohorts, maternal infant pairs received local PMTCT standard of care plus TDF as described in Table 1.
|Table 1: HPTN 057 Maternal/Infant Cohorts|
|Cohort||n||Maternal TDF (Single Dose in Labour)||Infant TDF|
|2||20||None||4 mg/kg within 12 hours of birth, day 3 and day 5|
|3||30||900 mg||6 mg/kg within 12 hours of birth, day 3 and day 5|
|4||30||600 mg||6 mg/kg daily for 7 days|
Data presented previously showed infants from cohorts 3 achieved cord blood tenofovir (TFV) concentrations above the target concentration of 50 ng/mL infants (the mean trough concentration in adults receiving treatment with TDF), but failed to keep infant concentrations above this target during the first week of life due to more rapid than expected TFV elimination.2
In an oral presentation at IAC 2012, Karin Nielsen-Saines showed data from cohort 4 in which women received 600 mg TDF at the onset of labour (or 4 hours before Caesarean section) and neonates received 6 mg/kg TDF suspension once daily for 7 days.3
In this study, 33 mother infant pairs were enrolled in Malawi (n=16) and Brazil (n=17). Twenty one infants were born by vaginal delivery and 12 by Caesarean section; the median time between maternal dose and delivery was 4.5 hours (range 0.6-11.4).
The investigators took samples from mothers at delivery, from cord blood and from infants before and 2, 10 and 24 hours after the 1st, 4th and 7th TDF doses.
TFV concentrations were determined by HPLC/MS/MS with a lower limit of quantitation of 5 ng/mL. Cord blood and maternal delivery concentrations are presented as geometric mean (%CV) in Table 2 and infant TFV PK in Table 3.
|Table 2: Cord Blood and Maternal Delivery TFV Concentrations|
|Cord blood||61 (69.3%) ng/mL|
|Cord blood TFV >50 ng/mL||24/31 (77%).|
|Maternal delivery concentrations||108 (76.1%) ng/mL|
|Cord blood/maternal delivery ratio||0.55 (64.0%)|
|Table 3. Infant TFV PK Parameters|
|Dose||Pre-Dose (ng/mL)||% With Pre-Dose >50 ng/mL||Tmax (hr)||Cmax (ng/mL)||AUC (ng*hr/mL)||T1/2 (hr)|
|1||29 (67%)||45||6.9 (54.8%)||288 (49.9%)||3939.4 (31.6%)||13.2 (80.1%)|
|4||146 (84.5%)||100||2.3 99.2%||336 (40.5%)||4714.1 (37.4%)||14.5 (45%)|
|7||79 (77.2%)||84||3.4 (84.6%)||221 (66.1%)||3061 (49.0%)||14.6 (96.1%)|
Amniotic fluid was obtained from a small subset of three women who had elective Casaerean sections. Paired amniotic fluid/serum samples (n=24) showed TDF achieved effective amniotic fluid concentrations with the highest levels 3 to 6 hours post dose.
The study team concluded that this regimen provides TFV exposure similar to adults receiving 300 mg daily doses and is appropriate for use in neonates in studies of TDF used for HIV prophylaxis or treatment.
One infant of 33 (3%) was infected in cohort 4 and 5/122 (4.1%) were infected in HPTN 057.
This presentation was interesting but perhaps the placement in the session that looked at PK in antiretrovirals for treatment a little misleading as this study used TDF as prophylaxis in the first week of life. To use it for treatment it would be very important to look at bone growth in infants given the large amount bone development at that age. There would need to be safety studies before a move toward routine use for treatment in infants.
The FDA recently approved TDF for the 2 to 12 age group and the EMA is looking at this. WHO has recently published the findings from a systematic review looking at the use of TDF in children and adolescents.4
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