Impact of pregnancy on abacavir pharmacokinetics
Best, Brookie Ma; Mirochnick, Markb; Capparelli, Edmund Va; Stek, Alicee; Burchett, Sandra Kc; Holland, Diane Ta; Read, Jennifer Sf; Smith, Elizabethg; Hu, Chengchengd; Spector, Stephen Aa; Connor, James Da; the PACTG P1026s Study Team
From the aUniversity of California San Diego, San Diego, California
cChildren's Hospital Boston
dHarvard School of Public Health, Boston, Massachusetts
eUniversity of Southern California, Los Angeles, California
fPediatric, Adolescent, and Maternal AIDS Branch, NICHD, NIH, DHHS
gNIAID, Bethesda, Maryland, USA.
*See the Appendix for study members.
Received 13 September, 2005
Revised 18 October, 2005
Accepted 27 October, 2005
Correspondence to Dr B. Best, University of California San Diego, 200 West Arbor Drive, MC 8214, San Diego, California 92103–8214, USA. E-mail: email@example.com
Objective: To describe abacavir pharmacokinetics during pregnancy and postpartum; physiological changes during pregnancy are known to affect antiretroviral drug disposition.
Design: The Pediatric AIDS Clinical Trials Group P1026s study is an on-going, prospective, non-blinded pharmacokinetic study of pregnant women receiving one or more antiretroviral drugs for routine clinical care, including a cohort receiving abacavir 300 mg twice daily.
Methods: Serial plasma samples (predose, 1, 2, 4, and 6 h postdose) obtained antepartum (30–36 weeks of gestation) and again postpartum (6–12 weeks after delivery) were assayed for abacavir concentration by reversed-phase high-performance liquid chromatography.
Results: Antepartum evaluations were available for 25 women [mean age, 28.6 years (SD, 6); mean third-trimester weight 92 kg (SD, 35.4); and race/ethnicity 52% black, 28% Hispanic, 16% white, 4% Asian], with geometric mean abacavir area under the concentration–time curve (AUC) of 5.9 mg·h/l [90% confidence interval (CI), 5.2–6.8] and maximum plasma concentration (Cmax) of 1.9 mg/l (90% CI, 1.6–2.2). Seventeen women completed postpartum sampling, and the ratios of antepartum to postpartum AUC and Cmax were 1.04 (90% CI, 0.91–1.18) and 0.79 (90% CI, 0.65–0.98), respectively.
Conclusions: Abacavir AUC during pregnancy was similar to that at 6–12 weeks postpartum and to that for non-pregnant historical controls (5.8 mg·h/l). Consequently, pregnancy does not appear to affect overall abacavir exposure significantly or to necessitate dose adjustments.
HIV-1-infected pregnant women commonly receive antiretroviral drugs. Combination antiretroviral regimens of nucleoside or nucleotide analogue reverse transcriptase inhibitors (NRTI) and either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor are recommended for pregnant women requiring antiretroviral therapy for their own health. In addition, women who do not meet criteria for treatment for their own health commonly receive antiretroviral drugs for prevention of mother-to-child transmission of HIV-1 .
Physiological changes during pregnancy affect antiretroviral drug disposition. The resultant changes in pharmacokinetics must be understood to use these drugs safely and effectively during pregnancy. Increased antiretroviral exposure during pregnancy may cause increased maternal adverse events and fetal toxicity. Inadequate antiretroviral exposure during pregnancy may yield inadequate virological control, increasing the risk of developing drug resistance mutations and of transmitting HIV-1 to the infant. However, clinical trials to study the pharmacokinetics of antiretroviral drugs in pregnant women are difficult to perform, and few published studies are available.
Abacavir is an oral, synthetic, guanosine analogue NRTI frequently used in pregnancy with potent activity against HIV-1. In non-pregnant adults, it has demonstrated fairly linear pharmacokinetics, predictable and extensive absorption, and no significant circadian variability [2–8]. Abacavir is primarily metabolized by alcohol dehydrogenase and glucuronyl transferase to inactive metabolites, with no significant metabolism by the cytochrome P450 enzyme system. The pharmacokinetics and appropriate dosing of abacavir in non-pregnant, adult, HIV-1-infected patients are well defined. However, no published studies describe the pharmacokinetics of abacavir during pregnancy, and no evidence is available to support the assumption that standard dosing will provide adequate exposure throughout pregnancy.
