PEDIATRICS Vol. 120 No. 2 August 2007, pp. e416-e423 (doi:10.1542/peds.2006-0925)
ARTICLE |
Long-term Safety and Efficacy of a Once-Daily Regimen of Emtricitabine, Didanosine, and Efavirenz in HIV-Infected, Therapy-Naive Children and Adolescents: Pediatric AIDS Clinical Trials Group Protocol P1021
a Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
b Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee
c Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
d Division of AIDS, National Institute of Allergy and Infectious Diseases
e Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
f Social & Scientific Systems, Inc, Silver Spring, Maryland
g Department of Pediatrics, Children's Memorial Hospital, Chicago, Illinois
h Department of Pediatrics, University of California, San Diego, California
i Frontier Science and Technology Research Foundation, Amherst, New York
j Department of Pediatrics, University of Florida Health Science Center, Jacksonville, Florida
k Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California
l Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado
m Department of Pediatrics, State University of New York Health Science Center, Syracuse, New York
n Department of Pediatrics, Harlem Hospital, New York, New York
o Gilead Sciences, Inc, Durham, North Carolina
p Bristol-Myers Squibb Company, Wallingford, Connecticut
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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BACKGROUND. Compliance with complex antiretroviral therapy regimens is a problem for HIV-1–infected children and their families. Simple, safe, and effective regimens are important for long-term therapeutic success.
METHODS. A novel, once-daily dosing regimen of 3 antiretroviral drugs, emtricitabine, didanosine, and efavirenz, was tested in 37 therapy-naive HIV-infected children and adolescents between 3 and 21 years of age (inclusive). Subjects were followed for 
96 weeks on an intention-to-treat basis. Signs, symptoms, plasma HIV-1 RNA viral load, CD4 counts, and safety laboratories were followed regularly. End points were the proportion of subjects with plasma HIV <400 or 50 HIV copies per mL and safety and tolerability of the regimen.
RESULTS. Thirty-seven subjects enrolled at 16 sites. Two subjects with rashes during the first 2 weeks of therapy were the only adverse events leading to study-drug discontinuation. Other early (before protocol-scheduled conclusion) study discontinuations included 3 viral failures on treatment and 5 patients who stopped therapy for apparently nonmedical reasons. Possible drug-related adverse events included 1 grade 4 low-glucose and 5 varied grade 3 events. There were no deaths. Virologic outcomes demonstrated that 32 (85%) of 37 subjects achieved viral suppression to <400 RNA copies per mL, and 26 (72%) of 37 subjects maintained sustained suppression at <50 copies per mL through week 96. The median baseline CD4 count was 310 per µL (17%), which increased at week 96 by a median of +329 cells per µL (by +18% CD4). Pharmacokinetic results were as predicted for emtricitabine, didanosine, and efavirenz capsules, whereas efavirenz concentrations in children receiving efavirenz oral solution were lower than anticipated, requiring a dose escalation after the planned assessment point.
CONCLUSIONS. A once-daily regimen of emtricitabine, didanosine, and efavirenz proved to be safe and tolerable and demonstrated good immunologic and virologic efficacy in this 2-year study.
