Efavirenz Pharmacokinetics during Pregnancy and Infant Washout

Abstract

Background

Limited data exist on efavirenz pharmacokinetics in HIV-positive pregnant women and neonatal washout.

Methods

HIV-infected pregnant women receiving 600 mg efavirenz once daily had intensive steady-state 24-h pharmacokinetics profiles during the second trimester (2T), third trimester (3T) and 6–12 weeks postpartum (PP). Maternal and umbilical cord blood samples were drawn at delivery and neonatal washout pharmacokinetics were determined. Therapeutic targets were the estimated 10th percentile efavirenz area under the concentration–time curve (AUC) in non-pregnant historical controls (40.0 μg•h/ml) and a trough concentration (C_{24 h}) of 1 μg/ml. Data were prospectively collected within two trials: IMPAACT P1026s (United States) and PANNA (Europe).

Results

Among 42 women studied, 15, 42 and 40 had efavirenz pharmacokinetic data available in 2T, 3T and PP, respectively. Median (range) 3T age 33 (20.7–43.5) years, weight 74 (50–132) kg and gestational age 33.4 (28.4–37.9 weeks). Efavirenz AUC during the 3T (60 μg•h/ml) was similar to that reported in non-pregnant adults (58 μg•h/ml). Exposure in the 2T was lower, but within the 0.80–1.25 range. C₂₄ concentrations during pregnancy were lower compared to historical controls on 600 mg efavirenz, however, they were similar to the C₂₄ concentrations after equally potent dose of 400 mg efavirenz. Cord blood/maternal plasma concentration ratio (range) was 0.67 (0.36–0.95). Among 23 infants with washout data available, median (interquartile range) elimination half-life was 65.6 h (40.6–129). HIV RNA viral loads at delivery were <400 and <50 copies/ml for 96.7% and 86.7% of women, respectively. In 3T and PP, respectively, 8/41 (19%) and 6/40 (15%) had AUC below target; 7/41 (17%) and 3/39 (8%) had C₂₄ below target.

Conclusions

Efavirenz exposure was similar during pregnancy compared with PP, C₂₄ was in line with C24 after 400 mg equipotent efavirenz dosing. Efavirenz readily crossed the placenta and infant elimination half-life was over twice that of maternal participants.

Clincaltrials.gov identifiers: NCT00825929 and NCT00042289.

Introduction

Efavirenz is the most widely used non-nucleoside reverse transcriptase inhibitor (NNRTI) and is recommended as part of combination antiretroviral treatment for HIV/AIDS in several adult treatment guidelines [1–3]. The World Health Organization (WHO) mother-to-child HIV prevention (PMTCT) guidelines include efavirenz as part of the first-line antiretroviral therapy (ART) regimens for treatment of HIV-infected pregnant women and this recommendation has been followed by several countries [3,4]. The past restriction of efavirenz use in women who are planning to become pregnant in prior US guidelines was based on a few case reports of congenital neural tube defects with first trimester exposure to efavirenz [5,6], leading the United States Food and Drug Administration (FDA) to originally classify efavirenz as a Class D drug (evidence of human fetal risk [7]. In 2014, a systematic review and meta-analysis of observational cohorts reported birth outcomes among women exposed to efavirenz during the first trimester. Twenty-three studies met the inclusion criteria and the analysis found no increased risk of overall birth defects among 2,026 women exposed to efavirenz during first trimester (n=44, 1.63%, 95% CI 0.78, 2.48%) compared with exposure to other antiretroviral drugs [8]. Efavirenz now has a descriptive risk summary rather than a pregnancy classification and is an alternative in US guidelines [1].

Physiological changes during pregnancy can substantially impact drug disposition. Efavirenz is primarily metabolized by the hepatic cytochrome 2B6 enzyme (CYP2B6) [9] and temporal changes in hepatic drug-metabolizing enzyme activities occur during pregnancy [10]. Several antiretroviral drugs metabolized via the hepatic cytochrome P450 enzymes have reduced exposure during pregnancy, particularly during the third trimester [11,12]. Data are scarce on the impact of pregnancy on efavirenz pharmacokinetics. The IMPAACT P1026s trial has previous assessed efavirenz pharmacokinetics during pregnancy but this primarily included Thai women [13]. In these women increased efavirenz clearance and lower trough concentrations during pregnancy were observed but the magnitude of changes was small and not likely clinically significant. A cohort study of South African HIV pregnant women with and without tuberculosis co-treatment evaluated efavirenz pharmacokinetics and described increased clearance during pregnancy [14]. Lower efavirenz and lopinavir/ritonavir exposure were described in underweight pregnant women with food insecurity when compared to well-nourished women in a clinical trial in Uganda [15]. Efavirenz has been shown to cross the placenta [13] but no data on the washout pharmacokinetics of efavirenz in neonates are available.

