JAIDS Journal of Acquired Immune Deficiency Syndromes:
Efavirenz Pharmacokinetics During the Third Trimester of Pregnancy and Postpartum
Cressey, Tim R. PhD*,†,‡; Stek, Alice MD§; Capparelli, Edmund PharmD‖; Bowonwatanuwong, Chureeratana MD¶; Prommas, Sinart MD#; Sirivatanapa, Pannee MD**; Yuthavisuthi, Prapap MD††; Neungton, Chanon MD‡‡; Huo, Yanling PhD§§; Smith, Elizabeth MD‖‖; Best, Brookie M. PharmD, MAS‖; Mirochnick, Mark MD¶¶; For the IMPAACT P1026s Team
*Program for HIV Prevention and Treatment (IRD URI 174), Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
†Harvard School of Public Health, Department of Immunology & Infectious Diseases, Boston, MA, USA
‡Institut de Recherché pour le Développement (IRD), UMI 174-Program for HIV Prevention and Treatment, Marseille, France
§University of Southern California School of Medicine, Department of Obstetrics and Gynecology, Los Angeles, CA
‖University of California San Diego School of Medicine and Skaggs School of Pharmacy & Pharmaceutical Sciences, San Diego, CA
¶Chonburi Hospital, Department of Internal Medicine, Chonburi, Thailand
#Bhumibol Adulyadej Hospital, Department of Obstetrics and Gynecology, Bangkok, Thailand
**Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand
††Prapokklao Hospital, Department of Obstetrics and Gynecology, Chantaburi, Thailand
‡‡Siriraj Hospital, Department of Obstetrics and Gynecology, Bangkok, Thailand
§§Statistical & Data Analysis Center, Harvard School of Public Health, Department of Immunology & Infectious Diseases, Boston, MA, USA
‖‖National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD
¶¶Boston University School of Medicine, Boston, MA.
Correspondence to: Tim R. Cressey, PhD, Program for HIV Prevention and Treatment Institut de Recherché pour le Développement-Program for HIV Prevention and Treatment 174 Department of Medical Technology, Faculty of Associated Medical Sciences, Department of Medical Technology, 6th Floor, 110 Inthawaroros Road, Muang Chiang Mai 50200, Thailand (e-mail: firstname.lastname@example.org).
Supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and #1 U01 AI068616 with the International Maternal Pediatric Adolescent AIDS Clinical Trials Group Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C). Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group was provided by the National Institute of Allergy and Infectious Diseases (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health (AI068632)
Presented at the 18th Conference on Retroviruses and Opportunistic Infections (CROI), February 27 to March 02, 2011, Boston, MA. Astract #754.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health.
The authors have no conflicts of interest to disclose.
The members of the IMPAACT P1026s team are listed in Appendix I.
Received August 31, 2011
Accepted November 1, 2011
Background: The impact of pregnancy on efavirenz (EFV) pharmacokinetics is unknown.
Methods: International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is an on-going, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving 600 mg EFV once daily as part of combination antiretroviral therapy. Intensive steady-state 24-hour blood sampling was performed during the third trimester and at 6–12 weeks postpartum. Maternal and umbilical cord blood samples were drawn at delivery. Pharmacokinetics targets were the estimated 10th percentile EFV area under the curve (AUC) in nonpregnant historical controls (40.0 mcg·hr−1·mL−1) and a trough concentration of 1 mcg/mL.
Results: Twenty-five women were enrolled during the third trimester: median (range) age was 29.3 (18.9–42.9) years, weight 69.0 (40–130) kg, and gestational age 32.9 (30.1–38.7) weeks. Median (range) EFV AUC0–24, Cmax, and C24 hours were 55.4 mcg·hr−1·mL−1 (13.5-220.3), 5.4 mcg/mL (1.9–12.2), and 1.6 mcg/mL (0.23–8.13), respectively. EFV AUC and Cmax did not differ during pregnancy and postpartum but C24 hours was lower during the third trimester (1.6 vs. 2.1 mcg/mL, P = 0.01). During the third trimester, 5 of 25 (20%) women had an EFV AUC below the target and 3 of 25 (12%) had a trough concentration below 1 mcg/mL. EFV cord blood/maternal concentration ratio was 0.49 (0.37–0.74). All women had a HIV-1 RNA viral load less than 400 copies per milliliter at delivery and 19 (76%) had a viral load below 50 copies per milliliter. One child was perinatally HIV infected. Three women were exposed to EFV throughout the first 6 weeks of pregnancy. EFV was well tolerated, and among the 25 infants, no congenital anomalies or newborn complications were reported.