Key Words: agents • antiretroviral • AIDS • child • didanosine • efavirenz • emtricitabine • HIV
Abbreviations: AUC—area under the curve • CI—confidence interval
One of the major obstacles to successful therapy for HIV disease has been the complicated regimens used in highly active antiretroviral therapy. Studies have demonstrated that the complexity of the regimen can be correlated with the degree of compliance and, ultimately, the success of therapeutic strategies.1 The study described in this article evaluated a novel combination of 3 antiretroviral drugs in pediatric subjects, each administered once daily: emtricitabine (Emtriva; Gilead Sciences, Foster City, CA), didanosine (Videx; Bristol Myers Squibb, Princeton, NJ), and efavirenz (Sustiva; Bristol Myers Squibb). This regimen has also been evaluated in therapy-naive adult subjects, with preliminary efficacy and safety that seem very satisfactory.2, 3 Emtricitabine has been evaluated previously in children,4 and has been approved by the Food and Drug Administration for use in children and adults. Pediatric AIDS Clinical Trials Group protocol 1021 was designed to evaluate the pharmacokinetics of the 3 agents and the safety of the regimen and to obtain preliminary efficacy information. The initial protocol design was for a duration of 48 weeks after the last enrollment. However, because of the efficacy and safety demonstrated during the trial and a desire to acquire long-term data, the protocol has been extended 3 times, with a current planned maximal time on study of 240 weeks. This article provides safety, tolerability, and efficacy data through 96 weeks on study for the last patient enrolled.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Study Population
The study enrolled HIV-1–infected children and adolescents between the ages of 3 and 21 years, inclusive. It was designed with 3 cohorts: 90 days to <3 years (group 1), 3 to 12 years (group 2), and 13 to 21 years (group 3). The children were either antiretroviral therapy naive (no exposure) or had limited exposure (
56 days of perinatal prophylaxis or <7 days of cumulative antiretroviral treatment). Subjects were required to have a screening plasma HIV-1 RNA concentration 5000 copies per mL. They could not have a history of hypersensitivity to any component of the regimen. Other exclusions included the following: renal impairment (serum creatinine >1.5 age-adjusted upper limit of normal); acute infection; chemotherapy for active malignancy within 1 year of screening; pregnancy (sexually mature female subjects were required to use 2 forms of contraception); anemia at grade 3 or worse (Pediatric AIDS Clinical Trials Group toxicity tables); absolute neutrophil count, platelet count, bilirubin, aspartate aminotransferase, alanine aminotransferase, or triglycerides at grade 2 or worse; positive hepatitis B surface antigen or hepatitis C serology; history of pancreatitis; malabsorption disorder; peripheral neuropathy; or current treatment for tuberculosis.
Study Regimen
The initial regimen was emtricitabine 6 mg/kg once daily to a maximum of 200 mg; didanosine 240 mg/m2 once daily to a maximum of 400 mg; and efavirenz once daily according to a dosing table (Table 1), with the dose adjusted for body weight up to a maximum of 600 mg as capsules or 720 mg as oral solution. Emtricitabine was given as either an oral solution (10 mg/mL) or capsules (200 mg). Didanosine was given as enteric coated beadlet capsules (Videx EC; Bristol Myers Squibb) for children with surface area 0.45 m2 who could swallow capsules or as an oral suspension mixed in antacid for smaller children. Efavirenz was administered as either oral solution (30 mg/mL) or capsules (50, 100, and 200 mg). The initial protocol design was for a duration of 48 weeks after the last enrollment. However, because of the efficacy and safety demonstrated during the trial and a desire to acquire long-term data, the protocol has been extended twice, with a current planned maximal time on study of 240 weeks.
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The protocol required a review of week 2 pharmacokinetic sampling results after 8 subjects had enrolled. If the area under the curve (AUC) of
3 of these 8 children failed to reach the 10th percentile of older pediatric or adult values for any study drug, the initial regimen would be changed. For emtricitabine, this value was <6 µg · hour/mL and a median AUC of 8.5 µg · hour/mL4; for didanosine, the value was <890 µg · hour/mL and a median AUC of 1980 µg · hour/mL5; for efavirenz, the value was <35 µg · hour/mL and a median AUC of 60 µg · hour/mL.6 The pharmacokinetic analyses for emtricitabine and didanosine were satisfactory, and there was no need for dose adjustment. Analysis of efavirenz findings demonstrated that children receiving liquid efavirenz had lower-than-expected AUC values, which resulted in an increased dose for children receiving the oral solution (see Table 1). Six subjects had their efavirenz dose increased, and subsequent subjects initially treated with efavirenz solution were started at a higher dose.
