Raltegravir, an integrase strand transfer inhibitor antiretroviral agent, is recommended as a preferred regimen for initial therapy in nonpregnant HIV-infected adults.1 Because data are limited on its use in pregnancy, raltegravir is recommended for use in special circumstances in pregnancy, such as when women have resistance or intolerance to more commonly used agents.2 Most reports are of raltegravir use in late pregnancy because of its rapid viral load reduction.3–6
Data on drug exposure in pregnant women receiving raltegravir and placental transfer are currently very limited. Croci et al7 reported a trough level of raltegravir of 0.21 μg/mL in the third trimester in 1 patient, compared with median trough concentrations in a trial of nonpregnant adults of 0.029–0.118 μg/mL. Maternal plasma raltegravir at delivery was 0.19 μg/mL with cord:maternal ratio of 1.0.7 In another case report, the maternal trough level was 0.162 μg/mL, cord blood was 0.173 μg/mL, and a cord:maternal ratio of 1.06.6 In a case series from London, maternal levels near delivery ranged from 0.022 to 0.493 μg/mL 5 to 13 hours after maternal dosing, and levels in infant blood 1 to 3 hours after delivery ranged from 7 to 9 times higher than concomitant maternal levels.5 In a recent presentation on 28 women treated with raltegravir during pregnancy, the drug was well tolerated and 81% had undetectable HIV RNA at delivery.8 Maternal levels in 16 women were 0.169 μg/mL (0.010–0.270 μg/mL) at delivery. Median cord blood levels were 0.198 μg/mL (0.005–0.198 μg/mL) with a cord:maternal ratio of 3.48.8
No systematic pharmacokinetic study of raltegravir in pregnant women has been reported. The purpose of this study was to describe the pharmacokinetics of raltegravir in the second and third trimesters of pregnancy compared with postpartum.
International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network Protocol 1026s is a multicenter, prospective opportunistic study to evaluate the pharmacokinetics of antiretrovirals among HIV-infected pregnant women from the United States, Thailand, Brazil, Argentina, and Uganda (Clinicaltrials.gov Identifier: NCT00042289). This report includes women receiving raltegravir 400 mg twice daily.
HIV-infected pregnant women receiving standard dose raltegravir as part of clinical care before the beginning of the 35th week of pregnancy were eligible. Exclusion criteria were concurrent use of medications known to interfere with the absorption, metabolism, or clearance of raltegravir (carbamazepine, phenobarbital, phenytoin, rifampin, esomeprazole, lansoprazole, omeprazole, and rabeprazole), multiple gestation, or clinical or laboratory toxicity that would likely require a change in the medication regimen during the study. Local institutional review boards approved the protocol at all participating sites, and written informed consent was obtained from all subjects before participation. Subjects continued to take their prescribed medications throughout pregnancy. The choice of additional antiretrovirals was determined by the subject's physician, who prescribed all medications and remained responsible for clinical management throughout the study. Women continued on study until the completion of postpartum pharmacokinetic sampling.
For women enrolled during the second trimester of pregnancy, intensive raltegravir pharmacokinetics were determined in real time (within 2 weeks of receiving the samples in the pharmacology laboratory) between 20 and 26 weeks of gestation and repeated between 30 and 36 weeks of gestation. Women enrolling in the third trimester had pharmacokinetic sampling performed between 30 and 36 weeks of gestation. Pharmacokinetic sampling was repeated between 6 and 12 weeks of postpartum. The observed raltegravir trough (C12h) for each woman was compared with the raltegravir C12h in nonpregnant adult populations.9 Each subject's physician was notified of the subject's plasma concentrations and C12h within 2 weeks of sampling during pregnancy. If the C12h was below the estimated 10th percentile in nonpregnant adult populations (0.035 μg/mL),9 the physician was offered the option of discussing the results and possible dose modification with a study team pharmacologist.
