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The aim of the study was to describe emtricitabine pharmacokinetics during pregnancy and postpartum.
The International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT), formerly Pediatric AIDS Clinical Trials Group (PACTG), study P1026s is a prospective pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including a cohort taking emtricitabine 200 mg once daily. Intensive steady-state 24-hour emtricitabine pharmacokinetic profiles were performed during the third trimester and 6–12 weeks postpartum, and on maternal and umbilical cord blood samples collected at delivery. Emtricitabine was measured by liquid chromatography–mass spectrometry with a quantification limit of 0.0118 mg/L. The target emtricitabine area under the concentration versus time curve, from time 0 to 24 hours post dose (AUC0-24), was ≥7 mg h/L (≤30% reduction from the typical AUC of 10 mg h/L in nonpregnant historical controls). Third-trimester and postpartum pharmacokinetics were compared within subjects.
Twenty-six women had pharmacokinetics assessed during the third trimester (median 35 weeks of gestation) and 22 postpartum (median 8 weeks postpartum). Mean [90% confidence interval (CI)] emtricitabine pharmacokinetic parameters during the third trimester vs. postpartum were, respectively: AUC: 8.0 (7.1–8.9) vs. 9.7 (8.6–10.9) mg h/L (P = 0.072); apparent clearance (CL/F): 25.0 (22.6–28.3) vs. 20.6 (18.4–23.2) L/h (P = 0.025); 24 hour post dose concentration (C24): 0.058 (0.037–0.063) vs. 0.085 (0.070–0.010) mg/L (P = 0.006). The mean cord:maternal ratio was 1.2 (90% CI 1.0–1.5). The viral load was <400 HIV-1 RNA copies/mL in 24 of 26 women in the third trimester, in 24 of 26 at delivery, and in 15 of 19 postpartum. Within-subject comparisons demonstrated significantly higher CL/F and significantly lower C24 during pregnancy; however, the C24 was well above the inhibitory concentration 50%, or drug concentration that suppresses viral replication by half (IC50) in all subjects.
While we found higher emtricitabine CL/F and lower C24 and AUC during pregnancy compared with postpartum, these changes were not sufficiently large to warrant dose adjustment during pregnancy. Umbilical cord blood concentrations were similar to maternal concentrations.
HIV-1-infected pregnant women commonly receive antiretroviral drugs. Combination antiretroviral regimens including nucleoside reverse transcriptase inhibitors (NRTIs) and either a protease inhibitor or a nonnucleoside 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 generally receive antiretrovirals for prevention of mother-to-child transmission of HIV-1 (HIV) .
Physiological changes during pregnancy affect antiretroviral drug disposition and previous studies of antiretroviral pharmacology during pregnancy have shown reduced antenatal exposure for many antiretrovirals . Inadequate antiretroviral exposure during pregnancy may yield inadequate virological control, increasing the risk of developing drug resistance mutations and of transmitting HIV to the infant. Understanding placental transfer of antiretrovirals to the foetus is of critical importance, as such transfer may subject the foetus to both the benefit of protection against HIV infection and the risk of potential antiretroviral toxicity [3,4]. Before any antiretroviral can be used safely and effectively in pregnancy, its pharmacology must be studied in pregnant women .
Emtricitabine, an oral, synthetic, cytidine analogue NRTI with potent activity against HIV-1, is frequently used in pregnancy. In nonpregnant adults, emtricitabine is well absorbed and has low protein binding, and the labelled dose of 200 mg once daily results in an average area under the concentration versus time curve (AUC) of 10.0 ± 3.1 mg h/L . This average is based on data from both women and men. In these studies, the pharmacokinetics of emtricitabine were similar in adult female and male patients, and the data were not presented separately for women and men. Emtricitabine is primarily eliminated unchanged in the urine, and its clearance is proportional to renal function. A minor portion of emtricitabine is metabolized by oxidation of the thiol moiety to form the 3′-sulfoxide diastereomers and conjugation with glucuronic acid to form 2′-O-glucuronide, with no significant metabolism by the cytochrome P450 enzyme system. While the pharmacokinetics and appropriate dosing of emtricitabine in nonpregnant, adult, HIV-1-infected patients are well defined, no data are available describing emtricitabine pharmacokinetics with chronic use during pregnancy [6–10].