Schedule of Evaluations
Subjects were screened within 21 days of entry. After study entry, visits were scheduled at weeks 2 and 4 and then every 4 weeks thereafter. At all of the visits, history and physical were performed. Adverse events are reviewed at every visit. All of the signs and symptoms of grade 2 or more, all central nervous system symptoms, and any grade of nausea, vomiting, or abdominal pain associated with increased lipase or pancreatic amylase were recorded. Chemistry and liver tests were obtained at each study visit. Hematology tests were performed every 4 weeks until week 24, then every 8 weeks. HIV-1 RNA testing was performed at screening; entry; weeks 2, 4, 8, 12, 16, and 24; and then every 12 weeks. CD4 counts were obtained at screening and baseline; weeks 4, 16, and 24; and every 12 weeks thereafter. Intensive 24-hour pharmacokinetic sampling was performed at week 2 and was repeated 4 weeks after dosage changes or at week 8 or 12 if no dosage changes were necessary. Intensive pharmacokinetic studies were also performed after virologic failure. Single-specimen pharmacokinetic samples were obtained at weeks 8, 12, 20, 28, 36, and 48.
The study required reporting of all grade 1 or higher laboratory abnormalities. Adverse events were graded using the Pediatrics AIDS Clinical Trial Group's standard toxicity table. The team evaluated each event for possible relationship with study treatment.
Study End Points
The primary objectives were to evaluate the safety and tolerability of this combination regimen in therapy-naive children and to obtain preliminary antiviral efficacy. Safety was evaluated by assessing the number of grade 3 and 4 adverse events attributed to study treatment. The primary virological measures were the proportion of children with plasma HIV-1 RNA of 400 copies per mL or 50 copies per mL at week 16. The secondary virological outcomes were the time to virological failure, defined as the first measurement >400 or >50 copies per mL or the time of study-drug discontinuation. The other secondary virological outcome was the change in viral load from baseline. Although the primary evaluation used week 16 data, as the study was extended, further sampling of HIV viral load was performed at week 24 and every 12 weeks thereafter, and these were assessed as secondary analyses. CD4 counts were also assessed as change from baseline (CD4 count and percentage of CD4s) at the same fixed intervals.
For clinical management, virological failure was defined as a <1 log decrease in viral load from baseline at any time from week 16 or beyond or as a viral load of >10000 HIV-1 RNA copies per mL at any time after a viral load of <400 copies per mL had been achieved. All of the end point tests were confirmed within 14 to 35 days of the first end point value.
Statistical Evaluation
For analysis, the study population was stratified by age cohort and by previous exposure to antiretroviral drugs (naive versus any previous exposure). The sample size of 36 subjects was chosen because if there were no grade 3 or 4 adverse events attributable to study treatment, the upper bound (95% confidence interval [CI]) on the true percentage of subjects experiencing such events would be <10%.
The numbers and proportions of subjects achieving suppression of plasma HIV-1 RNA to 400 and 50 copies per mL were calculated for various time points from week 2 through week 96. At each time point, an exact CI was calculated to show the precision of the estimated proportion. The primary analysis was intention to treat, and it evaluated the proportion of subjects who were suppressed and still on study treatment. Thus, the denominator for calculating the proportion includes all of the subjects to whom study drugs were dispensed.
Investigational Review Board Approval
The study was approved by each site's investigational review board before enrollment of the first subject at that site. Subjects were enrolled after they or their parents signed an investigational review board–approved informed consent document.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Subject Enrollment
Thirty-seven subjects enrolled at 16 sites in groups 2 and 3 between September 18, 2001, and October 23, 2002, and all began treatment. Group 1 (90 days to <3 years) enrolled its first subject in May 2005. Accrual in this cohort was delayed until after an appropriate efavirenz dose could be determined based on preliminary pharmacokinetic information from Pediatric AIDS Clinical Trials Group protocol 382. Twenty-one children were in group 2 and 16 adolescents were in group 3. The demographics and baseline characteristics are described in Table 2. One subject had taken stavudine, lamivudine, and lopinavir/ritonavir for 1 week before enrollment. All of the other subjects were antiretroviral naive. Data collection for this analysis concluded August 2, 2004. At the time of the data cutoff, the median follow-up was 106.6 weeks.
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The study population was 62% black, non-Hispanic, 24% Hispanic, and 14% non-Hispanic white. At entry, the median age was 10.5 years (range: 3.2–21.1 years), median CD4 count was 310 cells per µL (range: 2–1893 cells per µL), median CD4 percentage was 17% (range: 1%–40%), and median entry plasma HIV-1 RNA level was 47775 copies per mL (range: 3655–2370884 copies per mL).