Clinical and Laboratory Monitoring
HIV-related laboratory testing was performed at each study visit if not available as part of routine clinical care. Maternal clinical data used for this analysis were maternal age, ethnicity, weight, concomitant medications, CD4+ lymphocyte, and HIV RNA assay results. HIV RNA assays were performed locally and had lower limits of detection ranging from 20 to 400 copies per milliliter. Maternal clinical and laboratory toxicities were assessed through clinical evaluations (history and physical examination) and laboratory assays (liver transaminases, creatinine, blood urea nitrogen, albumin, bilirubin, and hemoglobin) on each pharmacokinetic sampling day, at delivery, and at 24-week postpartum. Infant birth weight, gestational age at birth, and HIV infection status were collected. Infants received physical examinations after birth; laboratory evaluations were done only if clinically indicated. 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 Experience was used to grade adverse events for study subjects (http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx). All toxicities were followed through resolution.
Subjects were stable on their antiretroviral regimen for at least 2 weeks before pharmacokinetic sampling. Seven plasma samples were drawn at the second trimester, third trimester, and postpartum pharmacokinetic evaluation visits, including predose, 1, 2, 4, 6, 8, and 12 hours after dosing. Women were required to fast for 2 hours before and 2 hours after the observed raltegravir dose to minimize the variability of the pharmacokinetic parameters. Information collected included the time of the 2 previous doses, the 2 most recent meals, and maternal height and weight. A single maternal plasma sample and an umbilical cord sample after cord clamping were collected at delivery.
Raltegravir concentrations were measured at the University of California, San Francisco Clinical Pharmacology Laboratory using a validated liquid chromatography tandem mass spectrometry method. The lower limit of quantitation was 0.010 μg/mL. The interassay coefficient of variation was 7.12% at the lower limit of quantitation and ranged from 3.36% to 6.95% of coefficient of variation for low, middle, and high controls. Overall recovery from plasma was 96.3%.
The predose concentrations (Cpredose), maximum plasma concentration (Cmax), corresponding time (Tmax), minimum plasma concentration (Cmin), and 12-hour postdose concentration (C12h) were determined by direct inspection. For concentrations below the assay limit of detection, a value of one-half of the detection limit was used in summary calculations. AUC0–12 during the dose interval (from time 0–12 hours postdose) was estimated using standard noncompartmental methods. Apparent clearance (CL/F) from plasma was calculated as dose divided by AUC0–12. The terminal slope of the curve (λZ) was estimated from the last 2 measurable and declining concentrations between 8 and 12 hours postdose. Half-life was calculated as dose divided by λZ, and apparent volume of distribution (Vd/F) was determined by CL/F divided by λZ.
Target enrollment was at least 12 second trimester subjects and 25 third trimester subjects with evaluable pregnancy and postpartum raltegravir pharmacokinetic assessments. To prevent ongoing enrollment of subjects receiving potentially inadequate dosing, early stopping of enrollment was to be considered if 6 of the first 25 study subjects had third trimester raltegravir C12 below the estimated 10th percentile for the nonpregnant historical controls. The statistical rationale for this early stopping criterion has been previously described.10
Descriptive statistics were calculated for pharmacokinetic parameters of interest during each study period. Raltegravir pharmacokinetic parameters during the second trimester versus third trimester and postpartum and during the third trimester versus postpartum were compared at the paired within-subject level using the Wilcoxon signed-rank test, with a P value <0.05 considered to indicate statistical significance. The Spearman rank correlation test was used to evaluate the relationship between covariates, such as weight, with raltegravir area under the curve (AUC). The Wilcoxon signed-rank test was used to compare raltegravir AUC between ethnic groups.
