The number of women of reproductive age living with HIV infection is increasing in worldwide and many of these women desire to have children.1–3 As guidelines evolve to initiate treatment at higher CD4 T-cell levels, the number of pregnant HIV-infected women receiving antiretroviral therapy can be expected to increase.4 The use of combination antiretroviral therapy during pregnancy has reduced the HIV transmission rate from approximately 20%–30% to <2% in developed countries.5,6 However, physiologic changes occurring during pregnancy can greatly alter the pharmacokinetics of antiretroviral drugs.7 Plasma concentrations of most protease inhibitors (PIs) have been reported to decrease during pregnancy.8–19 Increased doses are sometimes needed to ensure maintenance of virologic suppression in pregnancy with atazanavir, lopinavir/ritonavir (RTV), and saquinavir. This underscores the importance of optimizing treatment choices during pregnancy so as to prevent mother-to-child HIV transmission (p-MTCT) while minimizing the risks to both the mother and fetus.
The primary objective of this study was to assess the pharmacokinetics of fosamprenavir (FPV) boosted by RTV in pregnancy in the second and third trimesters compared with postpartum and to determine the transplacental transfer via cord blood/maternal amprenavir (APV) ratios.
Eligible participants were women age 18 years or older, HIV-infected as confirmed by western blot or HIV-1 viral load, who had an intrauterine pregnancy and had received FPV/RTV for at least 14 days before study entry. Individuals were excluded if they were intolerant or allergic to FPV, had a history of nonadherence, received concomitant drugs known to significantly interact with FPV or RTV, or had severe hepatic impairment. The FPV/RTV regimen could include any nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone.
This was a prospective, single-center, open-label, nonrandomized, single-arm study of on FPV/RTV 700/100 mg twice daily for p-MTCT. The participants meeting inclusion criteria who consented for enrollment were followed from their second or third trimester (depending on week of gestation at study entry) through week 12 postpartum. The protocol and informed consent were approved by the New York University School of Medicine Institutional Review Board and approved by the Office of Clinical and Health Services Research at New York City Health and Hospital Corporation Central Office.
Demographic, clinical, immunologic, virologic parameters, and self-reported adherence were documented at enrollment and at each visit. Pharmacokinetic (PK) evaluations were performed at the clinical research center of the NYU-HHC Clinical and Translational Science Institute. The participants were assessed for adverse events, anemia, renal function via glomerular filtration rate, and hepatic function every 2 months and again at least 4 weeks postpartum.20 The delivery mode and any complications relating to delivery were documented. Virologic and serologic testing of infants was performed at delivery, 3, 6, and 12 months.
Intensive 12-hour PK sampling for analysis of APV and RTV concentrations was performed during the second and third trimesters of pregnancy and again at least 4 weeks postpartum. Blood samples were collected at time 0, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose. All plasma samples, including maternal and umbilical cord plasma collected at delivery to assess APV transplacental transfer, were stored at −70°C pending bioanalysis for APV and RTV.
The bioanalytical method used for the determination of APV and RTV in human plasma was validated using a high-performance liquid chromatography assay with tandem mass spectrometric detection. Bioanalyses were performed at the GlaxoSmithKline reference laboratory. The accuracy (% bias) values calculated from the quality control samples ranged from −1.8% to 2.8% for APV, and from −3.1% to 1.4% for RTV. The overall precision (% coefficient of variation) calculated from the quality control samples was ≤4.2% for both APV and RTV.
Pharmacokinetic and Statistical Analysis
Plasma APV and RTV PK parameters were estimated by noncompartmental analysis of concentration–time data using WinNonlin Professional (version 5.2). The geometric mean and 95% confidence intervals (CIs) were computed for area under the plasma concentration versus time curve over 12-hour postdose (AUC), maximum plasma concentration (C max) and concentration at 12 hours postdose (C 12). A within-subject analysis was conducted using plasma PK parameter values for AUC, C max, and C 12. Estimated means were log transformed and expressed as geometric least-square (GLS) mean ratios and the associated 90% CI on the original scale to compare APV and RTV parameters from the second and third trimesters to postpartum values. Within-subject GLS mean ratios were computed using SAS PROC MIXED (version.9.2).
Subject Characteristics and Outcomes
Between February 2009 and May 2010, 10 women were screened, enrolled, and followed from their second or third trimester through week 12 postpartum. Five of the women were Black/African American, and the remaining 5 were of Hispanic ethnicity. The median age at the time of pregnancy was 29 years (range 19–38 years), and median CD4 T-cell count at the start of the p-MTCT regimen was 354 cells per cubic millimeters. There was 1 dizygotomous twin pregnancy included in this study.
All 10 women received FPV/RTV as prescribed by their primary care providers for p-MTCT. The most common NRTI backbone coadministered with FPV/RTV was the fixed-dose combination of tenofovir/emtricitabine, used by 7 of the 10 subjects. Two subjects used zidovudine/lamivudine and 1 received abacavir/lamivudine as a dual NRTI backbone. The subjects initiated FPV/RTV during pregnancy at a median of 19 weeks gestation (range, 6–31 weeks), including 2 women who initiated therapy in the third trimester after presenting to care relatively late in pregnancy. Nine women were treatment experienced, 6 of whom had previously discontinued antiretroviral therapy postpartum in accordance with historical treatment guidelines. Four had undetectable HIV-1 RNA viral loads (<50 copies per milliliter) at the time of initiation of the FPV/RTV regimen for p-MTCT, including 1 woman who was an elite controller having an undetectable viral load in the absence of antiretroviral treatment. One subject conceived while on a fully suppressive FPV-containing regimen. Of the 6 genotypes sent for resistance testing, 3 women had documented minor PI mutations. All 3 women with resistance mutations had an L63P and 2 had an A71 V/T mutation.