The primary objectives of this study were to describe the pharmacokinetic parameters of abacavir in HIV-1-infected pregnant women and to determine if the standard dose of abacavir produces adequate drug exposure during pregnancy compared with historical data from non-pregnant adults and the same women in the study cohort during the postpartum period. A secondary objective was to compare abacavir concentrations in plasma from cord blood with those in maternal plasma at the time of delivery.
Study population and design
The Pediatric AIDS Clinical Trials Group (PACTG) study P1026s is a multicenter, on-going, prospective trial to evaluate the pharmacokinetics of currently prescribed antiretroviral drugs and interacting combinations of these drugs in pregnant HIV-1-infected women. Eligible patients were those who already were enrolled in the parent study (P1025), were receiving abacavir 300 mg orally twice daily as part of routine clinical care for at least 2 weeks prior to pharmacokinetic sampling, and were planning to continue abacavir until at least 6 weeks postpartum. P1025, the Perinatal Core Protocol, is a prospective cohort study designed to assess the effectiveness, safety of, and adherence to interventions prescribed for prevention of vertical transmission of HIV-1 and/or for pregnant women's health, and to provide a framework and specimen repository for substudies. Institutional review boards approved P1025 and P1026s at all participating sites and all subjects consented prior to participation. Exclusion criteria were multiple gestation pregnancies and clinical or laboratory toxicity that, in the opinion of the site investigator, would likely require a change in the antiretroviral regimen during the study. Patients continued to take their prescribed medications during the study unless changed by their clinical physician for reasons of toxicity, lack of effectiveness, or the results of the individual woman's antepartum pharmacokinetic evaluation. Women continued on study until completion of postpartum pharmacokinetic sampling.
Clinical and laboratory monitoring
Historical, demographic, clinical, and laboratory data were collected in P1025. Data accessed for P1026s included maternal age, ethnicity, concomitant antiretroviral medications, plasma HIV-1 RNA concentration (viral load) and CD4 cell count at time of P1026s enrollment, infant infection status, and infant gestational age, birth length and weight. Information collected in P1026s included the time and description of the two most recent meals, and height and weight on days of sampling. On each sampling day, patients underwent medical histories, physical examinations, and laboratory studies including measurements of alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, blood urea nitrogen, albumin, and hemoglobin. The study team reviewed toxicity reports on monthly conference calls. Adverse events were reported according to the Division of AIDS (DAIDS) standardized Toxicity Table for Grading Severity of Adult Adverse Experiences (August 1992; http://rcc.tech-res-intl.com). All toxicities were followed through to resolution.
Plasma samples (5 ml) for pharmacokinetic evaluation were collected at three evaluation times: antepartum (between 30 to 36 weeks of gestation), at delivery, and postpartum (between 6 to 12 weeks after delivery). Women who did not complete the antepartum evaluation were replaced in the study. Patients were receiving a stable antiretroviral regimen for at least 2 weeks prior to pharmacokinetic sampling. Subjects were instructed to take their abacavir at the same times each day for the 3 days prior to and the day of the ante- and postpartum pharmacokinetic evaluations. Five plasma samples were drawn at both the ante- and postpartum pharmacokinetic evaluation visits, starting immediately before the morning oral abacavir dose and at 1, 2, 4 and 6 h after the witnessed dose. To assess transplacental passage, abacavir was measured in single maternal plasma and an umbilical cord sample obtained at delivery.
Abacavir concentration assays
Abacavir concentrations were measured in the Pediatric Clinical Pharmacology Laboratory of the University of California, San Diego by a validated, reversed-phase high performance liquid chromatography method. The laboratory is registered with the ACTG Quality Assurance/Quality Control Proficiency Testing Program and successfully completed three rounds of proficiency testing for abacavir during the study period. The lower limit of detection for abacavir was 0.04 mg/l. The interassay coefficient of variation was 7.8% at the limit of detection and ranged from 1% to 8.7% for low, middle and high controls. Overall recovery from plasma was 102.9%.