Forty-two women were enrolled, with 16 completing second trimester sampling between 20 and 26 weeks of gestation, 41 completing third trimester sampling between 34 and 41 weeks, and 38 completing sampling at 3–14 weeks of postpartum. The clinical characteristics of the women and their pregnancy outcomes are shown in Table 1. The majority of the women were of African descent and from the United States. Half of the women were on regimens of 2 or more nucleoside reverse transcriptase inhibitors only with raltegravir, whereas the remaining women were on regimens including drugs from at least 3 classes of antiretrovirals. Sixteen (94%) of the 17 women on raltegravir with only nucleosides were on their first antiretroviral regimen compared with 9 (39%) of 23 on regimens with drugs from 3 or more classes (P < 0.001). Two women were taking concomitant ritonavir-boosted atazanavir, which can increase raltegravir exposure. At least 90% of women had HIV RNA levels below 400 copies per millimeter in the third trimester and at delivery. All infants were at least 36 weeks of gestation at delivery. None of the infants were confirmed to be infected; thus far, 34 are HIV uninfected and 8 are indeterminate or pending further testing. Seven infants had congenital anomalies, but no major anomalies were judged to be related to raltegravir use based on timing of exposure and family history.
Raltegravir was well tolerated, with grade 3 or 4 toxicities noted in 4 women, including fever in 1, hypertension and shortness of breath in 1, gum pain and face/scalp rash in 1, and elevated amylase, drainage from the abdominal cesarean delivery incision, uterine pain, and vaginal bleeding in another. None of these were judged to be treatment related. Moderate (grade 2) possibly treatment-related findings included transient liver transaminase elevations in 1 subject and intermittent vomiting in another subject.
Raltegravir pharmacokinetic parameters at each sampling interval are presented in Table 2, and raltegravir concentrations versus time at each interval are shown in Figure 1. Six (38%) of 16 women in the second trimester, 13 (32%) of 41 women in the third trimester, and 5 (13%) of 38 women postpartum had delays in absorption of raltegravir, defined as a 1-hour postdose concentration lower than the predose concentration. Cmax ranged from 0.365 to 5.960 μg/mL in the second trimester, from 0.315 to 7.820 μg/mL in the third trimester, and from 0.312 to 12.600 μg/mL postpartum. Eleven (69%) of 16 subjects studied during the second trimester exceeded the target raltegravir C12h of at least 0.035 μg/mL, compared with 33 (80%) of 41 third trimester subjects, and 30 (79%) of 38 postpartum subjects. The trough concentration was significantly lower in the second trimester compared with postpartum, and the peak concentration was significantly lower in the third trimester compared with postpartum. C12h and other pharmacokinetic parameters were quite variable, and their variability increased from second to third trimester and into the postpartum period. Cmin during the second trimester ranged from below the quantifiable limit (BQL) to 0.162 μg/mL, in the third trimester from BQL to 0.607 μg/mL, and from BQL to 0.917 μg/mL postpartum. No significant differences were found between the second and third trimester parameters in a paired comparison including 16 women with sampling at both times.
Median AUC0–12 was significantly lower in the second (6.6 μg·h/mL) and third trimester (5.4 μg·h/mL) of pregnancy compared with postpartum (11.6 μg·h/mL). AUC0–12 showed wide variability, ranging from 2.1 to 18.5 μg·h/mL during the second trimester, 1.4–35.6 μg·h/mL during the third trimester, and 1.6–39.9 μg·h/mL postpartum. No significant difference in oral clearance, half-life, and volume of distribution between pregnancy and postpartum sampling was detected.
One subject taking concomitant atazanavir/ritonavir had trough concentrations above the target in the third trimester and postpartum. The other subject taking atazanavir/ritonavir had trough concentrations above the target in the second trimester and postpartum, but below the target during the third trimester. Weight inversely correlated with raltegravir AUC during the third trimester (Spearman ρ = −0.490, P = 0.002) and postpartum (Spearman ρ = −0.346, P = 0.033) but not significantly during the second trimester (Spearman ρ = −0.365, P = 0.164). No significant difference in raltegravir AUC was detected when the 2 largest ethnic groups represented in our sample, Black non-Hispanic subjects (n = 22) and Hispanic subjects (n = 16), were compared.
The median maternal raltegravir level at delivery was 0.140 μg/mL, and the median cord blood level was 0.154 μg/mL. The median cord/maternal ratio was 1.5. Maternal delivery and cord blood raltegravir concentrations and their ratio are plotted as a function of the time interval between maternal dosing and delivery in Figure 2.