Optimal antiviral exposure throughout pregnancy is critical to ensure maximal viral load suppression for the prevention of mother-to-child transmission of HIV and to prevent the selection of viral resistance. Thus, given the uncertainty regarding efavirenz drug exposure using the standard dose during pregnancy across different geographical regions our aim was to investigate the pharmacokinetics of efavirenz 600 mg once daily during pregnancy and in the early postpartum period in non-Thai women, and efavirenz washout pharmacokinetics in their infants.

Methods

Study population

The data reported were prospectively collected in two clinical trials: PANNA ‘Pharmacokinetics of Anti-retroviral Agents in HIV-infected Pregnant Women’ (ClinicalTrials.gov identifier: NCT00825929) and IMPAACT P1026s ‘Pharmacokinetics Properties of ARV Drugs During Pregnancy’ (NCT00042289). Both studies are parallel-group, multi-centre Phase IV studies in HIV-infected pregnant women. PANNA recruits pregnant women from HIV treatment centres in Europe and IMPAACT P1026s recruits pregnant women from sites in the USA, South America and Africa.

Patient eligibility included being HIV-infected, pregnant, ≥18 years of age at screening and treated with an ART regimen containing efavirenz (600 mg, once daily) as part of clinical care for ≥2 weeks before the day of the first pharmacokinetic evaluation. Participants continued to take their prescribed medications throughout pregnancy and until postpartum pharmacokinetic blood sampling was completed. Participants were excluded if they had a past medical history, concurrent condition or use of medication that might interfere with drug absorption, distribution, metabolism or elimination (such as renal or hepatic failure) or presented grade II–IV anaemia at screening (PANNA specific) or multiple gestation pregnancy (P1026s specific). Local institutional review boards approved the protocol at all participating sites and signed informed consent was obtained from all participants prior to participation. The choice of additional antiretrovirals and duration of treatment (that is, continuation of ART) was determined by the participant's physician, who prescribed all medications and remained responsible for her clinical management throughout the study. Maternal and infant safety follow-up continued until 24 weeks postpartum.

Each participant's physician was notified of the participant's plasma concentrations and area under the curve (AUC_0–24) within 2 weeks of sampling. If the AUC_0–24 was below the 10th percentile in non-pregnant adult populations (40.0 μg•h/ml), the physician was offered the option of discussing the results and possible dose modifications with a study team pharmacologist (P1026s specific).

Clinical and laboratory monitoring

Inclusion screening consisted of: medical history, physical examination, serum biochemistry and haematology, HIV-1 RNA vial load and CD4⁺ T-cell count. Laboratory safety assessments were performed at site. Blood samples for safety assessments were taken at visits for pharmacokinetic blood sampling and at delivery. Participants were asked for adverse events at each visit and serum biochemistry, haematology, HIV-1 RNA load and CD4⁺ T-cell count were measured. The HIV status of the infants was assessed per standard of care. The study team reviewed toxicity reports on monthly conference calls, although the participant's physician was responsible for toxicity management. The Division of AIDS (DAIDS)/NIAID Toxicity Table for Grading Severity of Adult Adverse Experiences was used to report adverse events for study participants [16]. All toxicities were followed through resolution. Infants were considered HIV-uninfected if they had at least two negative HIV nucleic acid tests, one after age 1 month and one after age 4 months.

Sample collection

The 24-h intensive pharmacokinetic profiles were performed in the second trimester, third trimester and at 6 to 12 weeks postpartum. Blood samples were drawn immediately before an efavirenz dose and at 1, 2, 4, 6, 8, 12 and 24 h post-dose. PANNA participants had additional blood samples drawn at 0.5 and 3 h post-dose. At each pharmacokinetic visit efavirenz was administered as an observed dose on an empty stomach (at least 1 h before or 2 h after a meal) in P1026s and with a meal in PANNA. Other information collected included the time of the two prior doses, the two most recent meals and maternal height and weight. A single maternal plasma sample and an umbilical cord sample after the cord was clamped were collected at delivery. P1026s newborns who were not breastfeeding had four plasma samples collected to evaluate efavirenz washout pharmacokinetics at 2–10 h, 18–28 h, 36–72 h and 5–9 days after birth.