Conclusions: Changes in EFV pharmacokinetics during pregnancy compared with postpartum are not sufficiently large enough to warrant a dose adjustment during pregnancy.
The use of combination antiretroviral drugs regimens during pregnancy for HIV/AIDS treatment and/or the prevention of mother-to-child transmission of HIV are increasing after the rapid scale-up of antiretroviral treatment programs. Recently, the World Health Organization updated its HIV treatment guidelines to include efavirenz (EFV) as a nonnucleoside reverse transcriptase inhibitor option for treatment-naive HIV-infected pregnant women after the first trimester. The restriction of EFV use during the first trimester is based on several case reports of congenital neural tube defects with first trimester exposure to EFV,1,2 which led the United States Food and Drug Administration to classify EFV as a Class D drug (evidence of human fetal risk). As a consequence, EFV use in HIV-infected women of reproductive age trying to conceive or not using effective contraception is also not recommended.3
To date, the impact of pregnancy on EFV pharmacokinetics (PKs) is unknown. Physiological changes during pregnancy can significantly impact drug disposition. EFV is primarily metabolized by the hepatic cytochrome 2B6 enzyme (CYP2B6),4 and temporal changes in hepatic drug-metabolizing enzyme activities occur during pregnancy.5 Several antiretroviral drugs metabolized via the hepatic cytochrome P450 enzymes have reduced exposure during pregnancy, particularly during the third trimester.6,7
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 resistance. Thus, given the uncertainty regarding EFV drug exposure using the standard dose during pregnancy, our aim was to investigate the PKs of EFV during the third trimester of pregnancy and in the early postpartum period.
MATERIALS AND METHODS
International Maternal Pediatric Adolescent AIDS Clinical Trials Network Protocol 1026s is an ongoing, multicenter, nonblinded, prospective study to evaluate the PKs of antiretrovirals among pregnant HIV-infected women (ClinicalTrials.gov Identifier: NCT00042289). This report includes women receiving EFV 600 mg once daily.
For women enrolled in the United States, P1026s is a substudy of P1025, a prospective cohort study of HIV-infected pregnant women receiving care at sites (NCT00028145).
Eligibility criteria for this EFV arm of P1026s were as follows: initiating the standard dose of EFV (600 mg, once daily) as part of clinical care before the beginning of the 35th week of gestation. Exclusion criteria were as follows: concurrent use of medications known to interfere with the absorption, metabolism, or clearance of EFV; multiple gestation pregnancy; and clinical or laboratory toxicity that, in the opinion of the site investigator, would likely require a change in the medication regimen during the study. Local institutional review boards approved the protocol at all participating sites and signed informed consent was obtained from all subjects before participation. Subjects continued to take their prescribed medications until postpartum blood sampling was completed. The choice of additional antiretrovirals and duration of treatment (ie, continuation of ARV treatment) was determined by the subject'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.
Women were enrolled during the third trimester. PK sampling was performed between 30 and 36 weeks gestation and between 6 and 12 weeks postpartum. EFV area under the concentration versus time curve (AUC0–24) was calculated for each woman and compared with the EFV AUC0–24 in nonpregnant adult populations.8 Each subject's physician was notified of the subject's plasma concentrations and AUC0–24 within 2 weeks of sampling. If the AUC0–24 was below the 10th percentile in nonpregnant adult populations (40.0 mcg·hr−1·mL−1), the physician was offered the option of discussing the results and possible dose modifications with a study team pharmacologist.
Clinical and Laboratory Monitoring
Maternal data accessed were as follows: maternal age, ethnicity, weight, concomitant medications, CD4 cells count, and plasma viral load assay results. Plasma viral load assays were performed locally at laboratories certified by the National Institute of Allergy and Infectious Diseases Virology Quality Assurance program. Maternal clinical and laboratory toxicities were assessed through clinical evaluations (history and physical examination) and laboratory assays (ALT, AST, creatinine, BUN, albumin, bilirubin, hemoglobin) on each PK sampling day and at delivery. Infant data included birth weight, gestational age at birth, and HIV infection status. Infants received physical examinations at 24–48 hours, 4–21 days, and 24 weeks after delivery. The study team reviewed toxicity reports on monthly conference calls, although the subject's physician was responsible for toxicity management. The Division of AIDS/National Institute of Allergy and Infectious Diseases Toxicity Table for Grading Severity of Adult Adverse Experiences was used to report adverse events for study subjects.9 All toxicities were followed through resolution.