The concentration data collected were analyzed by direct inspection to determine predose concentration, maximum plasma concentration (Cmax), the corresponding time (tmax), and the last measurable concentration (Clast). The area under the concentration–time curve (AUC) from time 0 to the time of the last measurable concentration (AUC0–last) for abacavir was estimated using the trapezoidal rule up to the last measurable concentration. The extrapolated area under the curve after the last measurable concentration was estimated as Clast/λz, where λz was the terminal slope of the curve. The AUC from time 0 to infinity (AUC0–∞) was calculated as AUC0–last + Clast/λz. Apparent clearance (CL/F) from plasma was calculated as dose divided by AUC0–∞. Half-life was calculated as 0.693/λz, and apparent volume of distribution (Vd/F) was determined by CL/F divided by λz. Both Vd/F and CL/F were also computed using a one-compartment model and maximum a-posteriori (MAP) Bayesian estimating algorithm with the program Adapt II . Pharmacokinetic parameters derived from each approach were compared to assess potential limitations of each methodology.
The study design incorporated a two-stage analysis approach. Each individual woman's abacavir exposure during pregnancy was determined in real time and compared with the 10th percentile AUC estimated from a published, non-pregnant, adult HIV-1-infected historical control population, and promptly reported to clinical providers. The clinical provider had the option to change the dose based on these pharmacokinetic results. An early stopping criterion was predefined as 6 of 25 women [(24%; exact 80% confidence limits (CI), 13–38] having AUC falling below the 10th percentile historical control AUC. These 80% CI values exclude 10%, showing 90% confidence that, if the stopping criterion is reached, the true percentage of pregnant women having AUC estimates below the 10th percentile for the non-pregnant population was > 10%. The goal was to prevent excess accrual to a cohort with known inadequate antiretroviral exposure.
Once all pharmacokinetic sampling had been completed on all subjects, antepartum and postpartum abacavir exposure measurements from each woman were compared using a repeated measures design. These comparisons were made at the within-subject level, using geometric mean ratios of antepartum to postpartum AUC and Cmax. When the true geometric mean ratio (the antilog of the true mean of the log ratios) of the pharmacokinetic exposure parameters for pregnant and non-pregnant conditions is 1, this indicates equal pharmacokinetic exposure parameters for the pregnant and non-pregnant conditions. The 90% CI of the geometric mean ratio was determined and a no-effect window was defined as 0.8–1.25. Therefore, if the entire 90% CI for the parameter mean ratio was within the range limits of 0.8 and 1.25, the pharmacokinetic exposure parameters for the pregnant and non-pregnant conditions were deemed to be equivalent . The magnitudes of difference in median values of AUC and Cmax ante- and postpartum also were assessed with the Wilcoxon signed-rank test. Descriptive statistics, including geometric least-squares means and 90% CI values, were calculated for pharmacokinetic parameters of interest at each study period.
P1026s enrolled 25 patients in the abacavir arm. Selected characteristics of study subjects are shown in Table 1. Antepartum pharmacokinetic visits occurred between June 2003 and December 2004. Seventeen women completed postpartum evaluations between August 2003 and December 2004. Six subjects self-discontinued abacavir prior to the postpartum visit, and two subjects were lost to follow-up. Nineteen patients were taking abacavir 300 mg in combination with zidovudine 300 mg and lamivudine 150 mg in a single tablet twice daily.
The target abacavir exposure was ≥ 4.1 mg·h/l, the estimated 10th percentile AUC from historical controls  and 22 of 25 patients (88%; 80% CI, 75–96) achieved this target during pregnancy. The three patients with AUC values below the target remained on the standard dose of 300 mg twice daily. The postpartum AUC values for these patients were below target as well. The antepartum concentration–time curves for each patient are shown in Fig. 1. Several patients who were enrolled in additional P1026s cohorts had samples drawn and assayed up until 12 h postdose. Most women had undetectable abacavir concentrations at the predose sample.