Raltegravir was well tolerated in pregnancy with no treatment-related grade 3 or 4 adverse events. Although numbers are too limited to rule out uncommon adverse events, ours is the largest series to date of raltegravir use in pregnancy. Previous reports have been generally reassuring,7,8 although 1 case report of markedly elevated liver transaminases in a pregnant woman started on raltegravir in late pregnancy suggest that until larger experience is gained with use in pregnancy, women should be monitored frequently for symptoms and laboratory abnormalities when starting raltegravir.11 Half of the women in our study were on raltegravir with only 2 nucleoside agents as concomitant therapy, almost exclusively on their first antiretroviral regimen. Raltegravir may have been chosen in these cases for its tolerability in nonpregnant adults or because of the need for concomitant therapy such as rifampin that would interact with protease inhibitors.2 In the other half of subjects, women were on multiclass regimens including drugs from at least 3 classes of agents, usually having been treated with previous regimens, and raltegravir was being used to provide an additional novel mechanism of activity. Even including women with multiple previous treatments, 92% of all women had undetectable HIV RNA levels at delivery.
Raltegravir exposure was reduced during pregnancy, with median AUC being approximately 50% lower during the second and third trimesters than in the same women postpartum. The C12h of raltegravir was below the target level in more than 10% of women at each sampling time, including postpartum. Furthermore, in about a third of women during pregnancy, the raltegravir concentration continued to decline after a dose (indicating an absorption lag), compared with about 10% of women postpartum. However, the C12h was also quite variable, ranging from 0.0114 to 1.340 μg/mL. This finding is consistent with raltegravir pharmacokinetic data in nonpregnant adults. In the Raltegravir Early therapy in African-Americans Living with HIV (REAL) study, Wohl et al12 found the median concentration at 12 hours after dosing to be 0.091 μg/mL with a range of 0.010–1.386 μg/mL. Despite the wide variability, 95% of subjects had an HIV RNA level below 200 copies per milliliter by week 4 of treatment.12 In the QDMRK trial comparing once-daily to twice-daily dosing, the trough level with twice-daily dosing was 0.128 μg/mL with a range of 0.015–1.074 μg/mL.13 In this trial, trough levels correlated with virologic response with once-daily dosing, but not with twice-daily dosing. Analysis of pharmacokinetic and viral response data from the BENCHMRK 1 and 2 trials also showed considerable variability in raltegravir plasma concentrations and little relationship between raltegravir concentrations and virologic response.14 Given the high rate of virologic response in this study, the large variability in raltegravir plasma concentrations seen in nonpregnant adults, and the lack of a clear relationship between raltegravir concentrations and virologic effect, we do not recommend a change in dosing from the 400 mg twice-daily standard dose in nonpregnant adults.
Women in this study were on a wide range of concomitant antiretroviral agents, with 49% on protease inhibitors, usually with ritonavir boosting. Raltegravir is primarily metabolized by uridine diphosphate glycosyltransferase (UGT) 1A1. Its pharmacokinetics is minimally affected by concomitant administration of ritonavir, a potent inhibitor of cytochrome P450 3A enzymes, and efavirenz, an inducer of cytochrome P450 enzymes.15 In contrast, raltegravir concentrations have been shown to be modestly increased when administered to patients receiving atazanavir, a known inhibitor of UGT1A1 activity.16 In our study, 2 women received atazanavir in addition to raltegravir, and their raltegravir exposures were not out of the range seen in the other subjects.
Median cord blood raltegravir concentrations were higher than concomitant maternal concentrations at delivery, with a median ratio of 1.5, suggesting high placental transfer. Previous studies of 1–16 subjects have found ratios of 1.0–3.48.6–8 In a study evaluating maternal levels near delivery and infant levels 1–3 hours after delivery, infant levels were 7–9 times higher than maternal levels.5 The high placental transfer suggests that raltegravir could provide pre-exposure prophylaxis against HIV exposure in the fetus before and during delivery.