The primary objectives of this study were to describe emtricitabine pharmacokinetics in HIV-infected pregnant women and to determine if the standard dose of emtricitabine produces equivalent drug exposure during pregnancy to that seen in: 1) historical data for nonpregnant adults; and 2) the same women in the study cohort during the postpartum period. We also sought to evaluate the transplacental passage of emtricitabine by comparing concentrations in cord blood and maternal blood.
The International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT), formerly Pediatric AIDS Clinical Trials Group (PACTG), study P1026s is a multicentre, ongoing, prospective study to evaluate the pharmacokinetics of currently prescribed antiretroviral drugs in pregnant HIV-1-infected women. Eligible subjects were those who: a) were already enrolled in the parent study, PACTG P1025; b) were receiving emtricitabine 200 mg orally daily as part of routine clinical care for at least 2 weeks prior to pharmacokinetic sampling; and c) were planning to continue emtricitabine until at least 6 weeks postpartum. P1026s is a substudy of P1025, the Perinatal Core Protocol, a prospective cohort study of HIV-infected pregnant women receiving care at PACTG or IMPAACT sites. Local institutional review boards approved P1025 and P1026s at all participating sites and all subjects provided signed informed consent prior to participation. Exclusion criteria were: current use of medications known to interfere with absorption, metabolism, or clearance of emtricitabine; multiple gestation; and clinical or laboratory toxicity that, in the opinion of the site investigator, would be likely to require a change in the antiretroviral regimen during the study. Subjects continued to take their medications, as prescribed by their physicians and dispensed by local pharmacies, during the study, unless changed by their physician because of toxicity or lack of effectiveness or based on the results of the individual woman’s antepartum pharmacokinetic evaluation. Women continued on the study until completion of postpartum pharmacokinetic sampling. Samples for the emtricitabine arm were obtained between November 2004 and March 2008.
Historical, demographic, clinical and laboratory data were collected in P1025. Maternal and infant clinical data were accessed from the P1025 database. On each sampling day and at delivery, subjects were interviewed to obtain medical histories, and underwent physical examinations and venipuncture to obtain blood for laboratory studies [including alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, creatinine, blood urea nitrogen (BUN), albumin and haemoglobin]. The study team reviewed toxicity reports in 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). The subject’s physician was responsible for toxicity management. All toxicities were followed until resolution.
Plasma samples for pharmacokinetic evaluation were collected at three evaluation times: antepartum (between 30 to 37 weeks of gestation), at delivery, and postpartum (between 6 to 12 weeks after delivery). Participants received a stable antiretroviral regimen for at least 2 weeks prior to pharmacokinetic sampling. Participants were instructed to take their emtricitabine at the same time each day for the 3 days prior to and on the day of the antepartum and postpartum pharmacokinetic evaluations. Eight plasma samples were drawn at both the antepartum and postpartum pharmacokinetic evaluation visits, starting immediately before the morning oral emtricitabine dose and at 1, 2, 4, 6, 8, 12 and 24 h after the witnessed dose. To assess transplacental passage, emtricitabine was measured in single maternal plasma and umbilical cord samples obtained at delivery.
Emtricitabine concentrations were measured in the Pediatric Clinical Pharmacology Laboratory of the University of California, San Diego using a validated, liquid chromatography–mass spectrometry (LC-MS) method. The laboratory is registered with the AIDS Clinical Trials Group (ACTG) Quality Assurance/Quality Control proficiency testing programme  and successfully completed three rounds of proficiency testing for emtricitabine during the study period. The lower limit of detection for emtricitabine was 0.0118 mg/L. The inter-assay coefficient of variation was 8.7% at the limit of detection and ranged from 3.1 to 5.7% for low, middle and high controls. Overall recovery from plasma was 91%.