A summary of the pharmacokinetic parameters for abacavir ante- and postpartum is provided in Table 2. The percentage of AUC extrapolated beyond the observed sampling period (extrapolated AUC/total AUC) was 9.25% (SD, 10.4) antepartum and 4.9% (SD, 4.2) postpartum. The coefficients of variation for AUC, CL/F, and Vd/F ante- and postpartum were 36 and 48%, 46 and 64%, and 52 and 65%, respectively. The geometric mean ante-/postpartum AUC ratio was 1.04 (90% CI, 0.91–1.18) (Fig. 2). The CI value for the AUC ratio fell completely within the limits of 0.8 and 1.25, showing that the ante- and postpartum AUC values were not different. The ante-/postpartum Cmax ratio was 0.79 (90% CI, 0.65–0.98). The CI value for Cmax did not fall between 0.8 and 1.25, indicating that this evidence did not support an equivalent Cmax ante- and postpartum. Within-subjects comparisons of individual AUC and Cmax values ante- and postpartum were performed to explore further the differences between pregnancy and postpartum. This within-subjects comparison also showed no difference in AUC (P = 0.74) but a significant decrease in Cmax during pregnancy (P = 0.0277). Because the concentration at 6 h after dosing (C6h) appeared different, the geometric mean ante-/postpartum C6h ratio was also calculated, yielding 2.3 (90% CI, 1.5–3.6); the within-subjects comparison showed that C6h was significantly higher antepartum (P = 0.004) (Fig. 3). The median tmax was 1 h for both ante- and postpartum evaluations; however, 12 women in the third trimester had tmax > 1 h while only three women had tmax > 1 h postpartum.
The one-compartment analysis yielded similar abacavir exposure parameters to the non-compartmental analysis. The one-compartment mean ante- and postpartum CL/F values were 48.4 l/h (SD, 26.3) and 66 l/h (SD, 43), and the mean Vd/F values were 117.9 l (SD, 73) and 92.7 l (SD, 88.8), respectively.
Maternal plasma samples were collected at delivery for 20 patients, and umbilical cord blood samples were collected for 24 patients. Eight maternal delivery and 11 cord blood abacavir concentrations were < 0.04 mg/l (the limit of detection). The high frequency of undetectable abacavir concentrations was probably caused by prolonged time since prior dose administration. The median times after dose for detectable and undetectable maternal delivery samples were 11 and 16 h. The geometric mean cord blood concentration was 0.26 mg/l (90% CI, 0.13–0.52), and the maternal concentration at delivery was 0.26 mg/l (90% CI, 0.12–0.59). The geometric mean ratio of cord/maternal concentration in 10 paired patient samples with detectable concentrations was 1.06 (90% CI, 0.9–1.2).
Clinical monitoring and tolerability
Abacavir was well tolerated during pregnancy and postpartum with no subjects experiencing serious adverse events related to abacavir therapy. Of the six patients who discontinued abacavir prior to the postpartum pharmacokinetic evaluation, none indicated intolerability to abacavir as a reason for discontinuation. All subjects had viral loads < 400 copies/ml at the antepartum evaluation and at delivery. At the postpartum evaluation, viral loads were < 400 copies/ml in 12 patients, 580–1610 copies/ml in three patients, and were not obtained in two patients. All three patients with detectable viral loads postpartum had abacavir AUC values above the target at both the ante- and postpartum pharmacokinetic evaluations. Of the three women with low abacavir exposure, one did not provide a postpartum viral load, while the other two had viral loads < 400 copies/ml at the postpartum visit. CD4 cell counts at delivery were 697 cells/μl (SD, 371) (n = 25), and postpartum were 569 cells/μl (SD, 274) (n = 15). Of the 25 infants, 22 were not infected with HIV-1, and HIV-1 infection status was not known at the time of this analysis for the other three infants. Infants born to the three women with low abacavir exposure, and infants born to the three women with increased viral loads postpartum, were all uninfected with HIV-1. The infants were delivered at 38.4 weeks of gestation (SD, 1.5), with mean body weight of 3.18 kg (SD, 0.67) and mean length of 48.9 cm (SD, 3.4).
This is the first study describing abacavir pharmacokinetics in pregnant women. The results show that overall exposure to abacavir on standard doses is similar in pregnant and non-pregnant states. Eighty-eight percent of women achieved third trimester AUC values above the estimated 10th percentile for non-pregnant adults derived from AUC data reported in the medical literature. Third trimester and postpartum AUC in this cohort, 5.9 and 5.4 mg·h/l, respectively, are comparable to a previously reported AUC of 5.8 mg·h/l in 20 HIV-1-infected non-pregnant adults . Abacavir CL/F in this study (51 and 55 l/h, ante- and postpartum, respectively) was consistent with CL/F from published studies of this dose in non-pregnant adults, which ranged from 43.7 to 58 l/h [2–4]. Vd/F in this group of 99 and 101 liters ante- and postpartum, respectively, are within range of the somewhat disparate previously reported values of 68  and 154  liters, respectively. The variability noted in this group of pregnant subjects was greater than that reported in non-pregnant adults, who had AUC and CL/F coefficients of variation of 25% and 23%, respectively .