Subjects were stable on their antiretroviral regimen for at least 2 weeks before PK sampling. Eight plasma samples were drawn at the third trimester and at the postpartum PK evaluation visits, starting immediately before an oral EFV dose and at 1, 2, 4, 6, 8, 12, and 24 hours postdose. EFV was given as an observed dose on an empty stomach (at least 1 hour before or 2 hours after a meal). Other information collected included the time of the 2 prior doses, the 2 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.
EFV plasma drug concentrations were measured using a validated reversed-phase high-performance liquid chromatography method with ultraviolet detection at 245 nm. This high-performance liquid chromatography method was validated over the concentration range of 0.78–10 mcg/mL. Plasma samples with EFV concentrations >10 mcg/mL were diluted and reassayed. The average accuracy was 91%–104% and precision (interassay and intra-assay) was <12% of the coefficient of variation. Overall extraction recovery from plasma was 99%. Plasma samples collected from women enrolled in Thailand were assayed at the Institut de Recherché pour le Développement-Program for HIV Prevention and Treatment laboratory at the Faculty of Associated Medical Sciences, Chiang Mai University, and samples collected from women enrolled in the United States were assayed at the Pediatric Clinical Pharmacology Laboratory at the University of California, San Diego. Both pharmacology laboratories participate in the AIDS Clinical Trial Group (University at Buffalo, NY), Pharmacology Quality Control (Precision Testing) program, which performs standardized interlaboratory testing twice a year.10
The predose concentration (Cpredose), maximum plasma concentration (Cmax), corresponding time (Tmax), minimum plasma concentration (Cmin), and 24-hour postdose concentration (C24 hours) were determined by direct inspection. AUC0–24 during the dose interval (from time 0 to 24 hours postdose) for EFV was calculated using the trapezoidal rule. Apparent clearance (CL/F) from plasma was calculated as dose divided by AUC0–24.
Target enrollment was at least 25 women with evaluable third trimester EFV PKs. To prevent ongoing enrollment of subjects receiving inadequate dosing, enrollment was to be stopped early if 6 study subjects had third trimester EFV AUC0–24 below the estimated 10th percentile for the nonpregnant historical controls (40.0 mcg·hr−1·mL−1). The statistical rationale for this early stopping criterion has been previously described.7 The number of subjects with AUC below 40.0 mcg·hr−1·mL−1 and trough concentration below 1 mcg/mL, the suggested minimum target trough concentration, were determined during pregnancy and postpartum.3,11 EFV PK parameters during the third trimester and postpartum were compared at the within-subject level using 90% confidence limits for the geometric mean ratio of AUC0–24, Cmax, and C24 hours. When the true geometric mean of the ratio (the antilog of the true mean of the log ratios) of the PK parameters for pregnant and nonpregnant conditions has a value of 1, this indicates equal geometric mean PK parameters for the pregnant and nonpregnant conditions. If the 90% confidence intervals (CIs) are entirely outside the limits (0.8 to 1.25), the PK parameters for the pregnant and nonpregnant conditions are considered different. If, on the other hand, the 90% confidence limits are entirely within the limits (0.8 to 1.25), the parameters are considered equivalent. If the 90% CI overlaps with (0.8 to 1.25), these data alone do not support any conclusions. Wilcoxon signed-rank test was used to assess the difference between third trimester and postpartum PK parameters. Descriptive statistics were calculated for PK parameters of interest during each study period.
Twenty-five HIV-infected pregnant women, 21 Thai and 4 American, were enrolled. The clinical characteristics of the study population at the antepartum, delivery, and 6–12 weeks postpartum visits are presented in Table 1. The majority of women initiated EFV after the first trimester of pregnancy. The median duration of EFV use at study entry (between 30 and 36 weeks gestation) was 6.7 weeks (interquartile range: 3.9–10.1). All 25 infants were live born, and the median (range) birth weight was 3000 g (2300–4070).