The concentration data collected were analysed by direct inspection to determine the pre-dose concentration (Cpre-dose), the maximum plasma concentration (Cmax), the corresponding time (tmax), and the last measurable concentration (Clast). The area under the concentration versus time curve from time 0 to 24 hours post dose (AUC0-24) for emtricitabine was estimated using the trapezoidal rule up to the last measurable concentration. The half-life (t1/2) was calculated as 0.693/λz, where λz was the terminal slope of the log concentration versus time curve. Apparent clearance (CL/F) from plasma was calculated as the dose divided by AUC0-24 and the apparent volume of distribution (Vd/F) was determined as CL/F divided by λz. AUC and CL/F were also computed using a one-compartment model in WinNonlin (Pharsight Corp., St Louis, MO). 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 emtricitabine exposure during pregnancy was determined in real time and compared with the AUC estimated for a nonpregnant, adult HIV-1-infected historical control population from the literature , and promptly reported to each subject’s physician. The target emtricitabine AUC0-24 was ≥7 mg h/L or ≤30% reduction from the typical AUC of 10 mg h/L in nonpregnant historical controls. Each subject’s physician had the option to change the dose based on the pharmacokinetic results. A stopping criterion to trigger an evaluation of the adequacy of drug exposure was predefined as six of 25 women (24%; exact 80% confidence limits: 13%, 38%) falling below the target AUC. The goal was to prevent excess accrual to a cohort with known inadequate anti-retroviral exposure.
Once pharmacokinetic sampling had been completed for all subjects, antepartum and postpartum emtricitabine exposure measurements for each woman were compared using a repeated measures design. For the comparison of third-trimester versus postpartum emtricitabine exposure, the comparisons were made at the within-subject level, using 90% confidence limits for the geometric mean ratios of antepartum to postpartum pharmacokinetic parameters. When the true geometric mean of the ratio (the antilog of the true mean of the log ratios) of the pharmacokinetic parameters for pregnant and nonpregnant conditions has a value of 1, this indicates equal geometric mean pharmacokinetic parameters for the pregnant and nonpregnant conditions. If the 90% confidence intervals (CIs) are entirely outside the limits (0.8 and 1.25), the pharmacokinetic exposure parameters for the pregnant and nonpregnant conditions are considered different. If, however, the 90% CIs are entirely within the limits (0.8, 1.25), the drug exposures are considered equivalent. If the 90% CIs overlap with (0.8, 1.25), these data alone do not support any conclusions. The magnitudes of the differences in the median values of pharmacokinetic parameters antepartum and postpartum were also assessed with the Wilcoxon signed-rank test. Descriptive statistics, including geometric least-squares means and 90% CIs, were calculated for pharmacokinetic parameters of interest in each study period.
Twenty-six participants taking emtricitabine were enrolled in P1026s. All 26 women completed antepartum pharmacokinetic sampling and 22 completed postpartum sampling. The clinical characteristics of the study subjects are summarized in Table 1.
The target emtricitabine exposure was AUC ≥7.0 mg h/L, for a ≤30% reduction from typical exposure for non-pregnant historical controls. Fifteen of 26 subjects (58%; 80% CI 45–70%) achieved this target during pregnancy. The 11 subjects with AUCs below the target remained on the standard dose of 200 mg once daily. The antepartum concentration versus time curves for each subject are shown in Figure 1. Twenty-one of 22 subjects (95%; 80% CI 89–100%) achieved the AUC target postpartum. The postpartum concentration versus time curves for each subject are shown in Figure 2. All 26 women had detectable emtricitabine concentrations at the antepartum pre-dose sampling; 18 of 22 postpartum women had detectable emtricitabine concentrations at pre-dose sampling.