Along with the comparison with historical controls, this study also compared third-trimester abacavir pharmacokinetics with those in the non-pregnant, postpartum state in these same subjects. This within-subjects comparison also demonstrated no difference in abacavir AUC during pregnancy and postpartum. However, these women had a slightly lower Cmax and higher C6h during pregnancy than postpartum. Theoretically, physiological changes during pregnancy, including increased gastric emptying, intestinal transit time, gastric pH, and increased blood volume, could result in delayed drug absorption and reduced peak concentrations . Although median peak times were 1 h both ante- and postpartum, 48% of these women had tmax > 1 h during pregnancy while only 12% had tmax > 1 h postpartum, suggesting delayed absorption as an explanation for the difference in Cmax. The increase in C6h during pregnancy also supports the explanation of a delay in the rate but not the extent of absorption. Even though peak concentrations were significantly lower antepartum, the magnitude of the decrease was small (1.9 versus 2.1 mg/l) and both values are not widely different from previously reported values of 2.2 mg/l  and 2.9 mg/l  in non-pregnant adults. This slight blunting of Cmax in pregnancy was not accompanied by a decrease in the extent of absorption, as evidenced by the equivalent overall exposure or AUC, and it is not likely to be clinically significant.
This study attempted to determine placental drug transport of abacavir at delivery. Paired maternal/umbilical cord samples showed equivalent abacavir concentrations, consistent with simple passive diffusion of abacavir across the placenta, and similar to a previously reported ratio of 1.03 in four HIV-1-infected women . Equivalent exposure between mother and fetus at delivery also has been noted for zidovudine, lamivudine, and stavudine [12–15]. Didanosine showed decreased penetration across the placenta, though this may have been a consequence of once daily dosing and lower maternal concentration compared with the other NRTI, which were taken twice daily [12,16]. The concentration of abacavir in umbilical cord blood samples in this study (0.26 mg/l) was above the median inhibitory concentration for wild-type HIV-1 virus: 0.07 mg/l  so doses of abacavir taken near delivery may afford some protection for the neonate against HIV-1 transmission.
The pharmacokinetics of some antiretroviral agents have been described during pregnancy, including lopinavir, saquinavir, nevirapine, didanosine, lamivudine, stavudine, and zidovudine . Zidovudine had lower exposure during late third trimester versus postpartum in some reports [15,18], while others have found no difference during pregnancy [14,19]. Didanosine (buffered capsules), stavudine, and nevirapine all have approximately equivalent exposure during pregnancy and postpartum [7,13]. Decreased antepartum exposure to lopinavir/ritonavir has been demonstrated compared with historical non-pregnant adult controls , whereas saquinavir boosted with ritonavir in pregnancy appeared to have comparable pharmacokinetics to that with non-pregnant exposure, although the ritonavir exposure in this same study was decreased during pregnancy . Changes in protease inhibitor exposure during pregnancy may result from changes in sex hormones, which will induce metabolism by cytochrome P450 enzymes . The cytochrome P450 system does not play a role in abacavir metabolism. The different effects of pregnancy on the pharmacokinetics of antiretroviral drugs, even in the same class, make prediction of exposure during pregnancy difficult.
Historically, pharmacokinetic studies of antiretroviral drugs during pregnancy using traditional phase I designs have accrued slowly. The current study incorporated several design elements that facilitated patient enrollment. Since antiretroviral drugs are generally widely used in pregnant women before phase I studies can be conducted during pregnancy, we enrolled pregnant women who were already receiving abacavir as part of their routine clinical care. We assayed all samples in real time and reported the results back to the clinical caregivers within 2 weeks of sample arrival in the laboratory. By incorporating early stopping rules based on published information in non-pregnant populations, therapeutic drug monitoring (providing real-time feedback to clinicians), and the opportunity to consult with pharmacologists and the study team when trying to interpret this information clinically, the risks to the mother and fetus were minimized and enrollment was encouraged. Our study design, incorporating opportunistic enrollment of pregnant women already receiving the drug of interest and real-time drug assays and pharmacokinetic interpretation, can serve as a model for studies of other medications during pregnancy.