Six subjects completed the second-trimester 12-hour PK study and 9 completed both the third-trimester and postpartum PK analysis, respectively. The geometric mean APV AUC0–12 was 26.0, 30.1, and 39.9 μg·h/mL, respectively, for each progressive phase of pregnancy, consistent with those observed in other nonpregnant individuals receiving FPV/RTV 700/100 mg twice daily22 (Table 1). APV PK parameters were significantly lower in both the second trimester and third trimester when compared with postpartum. Compared with postpartum, geometric mean APV AUC0–12, C max, and C 12 were 35%, 37%, and 36% lower in the second trimester, respectively, and 25%, 19%, and 38% lower in the third trimester. Geometric means C 12 for all pregnancy phases were 9- to 15-fold above the mean APV protein-adjusted IC50 of 0.146 μg/mL for wild-type HIV strains (Fig. 1). Second-trimester RTV AUC0–12 was approximately one-third that observed postpartum and less than half that seen during the third trimester.
In 7 infant cord blood samples, the mean (SD) umbilical cord APV blood concentration was 0.11 (0.07) μg/mL. The maternal plasma concentration at delivery was 0.43 (0.29) μg/mL. APV GLS mean ratio (95% CI) of fetal cord to maternal peripheral plasma concentration was 0.267 (0.241, 0.297).
One woman with a history of nephrolithiasis before pregnancy developed pyelonephritis during week 34 of gestation. Another woman developed a transient asymptomatic grade 3 transaminitis after receiving nitrofurantoin for a urinary tract infection. Her liver function tests rapidly returned to her normal baseline upon nitrofurantoin discontinuation while maintaining FPV/RTV as part her p-MTCT regimen. No changes in baseline hemoglobin or renal function based on glomerular filtration rate were noted in any subject. No subject met criteria for delivery via C-section for p-MTCT. At delivery, 9 subjects had HIV-1 viral loads <50 copies per milliliter, and 1 subject had a viral load of 111 copies per milliliter. All 11 infants born were HIV-1 RNA polymerase chain reaction negative at birth and remained so at 3, 6, and 12 months. Three infants (2 from the dizygotomous twin gestation) had low-birth weight (<2500 g). All infants met the WHO infant growth standards for height and weight at 3, 6, and 12 months postpartum.
FPV, the phosphoester prodrug of the PI amprenavir (APV), is approved for use in treatment-naive and treatment experienced HIV-infected individuals. APV is predominantly eliminated by the hepatic microsomal enzyme CYP3A4 and a substrate for an inducer of the efflux transporter P-glycoprotein.21,22 To date, little data have been published about the pharmacokinetics or safety of FPV during pregnancy.23–26 Second-trimester pharmacokinetics of APV after FPV administration have never been investigated.
The pharmacokinetics of FPV and magnitude of reduction in third-trimester APV plasma concentrations that we observed in pregnant HIV-infected women in our study were comparable with those reported by Capparelli et al.24 APV exposure seemed to be lower during the second trimester than during the third trimester, although wide CIs that included 1 limited conclusion of statistical difference between the 2 stages of pregnancy. Lower RTV exposures and, hence, less boosting of APV concentrations in the second trimester relative to third trimester may have produced the trend for reduced APV PK parameters observed in the second semester.
Despite lower APV PK parameters during pregnancy relative to postpartum values, HIV-1 RNA was <200 copies per milliliter in all mothers at delivery and CD4 counts were stable throughout the study, suggesting that APV exposures were sufficient to maintain viral suppression, particularly given the fact that 9 mothers were treatment experienced at enrollment.
The mean ratio of cord blood/maternal APV concentration was 0.27, suggesting that transplacental transfer of APV is higher than that reported for other PI.8,12,13,19,27,28 The mean umbilical cord blood concentration of 0.11 μg/mL seen in our study is within the range of the mean protein binding-adjusted IC50 for wild-type HIV (0.146 μg/mL), suggesting that APV cord concentrations may contribute to the prevention of HIV transmission to the fetus.
The FPV/RTV was well tolerated by both mother and infant consistent with the results of a previous study.26 There has been no association with FPV use in pregnancy and an increased risk of birth defects.29 The rate of birth defects for infants exposed to FPV in utero is 2.42%, similar to that of the general population of 2.72% reported by the Centers for Disease Control and Prevention.30
Our limited study demonstrated that the standard twice-daily FPV/RTV 700/100-mg regimen provided adequate APV exposure during the second and third trimesters of pregnancy. The observed reduction in APV concentrations seemed not to be clinically significant because all women remained virologically suppressed during the study, and no cases of vertical HIV transmission occurred. Transplacental passage of APV with the FPV/RTV regimen was relatively high compared with that reported for most other PIs. The regimen was well tolerated in both mothers and infants, with no reports of drug-related adverse events. The pharmacokinetics, safety, and efficacy results we observed suggest that dose adjustment is not required for FPV/RTV twice-daily administration during pregnancy. Close virologic monitoring is suggested with the use of FPV, as with the use of any PI, for p-MTCT in women with significant PI mutations.
The authors thank the study participants for their participation. GlaxoSmithKline contributed to protocol development, serum drug concentration determination, and statistical analysis and had no influence on interpretation of data. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the US Government. The authors give special thanks to outreach coordinator Luis A. Vargas for his contributions to the success of this study.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
fosamprenavir; pharmacokinetics; pregnancy; HIV