The one-compartment analysis yielded similar emtricitabine exposure parameters to the noncompartmental analysis. A summary of the pharmacokinetic parameters from the noncompartmental analysis for emtricitabine antepartum and postpartum is provided in Table 2. Figure 3 depicts the median antepartum and postpartum concentration–time curves. Geometric mean (90% CI) emtricitabine pharmacokinetic parameters during the third trimester compared with postpartum, respectively, for AUC were 8.0 (7.1–8.9) mg h/L vs. 9.7 (8.6–10.9) mg h/L (P = 0.072), for CL/F were 25.0 (22.6–28.3) L/hr vs. 20.6 (18.4–23.2) L/hr (P = 0.025), and for 24 hour post dose concentration (C24) were 0.058 (0.037–0.063) mg/L vs. 0.085 (0.070–0.010) mg/L (P = 0.006). All but one pregnant subject had C24 ≥0.037 mg/L, well above the inhibitory concentration 50%, or drug concentration that suppresses viral replication by half (IC50) for emtricitabine of 0.004 mg/L and close to the IC90 of 0.051 mg/L. The lowest postpartum C24 was 0.07 mg/L, exceeding the IC90. One pregnant woman had a detectable pre-dose emtricitabine concentration, but had C24 below the limit of detection (< 0.0118 mg/L). Postpartum, four different women had pre-dose emtricitabine levels below the limit of detection but all had detectable emtricitabine concentrations at 24 hours post-dose.
Umbilical cord blood samples were collected for 16 subjects; maternal plasma samples at delivery were available for 15 of the 16 subjects; emtricitabine was undetectable in three maternal and four cord blood samples. The geometric mean of the measurable maternal concentrations at delivery was 0.15 mg/L (90% CI 0.09–0.26 mg/L) and that of the cord blood concentrations was 0.26 mg/L (90% CI 0.17–0.39 mg/L). The geometric mean ratio of cord/maternal concentrations in 11 paired subject samples with detectable concentrations was 1.2 (90% CI 1.0–1.5). The median time between the last dose of emtricitabine and delivery was 18.6 hours (range 2.7–50.0 hours).
Overall, emtricitabine was well tolerated during pregnancy and postpartum, with only three subjects experiencing grade 3 adverse events of elevated bilirubin while taking emtricitabine. All three of these subjects were concomitantly taking atazanavir, which is known to cause hyper-bilirubinaemia. Of the four subjects who discontinued emtricitabine prior to the postpartum pharmacokinetic evaluation, none indicated side effects of emtricitabine as a reason for discontinuation. Twenty-four subjects had viral loads <400 HIV-1 RNA copies/mL at delivery; viral loads were missing in two subjects. At the postpartum evaluation, viral loads were < 400 copies/mL in 15 women, were ≥400 copies/mL in four women, and were not obtained in seven women. Median CD4 cell counts at delivery were 472 cells/μL (range 53–1494 cells/μL) (n = 25), and postpartum were 524 cells/μL (53–995 cells/μL) (n = 16). None of the 26 infants was infected with HIV. The infants were delivered at a median of 37.9 weeks of gestation (range 34.7–41.7 weeks) with a median birth weight of 2.9 kg (2.2–3.8 kg) and a median length of 48 cm (41–52 cm). Congenital anomalies were reported in two infants: one case of lachrymal duct stenosis and one case of grade 3 vesicoureteral reflux. These were deemed not related to the antiretroviral regimen by their physicians and by the study team.
This is the first study describing intensive steady-state emtricitabine pharmacokinetics in pregnant women. The pharmacokinetic results show that, while overall exposure to emtricitabine on standard doses is reduced in pregnant women compared with nonpregnant adults, this reduction is not of sufficient magnitude to warrant a dosing adjustment. Fifty-eight per cent of women achieved third-trimester AUCs above the target (≤30% reduction from the typical nonpregnant adult AUC), derived from AUC data reported in the medical literature. Postpartum AUC (9.7 mg h/L) and CL/F (20.6 L/h) in this cohort were consistent with AUC (10.0 mg h/L) and CL/F (18.1 L/h) from published studies of this dose in nonpregnant adults . The antepartum and postpartum Cmax values for emtricitabine were also within the reported limits of 1.8 ± 0.7 mg/L, being 1.4 mg/L at both time-points. The variability of AUC noted in this group of pregnant subjects was greater than that in nonpregnant adults after a single dose.