Efavirenz concentration assays

Efavirenz plasma drug concentrations were analysed by two centres. The PANNA samples were analysed at the Radboud University Medical Center, Department of Clinical Pharmacy, Nijmegen, the Netherlands, and the P1026s samples at the Pediatric Clinical Pharmacology Laboratory, University of California, San Diego. Both laboratories used a validated reversed-phase high performance liquid chromatography (HPLC) method with ultraviolet detection at 245 nm. The lower limits of quantification were 0.05 mg/l (PANNA) and 0.039 μg/l (P1026s). The linear calibration ranges in plasma were 0.2–20.0 mg/l. Both pharmacology laboratories participate in the AIDS Clinical Trial Group pharmacology quality control (precision testing) programme in the United States, which performs standardized inter-laboratory testing twice a year [17].

Pharmacokinetic analyses

The pre-dose concentration (C₀), maximum plasma concentration (C_max), time to maximum plasma concentration (T_max), minimum plasma concentration (C_min), and 24-h post-dose concentration (C₂₄) were determined by direct inspection. AUC_0–24 during the dose interval (from time 0 to 24 h post-dose) for efavirenz was calculated using the trapezoidal rule. Apparent clearance (CL/F) from plasma was calculated as dose divided by AUC_0–24. Half-life (t_1/2) was calculated as 0.693/λ_z; λ_z is the elimination rate constant derived from the terminal slope of the log concentration versus time curve. For participants with pre-dose concentrations below the assay quantification limit (indicating probable non-adherence), single-dose AUC from time 0 to infinity was estimated as AUC_0–24 plus the C₂₄ divided by λ_z. Undetectable concentrations were set at half the lower limit of quantification to calculate summary statistics.

Statistical analyses

The numbers of participants with efavirenz AUC below 40.0 μg•h/ml and trough concentration below 1 μg/ml, the suggested minimum target trough concentration, were determined during pregnancy and postpartum. Descriptive statistics were calculated for pharmacokinetic parameters of interest during each study period. Efavirenz pharmacokinetic parameters during the second trimester and third trimester were compared with those postpartum at the within-participant level using a Wilcoxon signed-rank test, with a two-sided P-value <0.10 considered statistically significant. Within-participant geometric mean ratios (GMR) and 90% CIs were calculated for efavirenz pharmacokinetic parameters in pregnant versus non-pregnant conditions to estimate the range of pharmacokinetic changes between the two conditions that would be consistent with the observed data and assess clinical importance, to inform dosing recommendations. GMRs and CIs between 0.80 and 1.25 (representing a pharmacokinetic parameter during pregnancy remaining within 80–125% of the postpartum value, in line with standard bioequivalence criteria) were considered to indicate pregnancy effects that were not clinically important. Cord blood: maternal blood concentration ratios were determined and recorded. Infant gestational age and birthweight were summarized with twins counted as one infant and their data averaged.

Results

Participant characteristics

A total of 42 pregnant women taking efavirenz 600 mg once daily were enrolled in the study. The clinical characteristics per trimester and pregnancy outcomes are presented in Table 1. All women gave birth to live infants, 41 singletons and one pair of twins. Among infants with data available, the median (range) gestational age at birth was 38 weeks of pregnancy (32–41 weeks) and the median (range) birth weight was 3,162 g (1,875–4,365 g).

Table 1

Patient characteristics

Characteristic	Value
Patients included, n	42 (27 IMPAACT;15 PANNA)
Median age at delivery, years (range)	33 (21–44)
Country
USA, n (%)	11 (26.2)
PANNA (Europe), n (%)	15 (35.7)
Brazil, n (%)	12 (28.6)
Argentina, n (%)	1 (2.4)
South Africa, n (%)	3 (7.1)
Race/ethnicity
Black or African American, n (%)	30 (71)
Caucasian/White, n (%)	10 (24)
Other, n (%)	2 (5)
Concomitant medications at third trimester
pharmacokinetic evaluation
Zidovudine, n	3
Lamivudine, n	14
Emtricitabine, n	25
Tenofovir, n	37
Lopinavir, n	1
Median CD4⁺ T-cell count at delivery, cells/μl (range); n	521 (166–975); 28
Median delivery plasma HIV-1 RNA concentration, copies/ml (range); n	40 (20–628); 30
Undetectable <400 copies/ml, n (%)	29 (96.7)
Undetectable <50 copies/ml, n (%)	26 (86.7)
Pregnancy outcome^a
Median gestational age at delivery, weeks (range); n	38.9 (32–41); 33
Median infant birth weight, g (range); n	3,162 (1,875–4,365); 40

Average data for twins was used and twins count as one infant demographic.