Based on these data and other reports, raltegravir offers another option for treatment of HIV-infected pregnant women. For pregnant women requiring medications such as rifampin with significant interactions with protease inhibitors, raltegravir offers a significant advantage. For pregnant women with resistance or incomplete virologic response to nonnucleoside reverse transcriptase inhibitors or protease inhibitors, raltegravir offers an attractive alternative or additional drug. In addition, studies have demonstrated more rapid decrease in HIV RNA levels with raltegravir compared with efavirenz, suggesting that raltegravir may be advantageous for rapidly reducing viral load before delivery in HIV-infected women who start antiretroviral therapy late in pregnancy.17 A study (IMPAACT P1081, ClinicalTrials.gov Identifier: NCT01618305) comparing viral decay with initiation of raltegravir, lopinavir/ritonavir and efavirenz regimens in the third trimester of pregnancy is underway. As experience with raltegravir use in pregnancy increases, this agent may become a recommended first-line agent for pregnant women.
The authors acknowledge 2802 New Jersey Medical School CRS (Linda Bettica, RN; Charmane Calilap-Bernardo, MA, PNPC; Arlene Bardeguez, MD, MPH); 3801 Texas Children's Hospital CRS (Shelley Buschur, RN, CNM; Chivon Jackson, RN, BSN, ADN; Mary Paul, MD); 4201 University of Miami Pediatric Perinatal HIV/AIDS CRS (Claudia Florez, MD; Patricia Bryan, BSN, MPH; Monica Stone, MD); 4601 University of California San Diego Mother-Child-Adolescent Program CRS (Andrew D. Hull, MD; Mary Caffery, RN, MSN; Stephen A. Spector, MD); 4701 Duke University Medical Center CRS (Joan Wilson, RN, BSN, MPH; Julieta Giner, RN, ACRN; Margaret A. Donnelly, PA-C); 5013 Jacobi Medical Center Bronx NICHD CRS (Mindy Katz, MD; Raphaelle Auguste, RN; Andrew Wiznia, MD); 5017 Seattle Children's Hospital NICHD CRS (Jane Hitti, MD, MPH; Corry Venema-Weiss, ARNP; Joycelyn Thomas, RN); 5018 University of South Florida–Tampa NICHD CRS (Karen L. Bruder, MD; Gail Lewis, RN; Denise Casey, RN); 5023 Washington Hospital Center NICHD CRS (Rachel Scott, MD; Patricia Tanjutco, MD; Vanessa Emmanuel, BA); 5048 University of Southern California School of Medicine–Los Angeles County NICHD CRS (Françoise Kramer, MD; LaShonda Spencer, MD; James Homans, MD); 5052 University of Colorado Denver NICHD CRS (Emily Barr, CPNP, CNM, MSN; Jenna Wallace, MSW; Torri Metz, MD); 5072 Hospital dos Servidores Rio de Janeiro NICHD CRS (Esau C. Joao, MD, PhD; Plinio Tostes Berardo Carneiro da Cunha, MD, PhD; Camile Medeiros Braga, MD); 5082 Hospital General de Agudos Buenos Aires NICHD CRS (Marcelo H. Losso, MD; Silvina A. Ivalo, MD; Alejandro Hakim, MD); 5093 Miller Children's Hospital NICHD CRS (Jagmohan Batra, MD; Tempe Chen, MD; Janielle Jackson Alvarez, RN); 5098 Hospital Santa Casa, Porto Alegre, Brazil NICHD CRS (Regis Kreitchmann, PhD, MD; Debora Fernandes Coelho, MN, PhD; Marcelo Comerlato Scotta, MSc, MD); 6501 St Jude CRS (Katherine M. Knapp, MD; Nina Sublette, FNP, PhD; Thomas Wride, MS); 6701 The Children's Hospital of Philadelphia (Steven D. Douglas, MD; Carol A. Vincent, PhD, CRNP; Samuel Parry, MD); 6901 Bronx-Lebanon Hospital CRS (Jenny Gutierrez, MD; Mary Elizabeth Vachon, MPH; Murli Purswani, MD).