All 25 women completed both the third trimester and postpartum PK sampling. Antepartum PK assessments were performed at a median (range) gestational age of 33 weeks (30–39) and postpartum sampling at 7.9 weeks (2.0–14.1) after delivery. Median (±interquartile range) EFV concentration versus time curves for the 25 HIV-infected women receiving 600 mg of EFV once daily during the third trimester and postpartum are shown in Figure 1.
EFV PK parameters during the third trimester and postpartum are presented in Table 2. The EFV AUC0–24 and Cmax were not significantly different during the third trimester compared with postpartum. EFV oral clearance (CL/F) was significantly higher during the third trimester compared with postpartum and the EFV concentration 24 hours after the dose (C24 hours) was also significantly reduced during the third trimester compared with postpartum (1.6 vs. 2.1 mcg·hr−1·mL−1, P = 0.0105). The 90% confidence limits (90%CI) for the geometric mean ratio of the EFV PK parameters during the third trimester and postpartum (antepartum/postpartum ratios) are also presented in Table 2. The median (range) EFV AUC and C24 hours were 54.5 mcg·hr−1·mL−1 (29.2–220.3) and 1.42 mcg/mL (0.7–8.1), respectively, for the 21 women enrolled in Thailand and 108.1 mcg·hr−1·mL−1 (13.5–177.6) and 1.26 mcg /mL (0.3–6.3), respectively, for the 4 women enrolled in the United States.
Individual EFV AUC and C24 hours during the third trimester and postpartum are presented in Figure 2. EFV AUC0–24 was below the study target (10th percentile for nonpregnant adults) in 5 women (20%) during the third trimester and 4 women (16%) during the postpartum period, with 3 women below the target at both time points (Table 2). Three women (12%) had an EFV C24 hours below the recommended efficacy threshold of 1.0 mcg/mL (0.23, 0.70, and 0.86 mcg/mL, Fig. 2) during the third trimester. During the postpartum period, 2 women had an EFV C24 hours below 1.0 mcg/mL (0.31 and 0.66 mcg/mL, Fig. 2). Of note, the women with the lowest C24 hours during pregnancy also had the lowest C24 hours postpartum. Three women with low EFV exposure during the third trimester had a dose increase to 800 mg once daily and PK sampling repeated and the EFV AUC increased to above the 10th percentile in 1 of the 3 women. Four women had EFV AUC0–24 >140 mcg−1·h−1·mL during the third trimester.
Twenty-five pairs of maternal delivery and cord blood samples were collected. Two pair of maternal/cord blood samples had no detectable concentrations of EFV and were excluded. The median time interval between the last dose of EFV and delivery was 15.1 (4.0–24.7) hours. Maternal plasma EFV concentrations were 2.24 mcg/mL (0.99–7.57) at delivery and 1.05 mcg/mL (0.47–4.51) in the cord blood. The median ratio of cord blood/maternal delivery EFV concentration was 0.49 (0.37–0.74). Maternal delivery and cord blood EFV concentrations and their ratios are plotted as a function of the time interval between maternal dosing and delivery in Figure 3. At delivery, all 25 women had a HIV-1 RNA viral load less than 400 copies per milliliter and 19 of 25 women (76%) had a viral load below 50 copies per milliliter (4 subjects had 238, 215, 114, and 81 copies/mL; 2 subjects were reported as <400 and <80 copies/mL).
Infant HIV Status and Safety
At 6 months of age, 22 infants were confirmed HIV negative, 1 infant was confirmed HIV infected, and the infection status for 2 infants were indeterminate. Both infants with indeterminate HIV status had HIV DNA polymerase chain reaction negative results at 1 and 2 months of age and were presumed uninfected by the clinical care provider.
Clinical and laboratory information for the mother of the infected child are summarized below: antiretroviral naive, started ZDV/3TC/EFV at 29 weeks 1 day gestation; CD4 cell count was 198 cells per cubic millimeter; and HIV-1 RNA viral load was 100,021 copies per milliliter (no viral resistance testing was performed). Intensive PK sampling was performed at 32 weeks gestation and her EFV AUC and C24 hours were 69.7 mcg·hr−1·mL−1 and 1.6 mcg/mL, respectively, both above the study targets, and her HIV-1 viral load had decreased to 1536 copies per milliliter. The baby was born at 37 weeks gestation by vaginal delivery (9.5 hours after membrane rupture). Maternal HIV-1 viral load at delivery was 238 copies per milliliter and EFV was detectable in the cord blood (0.89 mcg/mL). Infant prophylaxis included a single dose of nevirapine administered within 50 minutes of life and zidovudine for 1 week after delivery. Maternal postpartum PK sampling was performed 9 weeks after delivery and her EFV AUC and C24 hours were comparable with those during the third trimester (59.3 mcg·hr−1·mL−1 and 1.5 mcg/mL, respectively). Her HIV-1 viral load results were 73 and <40 copies per milliliter at 9 and 24 weeks postpartum. The mother reported that the infant was formula fed. The infant's HIV DNA polymerase chain reaction was negative at 2 and 10 days of life but positive at 1 and 2 months.
