Achieving optimal antiretroviral drug exposure during pregnancy is critical to ensure maximal HIV-1 viral load suppression to prevent mother-to-child transmission of HIV. The World Health Organization (WHO) HIV treatment guidelines now includes efavirenz-based combination antiretroviral therapy as a preferred first-line regimen for treating HIV-infected pregnant women after the first trimester. We found that standard efavirenz dosing of 600 mg once daily during the third trimester of pregnancy provides an exposure similar to that postpartum and in historical controls of non-pregnant adults.
The necessity to assess antiretroviral drug exposure during pregnancy is highlighted by several studies showing significant reductions in antiretroviral drug exposure with standard doses during pregnancy 6, 7
. Longer gastrointestinal emptying/transit times, reductions in gastric acid secretions, increases in body water, plasma volume, fat stores, and hepatic/renal blood flow, and temporal changes of hepatic metabolizing enzymes activities are among the physiological changes during pregnancy that can potentially impact a drugs disposition 13
. Efavirenz is metabolized via the hepatic cytochrome P450 enzymes, raising concerns regarding the risk of under exposure during pregnancy. However in our study, efavirenz AUC during the third trimester (55.4 mcg.hr/mL) was very similar to that reported in non-pregnant adults (58.1 mcg/hr/mL). Several women had an efavirenz drug exposure below the study target threshold of 40 mcg.hr/mL (10th
percentile in non-pregnant adults) but this proportion was not above that expected within a non-pregnant population.
A major strength of the current study design is the ability to perform within-subject comparisons during pregnancy and postpartum. Efavirenz AUC and Cmax were not significantly different during pregnancy and postpartum. While efavirenz Cl/F was increased and Cpre-dose and C24hour were decreased during pregnancy compared to postpartum, the magnitude of the differences does not appear to be sufficient to warrant a dosing adjustment as 22 of 25 women (88%) achieved a trough concentration above the recommended threshold of 1.0 mcg/mL. One woman had an AUC of 13.5 mcg.hr/mL and a C24hour of 0.23 mcg/mL during pregnancy which is well below the expected range in non-pregnant women; her AUC ante/post ratio of 0.56 was the largest change after delivery, suggesting that poor drug adherence prior to the PK sampling may have been a factor driving her individual results. Also, among the women with low trough concentrations during the third trimester, increasing the efavirenz dose from 600 to 800 mg once daily did not automatically ensure that target trough concentrations were achieved. In fact, both women who had an efavirenz trough concentration <1.0 mcg/mL and had a dose increase did not subsequently achieve target trough concentrations. Clearly, other factors may also be contributing to the low drug concentrations, particularly drug adherence, so it is difficult to conclude if a dose increase to 800 mg once daily should be routinely recommended in this situation. Thus, the decision for an efavirenz dose increase based on plasma drug concentration data should be taken on an individual basis. By study design, the efavirenz dose was reduced to the standard dose immediately following delivery but it could be argued that a woman who has had a dose increase during pregnancy should continue at the same dose until 6–12 weeks postpartum when the efavirenz concentrations are similar to those in non-pregnant adults.
Among the other non-nucleoside reverse transcriptase inhibitors, pharmacokinetic data during pregnancy are available for nevirapine and etravirine. In a study of chronic nevirapine use in US women during the second and third trimesters of pregnancy the mean nevirapine antepartum/postpartum AUC ratio was 0.90 (90% CI: 0.80–1.02) 14
. More recently, in a study of Ugandan pregnant women receiving nevirapine-based antiretroviral therapy the nevirapine AUC and C12hour
was reduced by 20% during the during the third trimester compared to postpartum 15
. In a preliminary report on the pharmacokinetics of the newer NNRTI etravirine in 4 women, etravirine exposure during the third trimester was similar to that in non-pregnant adults 16
. Host genetic polymorphisms can impact the pharmacokinetics of antiretroviral drugs 17
. The homozygous variant allele of the CYP2B6 516G>T
gene polymorphism is associated with higher efavirenz exposure 18
and the frequency of this allele varies between different ethnic populations, ranging from 3.4% in Caucasians, 6.7% in Hispanic and 20% in African Americans. The majority of the women in the current study were Thai and the frequency of the CYP2B6 516 TT
allele is 10.3% in HIV-infected Thai women 19
. Four women (16%) in our study had relatively high efavirenz exposures with AUC ranging from 146 to 220 mcg.hr/mL, consistent with the 516 TT genotype.
To date, efavirenz use in HIV-infected women during pregnancy and women of childbearing potential has been limited due to concerns of congenital neural tube defects following first trimester exposure. In a preclinical study, major central nervous systems anomalies were observed in 3 of 20 infants born to pregnant cynomolgus monkeys treated with efavirenz 8
. Analysis of prospective data from the antiretroviral pregnancy registry between January 1989 and 2010 found that birth defects occurred in 14 of 546 live births (2.6%, 95%CI 1.4 to 4.3%) with efavirenz first trimester exposure 20
. One of these reported defects was a neural tube defect (neural tube closes by about 4 weeks after conception). Sufficient numbers of efavirenz first trimester exposures reported within the registry allows the exclusion of a 2-fold increase in overall common birth defects. A recent systemic review and meta-analysis of observational cohorts reported a non-significant relative risk of 0.87 for overall birth defects among women exposed to efavirenz during the first trimester of pregnancy compared with exposure to other antiretroviral drugs 21
. However, the authors cautioned that to identify an increased incidence of rare defects such as neural tube defects (prevalence of approximately 0.1%) several thousand first trimester exposures are needed to exclude an increased risk, thus data are still insufficient to draw conclusions about neural tube defects with efavirenz exposure in the first trimester. Three of the 25 women enrolled in the current study were exposed to efavirenz throughout the first 6 weeks of pregnancy and no congenital anomalies or newborn complications were reported.
Efavirenz readily crosses the placenta in animal studies. Maternal and fetal blood concentrations in pregnant rabbits and cynomolgous monkeys are equivalent, while in pregnant rats fetal concentrations exceeded maternal concentrations22
. In our subjects, the median ratio of cord blood to maternal blood efavirenz concentrations was 49%. This ratio is lower than that achieved following nevirapine exposure during pregnancy (~93%) but higher than with protease inhibitors (normally below 20%) 6, 7, 23
. Although the efavirenz cord blood concentrations are below maternal concentrations throughout the dosing interval, virologically suppressive concentrations appear to be achieved in the fetus.
A limitation of the study is that the majority of women (84%) enrolled were Thai. Determining the optimal antiretroviral dose for HIV-infected pregnant women has shown to be population specific. For example larger reductions in lopinavir exposure during the third trimester of pregnancy have been observed in US women compared with Thai women.24, 25
Given the lack of impact of pregnancy of efavirenz exposure in the current study it is unexpected that a major impact will be observed in different populations but additional data in more diverse populations, including those with different frequencies of the CYP2B6 516
TT genotype, would be reassuring.
In conclusion, although efavirenz oral clearance is increased and pre-dose and trough concentrations are decreased during the third trimester compared to postpartum, efavirenz exposure during pregnancy following standard dosing appears adequate compared to historical data in non-pregnant adults and using within-subject ante/postpartum comparisons. With international and national antiretroviral treatment guidelines increasingly recommending efavirenz as an option in pregnant women after the first trimester, these data support the use of standard efavirenz dosing during pregnancy.