Study Treatment
As of July 31, 2004, 11 of 37 subjects had discontinued treatment. Two subjects discontinued before the 2-week pharmacokinetic study because of rash deemed probably related to study treatment. Three subjects had virological failure. Two subjects discontinued study treatment when they were incarcerated. Two study subjects withdrew consent because study visits were deemed inconvenient. One subject left the country, and 1 subject completed the original study protocol (106 weeks).
Abnormal Laboratory Values
Five subjects had 1 or more grade 3 or 4 laboratory abnormalities after entry. One subject had grade 3 and 4 
-glutamyl transferase concentrations during weeks 3 to 5 on study medication. Treatment was continued without modification, and the abnormality was resolved. No etiology could be determined. One subject had 2 episodes of grade 4 low serum glucose, classified as "possibly drug related," and 1 subject had a grade 3 low serum glucose (classified as "not drug related"). Two subjects had transiently elevated creatine phosphokinase concentrations (grade 3 in week 4 and grade 3 in week 40). In the first instance, the creatine phosphokinase returned to normal when study medication was interrupted. However, the subject withdrew from the study, so there was no further challenge to help determine a causal linkage. All of the creatine phosphokinase elevations were classified as "possibly drug related."
All 37 of the subjects had 1 laboratory abnormality of grade 1 or greater. For 16 subjects, the highest level was grade 1; for 16 subjects the worst value was grade 2. The abnormal laboratory values are summarized in Table 3.
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Signs and Symptoms
The study required evaluation of signs and symptoms at every clinic visit. Six subjects had grade 3 or 4 signs or symptoms. Two episodes were thought to be possibly drug related. One subject had grade 3 dizziness during the first week on the regimen, which resolved without intervention. Another subject had a grade 3 rash in the first week of therapy that led to discontinuation of study medication. A second subject who had grade 2 rash within 2 weeks of starting protocol treatment also discontinued therapy as a result.
There have been no deaths in the study population. A total of 12 patients developed serious adverse events, 6 of whom required hospitalization. None of the hospitalizations were drug related. The only serious adverse event leading to study-drug discontinuation was the aforementioned grade 3 rash.
Virological Studies
Twenty four of the 37 subjects had all of the required HIV-1 RNA measurements during the first 96 weeks of treatment. In this intention-to-treat study, 8 of the 11 subjects who permanently discontinued study treatment had all of the scheduled samples obtained. The proportions of subjects with plasma HIV-1 RNA <400 or 50 HIV copies per mL are shown in Fig 1. There were essentially no differences by age cohort. The results are reported conservatively, with discontinuation for any reason reported as failure. Three (8.1%) of the 37 subjects had virological failure. The other discontinuations were for nonvirological reasons. All 35 of the patients who took the study regimen for >2 weeks had suppression to <400 HIV-1 copies per mL on 1 measurement.
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Further analysis of the 3 viral failures demonstrated common problems in pediatric HIV studies. One child had a viral load of <50 copies per mL before his mother became ill and 18018 copies per mL at the next visit. He could not be resuppressed. One patient stated there was nonadherence, and the third patient failed after being started on rifabutin for an atypical mycobacterial infection.
At week 16, 32 (86%) of the 37 subjects (95% CI: 71%–95%) had plasma HIV-1 RNA suppressed below 400 copies per mL, and 27 (73% [95% CI: 56%–86%]) were suppressed below 50 copies per mL. Good viral suppression was maintained through week 96, at which time point 26 subjects (70% [95% CI: 53%–84%]) were suppressed below 400 copies per mL, all of whom were also suppressed below 50 copies per mL. For any subject with a missed visit, the viral load was considered to be suppressed below a certain level at a missed visit only if the HIV-1 RNA measurements immediately before and after the missed visit were both suppressed below the specified level.
CD4 Measurements
The median CD4 counts and percentages are shown in Table 4, whereas the changes in CD4 counts and percentages from baseline are shown in Fig 2. There was a steady improvement in CD4 numbers during the 96 weeks on treatment.
