Antiretroviral drug concentrations in breast milk and breastfeeding infants
Polly Clayden, HIV i-Base
A poster from the Breastfeeding, Antiretroviral, and Nutrition (BAN) study by Amanda Corbett and coworkers showed pharmacokinetic data in breast milk and plasma in mothers and breastfeeding infants.
BAN is enrolling >2400 pregnant women in Malawi to look at the effect on mother to child transmission of: 28 weeks of HAART given to mothers or daily NVP given to babies; weaning at 28 weeks; and nutritional supplementation.
In this study all mothers and infants receive single-dose NVP and 7 days AZT/3TC tail coverage. Mothers with CD4 >200 cells/mm3 and infants with birth weight >2kg were enrolled. To better understand infant drug exposure from breast milk, the investigators performed a longitudinal pharmacokinetic study in motherinfant pairs.
Breast milk, and mothers and infants blood plasma samples were taken at the end of 12-hour dosing intervals at 6, 12, and 24 weeks post partum. Mothers HAART regimens included a combination of AZT (or d4T), 3TC, and either NVP or NFV.
20 motherinfant pairs were enrolled in this study. Mothers were a median of 26 years old (range19-35) and weighed 53kg (range 46-54) with CD4 counts 518 cells/mm3 (range 216 to 931) at delivery. Babies weighed a median of 3.1 kg (2.2 to 2.6) kg at delivery, and 75% were male. Samples were obtained at a median of 12, 15, and 17 hours post-dose at 6, 12, and 24 weeks post partum.
The investigators reported, <20% of samples had detectable AZT and d4T. They found, maternal plasma concentrations for other antiretrovirals were similar to previous reports.
For concentration ratios for 3TC, NVP, and NFV with all time points included see table below. The investigators noted that 3TC and NVP infants plasma concentrations declined slightly from 6 to 24 weeks post-partum, while mothers plasma and breast milk concentrations did not change significantly.
Table 1: Concentration ratios for 3TC, NVP and NFV
|3TC (n=47)||NVP (n=21)||NFV (n=26)|
|Breast milk / mother’s plasma||2.6 (1.1-3.5)||0.7 (0.5-0.9)||0.08 (0.04-0.14)|
|Infant’s plasma / breast milk||0.01 (0.004-0.03)||0.2 (0-0.3)||N/A|
|Infant’s plasma / mother’s plasma||0.06 (0.01-0.1)||0.12 (0-0.3)||N/A|
n=number of samples, median (IQR)
The investigators concluded that although 3TC concentrations in breast milk were 2.6-fold higher than in maternal plasma, infant plasma exposure was minimal (1% of breast milk). NVP concentrations in breast milk were 70% that of maternal plasma, with low exposure (20% of breast milk) in infants. They found NFV exposure in breast milk was minimal (8% of maternal plasma), with no drug detected in the infants.
Overall, infants plasma concentrations for all antiretrovirals were well below therapeutic concentrations, which they suggested would have minimal toxicity risk. Both 3TC and NFV exposure in infants would suggest minimal risk for resistance in HIV-positive infants. But they noted, low-level NVP exposure via breast milk may predispose HIV-infected infants to resistance.
Corbett A, Kashuba A, Rezk N, et al. Antiretroviral drug concentrations in breast milk and breastfeeding infants. 15th CROI, February 2008, Boston, USA. Poster abstract 64B.