2. Panel on Treatment of HIV
-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV
-1-infected women for maternal health and interventions to reduce perinatal HIV
transmission in the United States. Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf
. Accessed January 30, 2014.
3. Westling K, Pettersson K, Kaldma A, et al.. Rapid decline in HIV
viral load when introducing raltegravir
-containing antiretroviral treatment late in pregnancy
. AIDS Patient Care STDS. 2012;26:714–717.
4. Jaworsky D, Thompson C, Yudin MH, et al.. Use of newer antiretroviral agents, darunavir and etravirine, with or without raltegravir
, in pregnancy
: a report of two cases. Antivir Ther. 2010;15:677–680.
5. Mckeown DA, Rosenvinge M, Donaghy S, et al.. High neonatal concentrations of raltegravir
following transplacental transfer in HIV
-1 positive pregnant women. AIDS. 2010;24:2416–2418.
6. Pinetti C, Baroncelli S, Villani P, et al.. Rapid HIV
-RNA decline following addition of raltegraivr and tenofovir to ongoing active antiretroviral therapy in a woman presenting with high-level HIV
viraemia at week 38 of pregnancy
. J Antimicrob Chemother. 2010;65:2050–2052.
7. Croci L, Trezzi M, Allegri MP, et al.. Pharmacokinetic and safety of raltegravir
. Eur J Clin Pharmacol. 2012;68:123–132.
8. Jeantils V, Messaouden H, Carbillon L. Pregnancy
and a regimen containing raltegravir
: a pilot study on the materno-foetal safety. Paper presented at: The 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12, 2013; Denver, CO, Abstract H-1463.
10. Stek AM, Mirochnick M, Capparelli E, et al.. Reduced lopinavir exposure during pregnancy
. AIDS. 2006;20:1931–1939.
11. Renet S, Closon A, Brochet MS, et al.. Increase in transaminase levels following the use of raltegrair in a woman with a high HIV
viral load at 35 weeks of pregnancy
. J Obstet Gynaecol Can. 2013;35:68–72.
12. Wohl DA, Dumond JB, Blevins S, et al.. Raltegravir pharmacokinetics
in treatment-naive patients is not influenced by race: results from the raltegravir
early therapy in African-Americans living with HIV
(REAL) study. Antimicrob Agents Chemother. 2013;57:784–788.
13. Eron JJ Jr, Rockstroh JK, Reynes J, et al.; The QDMRK Investigators. Raltegravir
once daily or twice daily in previously untreated patients with HIV
-1: a randomised, active-controlled, phase 3 non-inferiority trial. Lancet Infect Dis. 2011;11:907–915.
14. Wenning L, Hwang E, Nguyen BY, et al.. Pharmacokinetic/pharmacodynamics (PK/PD) analyses for raltegravir
(RAL) in phase III studies in treatment experienced HIV
-infected patients following 48 weeks of treatment. Paper presented at: The 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Infectious Disease Society of America Meeting; October 28, 2008, Washington, D.C. Abstract H4054. Available at: http://www.abstractsonline.com/viewer/SearchResults.asp
. Accessed February 3, 2014.
15. Iowamoto M, Wenning LA, Petry AS, et al.. Minimal effects of ritonavir and efavirenze on the pharmacokinetics
. Antimicrob Agents Chemother. 2008;52:4338–4343.
16. Iowamoto M, Wenning LA, Mistry GC, et al.. Atazanavir modestly increased plasma levels of raltegraivr in healthy subjects. Clin Infect Dis. 2008;47:137–140.
17. Andrade A, Rosenkranz Sl, Cillo AR, et al.; AIDS Clinical Trials Group A5248 Team. Three distinct phases of HIV
-1 RNA decay in treatment-naive patients receiving raltegravir
-based antiretroviral therapy: ACTG 5248. J Infect Dis. 2013;208:884–891.
Keywords:© 2014 by Lippincott Williams & Wilkins
HIV; pregnancy; raltegravir; pharmacokinetics