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Pharmacokinetic Results
The AUC (0–24 hours) measurements for emtricitabine and didanosine met predefined protocol expectations. Analysis of efavirenz AUC demonstrated that for children
12 years old who received liquid efavirenz, the AUC was not satisfactory. The protocol-specified target was that when the first pharmacokinetic sample set was performed, if 3 subjects were less than the 10th percentile in comparison with published AUCs in adults and children, an upward dosage adjustment would be made. Only 5 (42%) of 12 children receiving the solution achieved the target concentration range (35–120 µg · hour/mL), whereas 20 (95%) of 21 children receiving the capsule formulation hit the target range, including all of the group 2 children who received the capsule. As a result, the efavirenz solution-dosing algorithm was changed to increase the efavirenz dosage. There is not a statistically significant difference (at a P < .05) between AUC or total body clearance divided by bioavailability between group 2 and group 3 children receiving capsules, but with only 6 subjects on capsules in group 2, the power to detect a difference is limited. With regard to gender effects, the AUCs were similar between male and female subjects, with median AUC values of 57.9 and 53.4 µg · hour/mL for male and female subjects, respectively. |
DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Pediatric AIDS Clinical Trials Group protocol P1021 was designed to evaluate an entirely once-daily regimen for HIV-infected, therapy-naive children. The regimen was well tolerated by study participants: only 2 subjects had their treatment stopped because of adverse events. In both subjects, the problem was a rash shortly after initiation of the regimen, a known adverse effect with efavirenz. The 3-drug study regimen was effective for a sustained period, with 70% of subjects (using intention-to-treat analysis) having plasma HIV RNA concentrations still <50 copies per mL at week 96. The regimen also seemed to have a very positive effect on the immune system, as demonstrated in Table 4 and Fig 2. The median CD4 count rose from baseline by 329 cells per mm3 at week 96, an increase in the CD4 percentage of 18%.
Ten patients had their study treatment terminated before the end of the study. Only 5 of the 10 patients discontinued because of virologic failure or toxicity. The remainder did not seem to be related to the failings of the regimen. However, given the study's intention-to-treat design, all were scored as therapeutic failures. One patient chose not to accept a study extension beyond week 106.
Tolerance of the study medications was good. The most common problems reported were low glucose, anemia, and a low absolute neutrophil count. The low-glucose problems may have been laboratory artifacts, because in most subjects they occurred only sporadically and without symptoms. No subjects required a change or discontinuation of therapy as a result of a laboratory abnormality.
The subjects in this study were naive to antiretroviral therapy at entry, and the study did not consider the role that combination didanosine/emtricitabine /efavirenz might play in secondary therapy after the failure of an initial regimen. What the results do suggest is that this regimen is worthy of further evaluation as initial therapy for HIV in children, given the combination of convenience, tolerance, and efficacy. The study is limited by the sample size, which means that less common adverse effects may not have been detected, and by the lack of a comparator arm. The study is also limited in that only children 3 years of age were included in the initial cohorts. The younger-age population is now being enrolled in the third phase of Pediatric AIDS Clinical Trials Group protocol 1021.
Comparison data for the didanosine/emtricitabine /efavirenz regimen in adults have been obtained in several trials. For example, Saag et al7 compared emtricitabine /didanosine/efavirenz to stavudine/didanosine/efavirenz as a once daily regimen. Seventy-six percent of subjects on the emtricitabine-containing regimen had plasma HIV-1 RNA levels 50 copies per mL at week 60, whereas 54% of the stavudine-containing arm were below the same threshold. The probability of virological failure was 4% in the emtricitabine group and 12% in the stavudine group. The emtricitabine/didanosine/efavirenz results in that study are very similar to those in the current study.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Determining which antiretroviral regimen to use as initial therapy in HIV-infected children remains an open question. As protocol P1021 demonstrates, the combination of emtricitabine, didanosine, and efavirenz given once daily is clearly an option that warrants consideration and further study, given the combination of convenience, tolerability, and antiviral and immunologic efficacy.