EFV was tolerated well. There were 2 cases of premature rupture of membranes, 1 case of preterm labor, and 1 case of gestational diabetes mellitus in the study population. Three women experienced adverse events (appendicitis, pleural effusion, 2 days fever); none were attributed to the maternal EFV treatment. Four women were exposed to EFV during the first trimester. Three women were receiving EFV before becoming pregnant and 2 of them continued to receive EFV throughout the first trimester, although one women stopped EFV approximately 6 weeks after becoming pregnant but restarted EFV during the third trimester. One woman started EFV toward the end of the first trimester. The median duration of exposure during the first trimester was 73 days (12–98). No congenital anomalies or newborn complications were reported.
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 HIV treatment guidelines now includes EFV-based combination antiretroviral therapy as a preferred first-line regimen for treating HIV-infected pregnant women after the first trimester. We found that standard EFV dosing of 600 mg once daily during the third trimester of pregnancy provides an exposure similar to that postpartum and in historical controls of nonpregnant 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.12 EFV is metabolized via the hepatic cytochrome P450 enzymes, raising concerns regarding the risk of under exposure during pregnancy. However, in our study, EFV AUC during the third trimester (55.4 mcg·hr−1·mL−1) was very similar to that reported in nonpregnant adults (58.1 mcg/hr/mL). Several women had an EFV drug exposure below the study target threshold of 40 mcg·hr−1·mL−1 (10th percentile in nonpregnant adults), but this proportion was not above that expected within a nonpregnant population.
A major strength of the current study design is the ability to perform within-subject comparisons during pregnancy and postpartum. EFV AUC and Cmax were not significantly different during pregnancy and postpartum. Although EFV CL/F was increased and Cpredose and C24 hours were decreased during pregnancy compared with postpartum, the magnitude of the differences does not seem 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−1·mL−1 and a C24 hours of 0.23 mcg/mL during pregnancy, which is well below the expected range in nonpregnant women; her AUC antepartum/postpartum ratio of 0.56 was the largest change after delivery, suggesting that poor drug adherence before 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 EFV 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 EFV 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 EFV dose increase based on plasma drug concentration data should be taken on an individual basis. By study design, the EFV dose was reduced to the standard dose immediately after 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 EFV concentrations are similar to those in nonpregnant adults.
Among the other nonnucleoside reverse transcriptase inhibitors, PK 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 to 1.02).13 More recently, in a study of Ugandan pregnant women receiving nevirapine-based antiretroviral therapy, the nevirapine AUC and C12 hours was reduced by 20% during the during the third trimester compared with postpartum.14 In a preliminary report on the PKs of the newer nonnucleoside reverse transcriptase inhibitor etravirine in 4 women, etravirine exposure during the third trimester was similar to that in nonpregnant adults.15
Host genetic polymorphisms can impact the PKs of antiretroviral drugs.16 The homozygous variant allele of the CYP2B6 516G>T gene polymorphism is associated with higher EFV exposure17 and the frequency of this allele varies between different ethnic populations, ranging from 3.4% in whites, 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.18 Four women (16%) in our study had relatively high EFV exposures with AUC ranging from 146 to 220 mcg·hr−1·mL−1, consistent with the 516 TT genotype.
To date, EFV use in HIV-infected women during pregnancy and women of childbearing potential has been limited due to concerns of congenital neural tube defects after 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 EFV.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 EFV first trimester exposure.19 One of these reported defects was a neural tube defect (neural tube closes by about 4 weeks after conception). Sufficient numbers of EFV 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 nonsignificant relative risk of 0.87 for overall birth defects among women exposed to EFV during the first trimester of pregnancy compared with exposure to other antiretroviral drugs.20 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 EFV exposure in the first trimester. Three of the 25 women enrolled in the current study were exposed to EFV throughout the first 6 weeks of pregnancy, and no congenital anomalies or newborn complications were reported.