Efavirenz pharmacokinetics

In total, 15, 42 and 40 women completed second trimester, third trimester and postpartum pharmacokinetic sampling. The median efavirenz concentration versus time curves are shown in Figure 1 and efavirenz pharmacokinetic parameters during each of these three sampling periods are presented in Table 2. When comparing second and third trimester with postpartum, AUC_0–24 did not differ significantly and the 90% CI for the AUC_0–24 GMR was within the 0.80 to 1.25 range for the second trimester and just outside the range (0.90–1.32) for the third trimester. C₂₄ and C_min were statistically significantly lower in the third trimester than postpartum but C12 was not significantly lower. Efavirenz C_max was higher in the third trimester than postpartum. The 90% CI for C₂₄ and C_min were just outside the 0.80–1.25 range, while C12 was within the range. The 90% CIs for C_max were within the 0.80–1.25 range for the second trimester and C_max was higher than postpartum in the third trimester (1.01–1.56). One participant had extremely low post-partum concentrations. In a sensitivity analysis excluding this participant's data, the third trimester 90% CIs for the C₂₄, C_min and C_max GMRs all excluded 1.0 (GMR 0.84 [90% CI: 0.78,0.89] for C₂₄, 0.78 [0.65,0.93] for C_min and 1.12 [1.03,1.21] for C_max); the CI for C_max was within the 0.80 to 1.25 range but the CI for C₂₄ and C_min extended below 0.80, indicating that a clinically important decrease in C₂₄ and C_min could not be ruled out.

Table 2

Maternal efavirenz pharmacokinetic parameters

Parameter	2T (n=15)	2T versus PP (n=14)		3T (n=42)	3T versus PP (n=40)		PP (n=40)
Parameter	2T (n=15)	GMR (90% CI)	P-value	3T (n=42)	GMR (90% CI)	P-value	PP (n=40)
AUC_0-24, μg•h/ml	47.30 (40.10–79.70)	0.94 (0.85, 1.03)	0.241	60.02 (42.96–85.40)	1.09 (0.90, 1.32)	0.837	62.70 (43.75–87.51)
C_max, μg/ml	3.87 (2.82–5.67)	1.05 (0.94, 1.18)	0.296	5.13 (3.62–5.90)	1.26 (1.01, 1.56)	0.007^a	4.41 (3.38–5.79)
C_min, μg/ml	1.47 (0.96–2.23)	0.86 (0.76, 0.97)	0.104	1.36 (1.059–2.57)	0.86 (0.68, 1.10)	0.010^a	1.60 (1.19–2.67)
C_{12 h}, μg/ml	1.69 (1.37–3.12)	0.89 (0.81, 0.97)	0.119	1.99 (1.50–3.02)	1.00 (0.83, 1.21)	0.071	2.21 (1.72–3.27)
C_{24 h}, μg/ml	1.49 (1.14–2.23)	0.87 (0.78, 0.97)	0.079^a	1.48 (1.10–2.61)	0.92 (0.77, 1.09)	0.01^a	1.94 (1.28–3.09)
CL/F, l/h	12.69 (7.53–14.96)	1.07 (0.97, 1.18)	0.104	10.00 (7.03–14.00)	0.91 (0.76, 1.11)	0.691	9.59 (6.86–13.72)
T_1/2, h	27.82 (16.95–34.98)	0.66 (0.47, 0.93)	0.191	32.71 (25.22–49.14)	0.96 (0.82, 1.12)	0.285	34.67 (25.40–59.62)
n (%) above	12/15 (80.0)			33/41(80.5)			34/40 (85)
10th percentile
non-pregnant AUC

Data are median (IQR) unless otherwise indicated. ^aP<0.10, Wilcoxon signed rank test. AUC, area under the curve; CL/F, apparent oral clearance; C_max, maximum plasma concentration; C_min, minimum plasma concentration; C_{12 h}, 12-h post-dose concentration; C_{24 h}, 24-h post-dose concentration; GMR, geometric mean ratio; PP, postpartum; T_1/2, half-life; 2T, second trimester; 3T, third trimester.