Along with the comparison to historical controls, this study also compared third-trimester emtricitabine pharmacokinetics to pharmacokinetics for the nonpregnant, post-partum state in these same subjects. The within-subject comparisons demonstrated no difference in emtricitabine Vd/F and Cmax during pregnancy and postpartum. However, these women had a slightly lower AUC and a slightly higher CL/F during pregnancy. Physiological changes during pregnancy can increase excretion of drugs and their metabolites by the kidney. Pregnancy is associated with a 25–50% increase in renal plasma flow and a 50% increase in glomerular filtration rate, which results in an increase in clearance of drugs eliminated predominantly by renal clearance . A lower C24 was observed in this study, 0.058 mg/L antepartum vs. 0.085 mg/L postpartum, which also supports the conclusion that emtricitabine is cleared at a faster rate and has lower drug exposure during pregnancy. Pregnancy is associated with increased plasma progesterone, decreased intestinal motility, increased gastric emptying time and increased intestinal transit time . While these physiological changes would be expected to result in delayed drug absorption and reduced peak maternal blood concentrations, the absorption of emtricitabine among pregnant women enrolled in this study was not affected. All four of the instances of pre-dose levels below the detection limit occurred postpartum. These were probably attributable to nonadherence, even though the subjects reported taking their prior dose. Only one C24 was below the detection limit; this was in the third trimester and we surmise that it was a result of the increased clearance. Adherence to antiretrovirals is often poorer during the postpartum period than during pregnancy. In our study, four of 19 women with viral load measured at the post-partum pharmacokinetic visit had viral loads >400 copies/mL, which we attribute to decreased antiretroviral adherence.
This study also evaluated placental drug transport of emtricitabine by comparing maternal and cord blood emtricitabine concentrations at delivery. Paired umbilical cord/maternal samples showed excellent foetal emtricitabine concentrations, with a geometric mean ratio of 1.2. Transfer of emtricitabine through the placenta appears to be mainly via simple passive diffusion. No data are available regarding active transport. The only previous data describing cord and maternal blood emtricitabine concentrations found a ratio of 80% following single 400 mg emtricitabine doses administered during labour . Equivalent exposure between mother and foetus at delivery has been noted for other nucleoside and nonnucleoside reverse transcriptase inhibitors, including zidovudine, lamivudine, abacavir, stavudine and nevirapine [14–20]. The concentration of emtricitabine in umbilical cord blood samples in this study (0.23 mg/L) was well above the mean in vitro IC50 and IC90 for wild-type HIV-1 viral replication: 0.004 and 0.051 mg/L, respectively. This cord concentration was also above the minimum adult concentration, 0.077 mg/L, reported in previous studies [13,18], optimizing protection for the foetus against HIV-1 transmission.
The pharmacokinetics of a number of other antiretroviral agents have been described during pregnancy. Of the nucleoside/tide reverse transcriptase inhibitors, exposure to zidovudine, abacavir, didanosine, stavudine and tenofovir is reduced during pregnancy but not to a degree that requires dosing adjustment [13–26]. Exposure to the non-nucleoside reverse transcriptase inhibitor nevirapine has been shown to be reduced by 10–20% during pregnancy [19,20]. Of the protease inhibitors, lopinavir/ritonavir, nelfinavir, atazanavir and indinavir demonstrated decreased exposure antepartum compared with historical nonpregnant adult controls, whereas the exposure of saquinavir boosted with ritonavir in pregnancy appeared comparable to nonpregnant exposure, although the ritonavir exposure in this same study was decreased during pregnancy [21–26]. Recommendations for the use of increased doses of lopinavir/ritonavir, nelfinavir and atazanavir during pregnancy have been made . Changes in protease inhibitor exposure during pregnancy may be attributable to changes in absorption, distribution and/or metabolism/elimination associated with pregnancy. Increased plasma progesterone during pregnancy causes induction of metabolism by cytochrome P450 enzymes and may play a role in increasing protease inhibitor metabolism during pregnancy. As emtricitabine is metabolized by oxidation of the thiol moiety and conjugation with glucuronic acid, the cytochrome P450 system does not play a role. However, emtricitabine is renally eliminated by both glomerular filtration and active tubular secretion, which are both increased during pregnancy and could explain the observations in this study.