EFV readily crosses the placenta in animal studies. Maternal and fetal blood concentrations in pregnant rabbits and cynomolgous monkeys are equivalent, whereas in pregnant rats, fetal concentrations exceeded maternal concentrations.21 In our subjects, the median ratio of cord blood to maternal blood EFV concentrations was 49%. This ratio is lower than that achieved after nevirapine exposure during pregnancy (∼93%) but higher than with protease inhibitors (normally below 20%).6,7,22 Although the EFV cord blood concentrations are below maternal concentrations throughout the dosing interval, virologically suppressive concentrations seem 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.23,24 Given the lack of impact of pregnancy of EFV 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 EFV oral clearance is increased and predose and trough concentrations are decreased during the third trimester compared with postpartum, EFV exposure during pregnancy after standard dosing seems adequate compared with historical data in nonpregnant adults and using within-subject antepartum/postpartum comparisons. With international and national antiretroviral treatment guidelines increasingly recommending EFV as an option in pregnant women after the first trimester, these data support the use of standard EFV dosing during pregnancy.
The authors wish to thank the women who participated in the protocol and the staff of the participating International Maternal Pediatric Adolescent AIDS Clinical Trials centers.
1. De Santis M, Carducci B, De Santis L, et al.. Periconceptional exposure to efavirenz and neural tube defects. Arch Intern Med. 2002;162:355.
2. Fundaro C, Genovese O, Rendeli C, et al.. Myelomeningocele in a child with intrauterine exposure to efavirenz. AIDS. 2002;16:299–300.
3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents Developed by the DHHS panel on antiretroviral guidelines for adults and adolescents—A Working Group of the Office of AIDS Research Advisory Council. Available at: http://aidsinfonihgov
. Accessed January 10, 2011.
4. Ward BA, Gorski JC, Jones DR, et al.. The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther. 2003;306:287–300.
5. Tracy TS, Venkataramanan R, Glover DD, et al.. Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancy. Am J Obstet Gynecol. 2005;192:633–639.
6. Mirochnick M, Best BM, Stek AM, et al.. Atazanavir Pharmacokinetics With and Without Tenofovir during Pregnancy. J Acquir Immune Defic Syndr. 2011;56:412–419.
7. Stek AM, Mirochnick M, Capparelli E, et al.. Reduced lopinavir exposure during pregnancy. AIDS. 2006;20:1931–1939.
8. Sustiva (Efavirenz) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company, 2007.
9. The Division of AIDS (DAIDS). Standardized toxicity table for grading severity of adult adverse experiences. Available at: http://rcc.tech-res-intl.com
. Accessed August 3, 1997.
10. Holland DT, DiFrancesco R, Stone J, et al.. Quality assurance program for clinical measurement of antiretrovirals: AIDS clinical trials group proficiency testing program for pediatric and adult pharmacology laboratories. Antimicrob Agents Chemother. 2004;48:824–831.
11. la PorteBack C, Back D, Blaschke T, et al.. Updated guideline to perform therapeutic drug monitoring for antiretroviral agents. Rev Antivir Ther. 2006;3:4–14.
12. Mirochnick M, Capparelli E. Pharmacokinetics of antiretrovirals in pregnant women. Clin Pharmacokinet. 2004;43:1071–1087.
13. Capparelli EV, Aweeka F, Hitti J, et al.. Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics. HIV Med. 2008;9:214–220.
14. Lamorde M, Byakika-Kibwika P, Okaba-Kayom V, et al.. Suboptimal nevirapine steady-state pharmacokinetics during intrapartum compared with postpartum in HIV-1-seropositive Ugandan women. J Acquir Immune Defic Syndr. 2010;55:345–350.
15. Izurieta P, Kakuda TN, Feys C, et al.. Safety and pharmacokinetics of etravirine in pregnant HIV-1-infected women. HIV Med. 2011;12:257–258.
16. Cressey TR, Lallemant M. Pharmacogenetics of antiretroviral drugs for the treatment of HIV-infected patients: an update. Infect Genet Evol. 2007;7:333–342.
17. Haas DW, Ribaudo HJ, Kim RB, et al.. Pharmacogenetics of efavirenz and central nervous system side effects: an Adult AIDS Clinical Trials Group study. Aids. 2004;18:2391–2400.
