The results of this study demonstrated that in rhesus macaques, a single intrapartum maternal dose of maraviroc was poorly transferred to the fetus. Plasma maraviroc concentrations in the newborn macaques were less than 1% of the mothers’ plasma concentrations. While the single intrapartum doses used in this study (60 to 100 mg/kg) were 15- to 25-fold higher than the standard human dose (300 mg, or 5 mg/kg), the Cmax
and AUC for the macaque mothers were similar to those found for humans (1
). However, Cmax
and AUC values plateau above doses of 300 mg in humans (1
), and thus, the similar plasma concentrations found in the macaques were not unexpected. The high maraviroc doses were designed to achieve maximal concentrations in maternal blood, suitable for assessing placental transfer into fetal compartments; however, only low fetal levels were found.
MTCT of HIV is associated with high maternal viral loads (8
). Potent antiretroviral therapy that reduces or suppresses maternal circulating HIV levels in advance of delivery has been shown to reduce the rate of MTCT to less than 1% (15
). In resource-poor settings, where access to HIV diagnostic testing or potent ARV therapy is limited, administration of a single intrapartum dose of NVP at delivery has been shown to substantially reduce MTCT and is recommended as a minimum intervention (4
). However, previous studies showed single-dose NVP (29
) or AZT (34
) administered during labor did not significantly affect the maternal viral load by the time of delivery, although reductions were measured at later time points. Thus, protection from intrapartum/early-postpartum MTCT is likely due to a combination of reduction in the maternal breast milk viral load and provision of prophylactic NVP concentrations to the newborn (9
). Pharmacologically, NVP reaches concentrations in newborns that are approximately 90% of maternal concentrations, and it is detectable in newborn plasma for up to 1 week (25
). NVP has a low molecular mass (267 Da) and low protein binding (<30%), which are favorable characteristics of drugs that efficiently cross the placenta (35
). In contrast, maraviroc has a high molecular mass (513 Da) and is approximately 76% protein bound (17
), and in the present study, it was no longer detectable in the plasma of newborn macaques within 48 h of birth.
Studies in humans have shown that maraviroc may have extended antiviral activity despite being discontinued or undetectable in the blood. A delayed rebound in the viral load in humans following cessation of treatment was hypothesized to be due to prolonged occupancy of CCR5 receptors (16
). In results presented here, receptor occupancy on maternal CD4 lymphocytes waned in a temporal relationship with plasma maraviroc levels. By 48 h after dosing, a proportion of CCR5 receptors were unoccupied when plasma maraviroc concentrations were only slightly above the limit of detection. Evidence of unoccupied CCR5 receptors suggests CCR5-using HIV could infect these CD4+
lymphocytes. In the infant macaques, our attempts to measure receptor occupancy in the ex vivo
assay were compromised by extremely low CCR5 expression on CD4+
lymphocytes, which is consistent with extremely low CCR5 expression (<1%) on CD4+
lymphocytes in human neonates (6
). Indeed, subsequently analyzed data from other newborn macaques showed that 0.5 to 2.4% of lymphocytes (12 to 51 cells per μl of blood) express CCR5 receptors in 1- to 3-day-old macaques (K. K. A. Van Rompay, unpublished data). Nevertheless, given that CCR5 receptors became unoccupied within 48 h after dosing in mothers who had plasma maraviroc concentrations that were 44-fold higher than those of the infants, it seems unlikely that CCR5 receptors on infant CD4+
cells remained occupied for any longer period of time.
The work presented here included only a maternal dose of maraviroc. The current minimum recommended intervention to reduce MTCT of HIV is a single maternal NVP dose at delivery plus a single NVP dose to the infant following delivery. The goal of this study was to determine whether maraviroc possessed maternal-fetal pharmacokinetic parameters that were similar to those of NVP (good placental transfer and a long half-life in the infant). It is possible that alternative maraviroc-based pre- and postpartum protocols, such as infant dosing with maraviroc or inclusion of additional drugs, such as ritonavir, to reduce maraviroc clearance, may change the PK profile and improve the potential efficacy of single-dose maraviroc to reduce MTCT.
The results presented here show that a single maternal intrapartum dose of maraviroc resulted in low fetal maraviroc concentrations. While this study included a small number of macaques, the overall findings were consistent among all animals. Overall, poor transplacental transfer and a short pharmacokinetic profile of maraviroc in newborn macaques in this study suggest that as a sole treatment intervention, a single intrapartum dose of maraviroc would not be effective in reducing MTCT of HIV.