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ACKNOWLEDGMENTS |
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Funding for this study was provided by the Pediatric AIDS Clinical Trials Group, supported by the National Institute of Allergy and Infectious Diseases and the National Institute of Child Health and Human Development. Protocol drugs were provided by Gilead Sciences, Inc, and Bristol-Myers Squibb Company.
We thank the children and their families for their participation in this research and the personnel at the following institutions involved in the conduct of the Pediatric AIDS Clinical Trials Group Protocol P1021: St Jude Children's Research Hospital, Memphis (Katherine Knapp, MD, Jill Utech, RN, MSN, and Sandra Jones, RN MSN); Chicago Children's Memorial Hospital (Pediatric) (Ellen G. Chadwick, MD, Lynn Heald, CPNP, Amy Talsky, CPNP, and Jennifer Kershaw, CPNP); University of California San Diego Mother, Child & Adolescent HIV Program (Rolando Viani, MD, MTP, and Anita Darcey, RN, PN); Duke University (Pediatrics) (Carole Mathison, Yong II Choi, RN, Jean Hurwitz, RPh, and Juliana Simonetti, RN); Harlem Hospital (Maxine Frere, RN, and Susan Champion, MD); State University of New York Upstate Medical University (Leonard B. Weiner, MD, Kathie A. Contello, NP, MSN, Wendy Holz, MS, PNP, and Maureen Famiglietti, BSN, CCRP); University of Miami (Pediatric) (Gwendolyn B. Scott, MD, Charles D. Mitchell, MD, Liset Taybo, MD, and Sylvia Willumsen, RN; grant 5UO1 AI 27560–18); University of Florida Health Science Center (Michelle Tucker, RN, and Saniyyah Mahmoudi, ARNP); Children's Hospital, University of Colorado, Denver (Mark Abzug, MD, Emily Barr, CPNP, CNM, and Suzanne Paul, RN, CFNP; grant 5 M01 RR00069, General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health); Children's Hospital of Boston (Sandra Burchett, MD, and Catherine Kneut, PNP); Baylor, Texas Children's Hospital (Nancy Calles, RN, Chivon Jackson, RN, and Mary E. Paul, MD); University of California San Francisco, Moffitt Hospital (Pediatric) (Diane W. Wara, MD, and Deborah Trevithick, RN, MS; grant 5 M01 RR-01271, Pediatric Clinical Research Center, University of California San Francisco, funded by National Center for Research Resources, US Public Health Service); New York University School of Medicine (Nagamah Deygoo, William Borkowsky, MD, Sulachni Chandwani, MD, and Siham Akleh, RN); San Juan City Hospital (Eleanor Jiménez, MD, Midnela Acevedo, MD, Isis Moraima Burgos, RN, and Lizbeth Fábregas); University of Puerto Rico, University Children's Hospital AIDS (Irma L. Febo Rodriguez, MD, Ruth E. Santos Otero, RN, MPH, Maritza Cruz, and Lisette Lugo, MD); and Site 7301, University of Massachusetts Medical School (Katherine Luzuriaga, MD).
This article is dedicated to the memory of Dr John Rodman, PharmD, who was instrumental to the performance of this study and who died while working in his laboratory shortly after submission of the initial article on Saturday, April 29, 2006.
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FOOTNOTES |
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Accepted Jan 26, 2007.
Address correspondence to Ross E. McKinney, Jr, MD, Department of Pediatrics, Duke University Medical Center, Box 3461, Durham, NC 27710. E-mail: ross.mckinney{at}duke.edu
Deceased. 
Dr Cunningham's current affiliation is Department of Pediatrics, Duke University Medical Center, Durham, NC.
Financial Disclosure: Mr Chittick and Dr Blum are employees of Gilead Sciences, Inc; Ms Reynolds is employed by Bristol-Myers Squibb; Dr Hughes, during the course of this study, received grant support from Roche and had honoraria or consultancies with Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Chiron, Roche, and Tibotec. These companies are all manufacturers of antiretroviral therapies or other therapy for HIV infection. The remaining authors have indicated they have no financial relationships relevant to this article to disclose.
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