18. Chantarangsu S, Cressey TR, Mahasirimongkol S, et al.. Influence of CYP2B6 polymorphisms on the persistence of plasma nevirapine concentrations following a single intra-partum dose for the prevention of mother to child transmission in HIV-infected Thai women. J Antimicrob Chemother. 2009;64:1265–1273.
20. Ford N, Mofenson L, Kranzer K, et al.. Safety of efavirenz in first-trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. AIDS. 2010;24:1461–1470.
22. Moisan A, Desnoyer A, Bourgeois-Moine A, et al.. Placental transfer of antiretroviral drugs in HIV-infected women: a retrospective study from 2002 to 2009. Presented at: 11th International Workshop on Clinical Pharmacology of HIV Therapy. April 7–9, 2010; Sorrento, Italy.
23. Cressey TR, Jourdain G, Rawangban B, et al.. Pharmacokinetics and virologic response of zidovudine/lopinavir/ritonavir initiated during the third trimester of pregnancy. AIDS. 2010;24:2193–2200.
24. Ramautarsing RA, van der Lugt J, Gorowara M, et al.. Thai HIV-1-infected women do not require a dose increase of lopinavir/ritonavir during the third trimester of pregnancy. AIDS. 2011;25:1299–1303.
APPENDIX I IMPAACT P1026S TEAM
Team/Site Investigators—Study Team: Elizabeth Hawkins, Jennifer Read, Heather Watts, Sandra K. Burchett, Francesca Aweeka, Gonzague Jourdain, Steve Rossi, Michael Basar, Kathleen Kaiser, Emily Barr, Kenneth D. Braun, Jr, Jennifer Bryant, Kathleen A. Medvik, and Amy Jennings. Chonburi Hospital, Chonburi, Thailand (#8356): Nantasak Chotivanich, Suchat Hongsiriwon, Donyapattra Ekkomonrat, Ladda Argadamnuy, Kessarin Chaisiri, Suluck Soontaros, Prakit Yothipitak, Somrat Matchua, Duangporn Wiwattanasorn. Bhumibol Adulyadej Hospital, Bangkok, Thailand (#8355): Prapaisri Layangool Sommai Tratong, Marina Thitathan, Titima Taweewattanapan. Research Institute for Health Sciences, Chiang Mai University, Chiang Mai (#20101): Virat Sirisanthana, Linda Aurpibul, Chintana Khamrong, Nataporn Kosachunhanan, Watcharaporn Taeprajit, Jiraporn Chanthong. Prapokklao Hospital (#8354): Prapap Yuthavisuthi, Chaiwat Ngampiyaskul, Ubon Chanasit, Wanna Chamjamrat, Nuttupassasorn Tungtongcha, Pisut Greetanukroh, Pathanee Teirsonsern. Siriraj Hospital, Bangkok (#8251): Nirun Vanprapar, Kulkanya Chokephaibulkit, Orasri Wittawatmongkol, Wimon Anansakunwatt, Pilaipan Puthavathana, Kaewta Intalapaporn, Nantaka Kongstan, Pirom Noisumdaeng, Wanatpreeya Phongsamart, Pimpanada Chearskul, Karnchana Sriworakul, Yuitiang Durier, Sirijit Kanakool, Benjawan Khumcha. Seattle Children's Hospital and University of Washington (#5017): Corry Venema-Weiss, Joycelyn Thomas, Gloria Bowen, Lauren Asaba, Ann Melvin, Jane Hitti and Lisa Frenkel. University of Southern California (#5048): Françoise Kramer, LaShonda Spencer, James Homans and Andrea Kovacs. University of Miami Pediatric Perinatal HIV/AIDS CRS (#4201): Amanda Cotter, Gwendolyn B. Scott, Patricia Bryan, Claudia Florez. Institut de Recherché pour le Développement-Program for HIV Prevention and Treatment 174, Chiang Mai (#8351): Marc Lallemant, Gonzague Jourdain, Nicole Ngo-Giang-Huong, Pra-ornsuda Sukrakanchana, Kanchana Than-in-at, Nusara Krapunpongsakul, Renoo Wongsrisai, Patcharaporn Krueduangkam, Yardpiron Taworn, Pimpinun Punyati, Suriyan Tanasri. Cited Here...
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efavirenz; HIV; pregnancy; pharmacokinetics; prevention of mother-to-child transmission of HIV
© 2012 Lippincott Williams & Wilkins, Inc.
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