Figure 1

Median concentration versus time curves for efavirenz (600 mg once daily) during the 2T, 3T and PP

Median third trimester and postpartum geometric mean AUCs were 60.0 and 62.7 μg•h/ml, respectively, compared to historical control AUC of 67.2 μg•h/ml after 600 mg dosing [18]. Median second trimester AUC was lower (47.3 μg•h/ml), with high variation (range, 30.8–138.4 μg•h/ml), comparable to AUC after 400 mg efavirenz dosing in historical controls of 49.2 μg•h/ml [18]. Median C_max during pregnancy and post-partum were comparable to that seen in historical data (3.67 μg/ml) [18]. Efavirenz C₂₄ was lower during pregnancy compared to postpartum. The median postpartum C₂₄ of 1.94 μg/ml was equivalent to that seen in non-pregnant adults [18].

Individual efavirenz AUC and C₂₄ during second trimester, third trimester and postpartum are presented in Figure 2. Efavirenz AUC_0–24 was below the study target (10th percentile for non-pregnant adults) in 3/15 women (20%) during the second trimester, in 8/42 women (19%) during the third trimester and in 6/40 (15%) during the postpartum period. No women had an efavirenz C₁₂ (mid-dose) below the proposed target of 1.0 μg/ml during the second trimester or third trimester of pregnancy. The proportion of women with a C₂₄ below 1.0 μg/ml were 2/15 (13%), 7/42 (17%) and 3/40 (8%) during second trimester, third trimester and postpartum, respectively.

Figure 2

Individual efavirenz AUC and C_{24 h} for women using 600 mg once daily, during the second trimester, third trimester and postpartum

Seventeen pairs of maternal and cord blood were collected at delivery. Median (range) maternal plasma efavirenz concentrations at delivery were 1.43 μg/ml (0.68 to 5.95) and 0.95 μg/ml (0.40–3.99) was obtained in the cord blood; the median ratio of cord blood to maternal blood was 0.67 (range, 0.36–0.95). In 23 infants whose pharmacokinetic samples were obtained after birth, the median efavirenz C_max was 1.2 μg/ml (range, 0.5–3.5) at median 20.2 h (range, 2.5–165.2) after birth. Concentrations at 9 days of life are shown in Figure 3 and Table 3. At the final washout sample (between 5–9 days of life) 22 samples assayed still had measurable efavirenz (above 0.039 μg/ml). The median (IQR) infant efavirenz half-life was 65.6 h (40.6–128.7). None of the mothers were breastfeeding.

Table 3

Efavirenz infant washout after delivery

Characteristic	Total n (n=23); median (Q1, Q3)
T_1/2, h	18; 65.6 (40.6, 128.7)
C_max, μg/ml	22; 1.2 (0.9, 1.5)
T_max, h after birth	20; 20.2 (6.3, 45.4)
Concentration at 2-10 h after birth, μg/ml	18; 1.1 (0.8, 1.5)
Concentration at 18-28 h after birth, μg/ml	21; 1.0 (0.8, 1.2)
Concentration at 36-72 h after birth, μg/ml	20; 0.9 (0.6, 1.4)
Concentration at 5-9 days after birth, μg/ml	22; 0.4 (0.2, 0.9)

C_max, maximum plasma concentration; T_max, time to maximum plasma concentration; T_1/2, half-life.

Figure 3

Infant washout: efavirenz concentration versus time after birth

Maternal and infant HIV status and safety

At delivery, 29 out of 30 (96.7%) women had HIV-1 RNA viral load less than 400 copies/ml and 26 of 30 (86.7%) women had viral load below 50 copies/ml. Seven women experienced adverse events grade 3 or greater: one case of premature rupture of membranes and preterm delivery, three cases of pregnancy-induced hypertension, two cases of postpartum haemorrhage, one pyelonephritis, one case of acute liver failure. This participant presented with fulminant hepatitis and was using efavirenz for 7 months before the event. She received a liver transplant and changed her antiretroviral regimen with good outcome. This event was considered as possibly related to efavirenz.

Two congenital abnormalities were reported and were judged by the study team as possibly related to efavirenz: bilateral ulnar postaxial polydactyly and oedema of penis head. Grade 3 or greater adverse events were reported for 8 infants and included prematurity, neonatal sepsis, urinary tract infection, low glucose, respiratory distress and congenital syphilis. At 6 months of age, 30 infants were confirmed HIV-negative and the infection status for 11 infants was indeterminate or pending results. Infant characteristics at birth are described in Table 1.