Historically, pharmacokinetic studies of antiretrovirals during pregnancy using traditional Phase I designs have accrued slowly. The current study incorporated several design elements that facilitated enrolment. As antiretrovirals are generally widely used in pregnant women before Phase I studies can be conducted during pregnancy, we enrolled pregnant women who were already receiving emtricitabine as part of their routine clinical care. We assayed all samples in real time and reported the results back to the subjects’ physicians 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 foetus were minimized and enrolment was encouraged. Our study design incorporated opportunistic enrolment of pregnant women already receiving the drug of interest and real-time drug assays and pharmacokinetic interpretation, and can serve as a practical and efficient model for studying pharmacokinetics during pregnancy.
One limitation of this study was the incomplete collection of maternal plasma and cord plasma samples at the time of delivery. However, 16 women were evaluated to provide adequate and crucial data for analysis. Post-partum evaluation was incomplete for four subjects who self-discontinued emtricitabine before completing the postpartum pharmacokinetic evaluation. Nevertheless, 22 women completed both intensive evaluations, providing adequate data for comparisons. Another limitation of this study is that we measured plasma but not intracellular emtricitabine concentrations. Intracellular emtricitabine triphosphate, the active drug moiety, has a much longer half-life than plasma emtricitabine. Concentrations of intracellular emtricitabine triphosphate are more useful in evaluating pharmacokinetic–pharmacodynamic relationships and in deriving a dose selection strategy. Measurement of intracellular concentrations is primarily limited by the available resources. Despite these limitations, this study serves as an initial description of the pharmacokinetic parameters of emtricitabine in HIV-infected pregnant women.
In summary, lower emtricitabine AUC and C24 and higher emtricitabine clearance were found during pregnancy when compared with postpartum. However, the magnitude of the AUC decrease during pregnancy was less than 20% and C24 exceeded the IC50 in all subjects. Therefore, dosing adjustment during pregnancy does not appear to be necessary. Emtricitabine crosses the placenta well and provides antiretroviral concentrations in the newborn at birth that help provide neonatal protection against HIV transmission if mothers have been taking emtricitabine on a chronic basis. However, the decrease in C24 and in AUC during pregnancy together with the increase in oral clearance in our population demonstrates the effect pregnancy may have on antiretroviral pharmacokinetics and the need for pharmacokinetic evaluations during pregnancy of all antiretrovirals used in pregnant women.
Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (AI068632). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was 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 IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C).
In addition to the authors, members of the IMPAACT 1026s protocol team include Francesca Aweeka, Michael Basar, Kenneth D. Braun Jr, Jennifer Bryant, Elizabeth Hawkins, Kathleen Kaiser, Kathleen A. Medvik and Beth Sheeran.
Los Angeles County and University of Southern California Medical Center: Françoise Kramer, LaShonda Spencer, James Homans and Andrea Kovacs; Texas Children’s Hospital: Shelley Buschur, Chivon Jackson, Mary E. Paul and William T. Shearer; Seattle Children’s Hospital: Joycelyn Thomas, Corry Venema-Weiss, Barbara Baker and Ann Melvin; St Jude/UTHSC/Regional Medical Center at Memphis: Edwin Thorpe Jr, Nina Sublette and Jill Utech; Columbia University: Seydi Vazquez, Marc Foca, Diane Tose and Gina Silva; University of Colorado Denver: Jill Davies, Tara Kennedy, Kay Kinzie and Carol Salbenblatt; University of Maryland Baltimore: Douglas Watson, Susan Lovelace and Judy Ference; Bronx-Lebanon Hospital: Mavis Dummit, Mary Elizabeth Vachon, Rodney Wright and Murli Purswani; Baystate Health, Baystate Medical Center: Barbara W. Stechenberg, Donna J. Fisher, Alicia M. Johnston and Maripat Toye.
*This work was presented in part at the 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, February 2008 (Abstract 629).