One limitation of this study was the lack of a postpartum evaluation in 32% of the women. Because many of these women were only on therapy to prevent transmission of HIV-1 to their infant, several self-discontinued abacavir before completing the postpartum pharmacokinetic evaluation. However, even with the self-discontinuations and losses to follow-up, 17 women completed both intensive evaluations, providing adequate data for comparisons.
In summary, abacavir overall exposure at steady state during the third trimester of pregnancy is approximately equal to that of non-pregnant historical controls, and to that of these same women at 6–12 weeks postpartum. Abacavir crosses the placenta and gives drug concentrations in the newborn at birth that may provide neonatal protection against HIV-1 transmission if mothers have recently taken a dose. Since pregnancy does not appear to alter plasma exposure to abacavir significantly, no dose adjustment is required in pregnancy. However, the decrease in Cmax during pregnancy and the increase in variability in AUC and oral clearance in our population demonstrate the effect pregnancy may have on antiretroviral pharmacokinetics and the need for pharmacokinetic evaluations during pregnancy of all antiretroviral drugs used in pregnant women. By incorporating an opportunistic enrollment strategy with real-time drug assay and pharmacokinetic analysis, necessary pharmacokinetic studies can be rapidly performed in pregnant women. The design of this protocol can serve as a practical and efficient model for studying antiretroviral pharmacokinetics during pregnancy.
The authors thank the participating women and staff of the clinical centers. We appreciate the vital contributions of Elizabeth Sheeran, Carol Elgie, Joanne Schiffhauer, and Maureen Shannon to the conduct of this study. We thank Lisa Frenkel, John Rodman, and Robert Maupin for their contributions to this study.
Sponsorship: This study was supported in part by the Pediatric AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases (Grants U01 AI04189, U01 AI41089), the General Clinical Research Center Units funded by the National Center for Research Resources, and by the Pediatric/Perinatal HIV Clinical Trials Network of the National Institute of Child Health and Human Development (Contract N01-HD-3-3365). B. Best received support from the Pediatric Pharmacology Research Unit Network of the National Institute for Child Health and Human Development (Grant U10-HD-031318-11).
Note: the results in this paper were presented in part at the 33rd Annual Meeting of the American College of Clinical Pharmacology, October 2004.
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Members of the PACTG P1026s Study Team: Arlene Bardeguez, Paul Palumbo, Phillip Andrew, Charmane-Calilap-Bernardo (University of Medicine & Dentistry of New Jersey/University Hospital, Newark, New Jersey); Ruth Tuomala, Arlene Buck, Dorothy Pender (Brigham & Women's Hospital, Boston, Massachusetts); Daniel Johnson, Dominka Kowalski, Brenda Wolfe (Mt. Sinai Children's Hospital, Chicago, Illinois); Alice Higgins, Marc Foca (Columbian Presbyterian Medical Center, New York); Amanda Cotter, Mary Jo O'Sullivan, Gwendolyn B. Scott, Liset Taybo (University of Miami, Miller School of Medicine, Miami, Florida); Andrew D. Hull, Mary Caffery, Linda Proctor (University of California San Diego, San Diego, California); Deb Goldman, Michele Acker, Connie McLellan, Jane Hitti (University of Washington, Seattle, Washington State); Jorge Gandía, Rodrigo Díaz, Elvia Pérez, Lourdes Angel (San Juan City Hospital, San Juan, Puerto Rica); Jennifer Griffin, Denise Ferraro, Silvia Muniz, Sharon Nachman (State University of New York at Stony Brook, Stony Brook, New York); Ana M. Melendrez, Yvonne Rodriguez, Françoise Kramer, LaShonda Spencer (Los Angeles County Medical Center & University of Southern California Medical Center, Los Angeles, CA); Katherine Knapp, Nina Sublette, Edwin Thorpe, Jr, Jill Utech (St. Jude Children's Research Hospital, University of Tennessee Health Science Center, Memphis, Tennessee); Diane W. Wara, Maureen T. Shannon, Marya G. Zlatnik, Shantrice M. Williams (University of California San Francisco, San Francisco, California).
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© 2006 Lippincott Williams & Wilkins, Inc.
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