Discussion

Achieving optimal antiretroviral drug exposure during pregnancy is critical to obtain maximal viral load suppression to prevent HIV mother-to-child transmission. Efavirenz-based regimens have been widely used during pregnancy in several countries. We found that standard efavirenz dosing of 600 mg once daily during the second and third trimesters among women with wide racial diversity provides an exposure similar to that during the early postpartum period and historical controls of non-pregnant adults. The necessity to assess antiretroviral exposure during pregnancy is highlighted by several studies showing reduced drug exposure with standard doses. Longer gastrointestinal emptying/transit times, reductions in gastric acid secretions, increases in body water, plasma volume, fat stores, and hepatic/ renal blood flow, temporal changes in hepatic metabolizing enzyme activities are among the physiological changes during pregnancy that can potentially impact drug disposition. However, in our study, efavirenz median AUC during the second and third trimesters were not different from postpartum and were similar to that reported in non-pregnant adults [19], exposure in the second trimester was within the 0.80–1.25 range, exposure in the third trimester was similar, or even higher than postpartum (90% CI 0.90, 1.32). C₂₄ concentrations during the second and third trimester pregnancy were lower compared to postpartum but were similar to the C₂₄ concentrations seen in the ENCORE1 study with the equally potent dose of 400 mg [18].

Efavirenz readily crossed the placenta in our participants, with a median ratio of cord blood to maternal concentration of 67%. Median half-life in neonates in our study was 65.6 h (8.7 to 245), which is over twice that of maternal participants. This may be related to metabolic processes that are often immature at birth, which can lead to a reduced clearance and a prolonged half-life for drugs where cytochrome P450 enzyme metabolism is a primary route for elimination, such as efavirenz [20]. The prolonged neonatal washout elimination of efavirenz may contribute to the efficacy of neonatal prophylaxis against HIV transmission with infant efavirenz dosing in the first weeks of life and make it difficult to precisely determine breast milk transfer of efavirenz during this period. There was a small observed increase in neonatal plasma concentration in some infants following delivery. One explanation for this could be the rapid loss of water and relative increase in albumin (and drug) levels, with a corresponding drop in the fraction of unbound drug. Such temporal changes could lead to a transient increase in total plasma concentrations in neonates following delivery. Infant washout pharmacokinetic data has not been previously described. This information may be helpful to design an efavirenz-based intervention for infants who might benefit from initiation of therapy shortly after birth.

A major strength of our study is the ability to perform within-participant comparisons during pregnancy and postpartum. Efavirenz AUC was not clinically significantly lower during pregnancy. C_max was higher during the third trimester compared to postpartum, whereas C₂₄ was lower during second and third trimester compared to postpartum, but these effects were similar to or above the exposure and C₂₄ observed in the ENCORE1 study. Another strength of this study is the combination of data from the PANNA and P1026s studies, which provided a sample with wide geographic diversity, including women from South America, USA, South Africa and European countries. A limitation of our study is that our sample size was too small to allow assessment of the impact of maternal and infant genetic variation on maternal and neonatal efavirenz exposure, as had been demonstrated in nursing mothers and their breastfed infants [21]. Another weakness is that the opportunistic recruitment of women who were already taking efavirenz selects women who are responding to and not experiencing adverse effects from this regimen at the time of enrolment. This selection bias overestimates positive outcomes and underestimates adverse events. Some of the women in the study experienced adverse events, including one who developed acute liver failure that required a liver transplant. Mild liver toxicity with resolution after stopping therapy is described in few women using efavirenz but fulminant hepatitis rarely occurred [22,23].

In summary, although efavirenz exposure did not fall in the bioequivalence ranges, exposure in pregnancy was sufficient, as third trimester AUCs were similar to non-pregnant AUCs. C₂₄ efavirenz concentrations were marginally lower during pregnancy, but exposures were deemed sufficient to meet the therapeutic target during pregnancy and no dose adjustment is needed. Standard 600 mg daily efavirenz dosing during pregnancy is adequate to obtain high rates of viral suppression and prevent HIV mother-to-child transmission.

Footnotes

The authors declare no competing interests.

Additional file 1: A list of the staff from the centres participating in the PANNA and IMPAACT networks can be found at

Acknowledgements

We thank the patients for participating in the studies and the laboratory personnel at the Laboratory of the Department of Pharmacy of the Radboud university medical center, Nijmegen, the Netherlands for analysing the pharmacokinetic samples. We thank the staff from the centres participating in the PANNA network (see Additional file 1).

The PANNA network is supported by the European AIDS Treatment Network, The European Commission, DG Research, Sixth Framework program, contract LSHP-CT-2006-037570, Bristol-Myers Squibb, Merck Sharp & Dohme Corp. and Janssen Research. Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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