Flynn, Patricia M MD*†; Cunningham, Coleen K MD‡; Rudy, Bret MD§; Wilson, Craig M MD‖; Kapogiannis, Bill MD¶; Worrell, Carol MD¶; Bethel, James PhD**; Monte, Dina RN, BSN, CCRC**; Bojan, Kelly DNP, APN, CFNP††; for the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN)
Suboptimal response to hepatitis B virus (HBV) vaccination in HIV-infected adults and children has been well documented. In children with perinatally acquired infection, response rates range from 20% to 78%.1-6 Correlation of response with CD4+ T-cell (CD4) counts or percentages, HIV-related symptoms, and younger age are reported but with inconsistent findings. Among HIV-infected adults, response rates for HBV vaccination vary between 17% and 71%.7-24 Factors thought to be associated with improved vaccine response include higher CD4 count, undetectable HIV-1 viral load, younger age, and increased dose and number of vaccines. Although studies are difficult to compare because of varied study design and heterogeneous populations, disease and treatment status of subjects, higher CD4 count, and undetectable HIV-1 viral load at the time of vaccination are considered important predictors of improved vaccine response among adults.
To date, there is no randomized trial of HBV vaccination in HIV-infected youth. A retrospective study from Reaching for Excellence in Adolescent Care and Health (REACH), a cohort of youth infected with HIV through high-risk behaviors and uninfected but at-risk youth, demonstrated only 41% of HBV previously immunized HIV-infected youth exhibited protective levels of antibody.25 The temporal relationship of HBV vaccination to the HIV infection in this population could not be determined; however, reduced response rates were also seen among those HIV-infected subjects who were vaccinated during the study period (37%).
Excellent response rates to both hepatitis A virus (HAV) and HBV vaccination in healthy youth populations have been demonstrated with Twinrix.26-29 Ambrosch demonstrated higher titers of antibody in youth who received the combined vaccine compared with those receiving monovalent vaccines.27 Likewise, Knoll demonstrated a trend toward higher antibody titers with the Twinrix in healthy young adults.29
We undertook a randomized trial of increased dose HBV antigen using Engerix B, 40 μg HBsAg, compared with the recommended dose of Engerix B, 20 μg, in HIV-infected youth. A third arm combined HBV and HAV vaccine using Twinrix. Here, we report the immunogenicity, vaccine response predictors, and safety of these vaccination regimens in HIV-infected youth.
HIV-infected youth, regardless of route of infection, aged 12 to younger than 25 years, with no history of previous HBV vaccine or only one previous HBV vaccine received 4 weeks or more before screening and who had no serologic evidence of HBV surface antibody (HBsAb), surface antigen (HBsAg), or core antibody (HBcAb) were recruited from Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) Units and International Maternal, Pediatric, and Adolescent AIDS Clinical Trials (IMPAACT) Units in the United States and South Africa and National Institute of Child Health and Human Development-sponsored international clinical trial sites in Brazil and Bahamas. Prior HBV vaccination was ascertained by review of all available medical records, immunization cards, subjects, and, when applicable, parent recall.
Females of childbearing potential were required to have a negative pregnancy test at screening and agree to avoid pregnancy through the completion of the vaccine phase of the study. Subjects were excluded for previous allergic reaction to any HBV or HAV vaccines or their constituents, any serious clinical or laboratory toxicity at time of screening, high-dose or long-term steroid use (more than 10 mg/day of prednisone or equivalent for 2 or more consecutive weeks) within the prior 3 months, other diseases of the immune system, or receipt of immune globulin or plasma product within the prior 6 months, blood product or transfusion within the prior 4 weeks, or any vaccine within the prior 4 weeks. Prior infection with HAV or vaccination with HAV vaccine was not an exclusion criterion.
The study was approved by the Institutional Review Board or Ethics Committee at each site. An independent Data and Safety Monitoring Board monitored the trial for safety every 6 months during the course of the study.
Before entry, subjects were assessed by history and physical examination. Medical records were reviewed to determine nadir CD4 count, highest HIV-1 viral load, presumed route of HIV infection, and antiretroviral therapy (ARV) history.
Subjects were randomized into one of three arms using blocks of six and stratified by absolute CD4 count (less than 500 and 500 cells/mL or greater) and previous HBV vaccination (0 and 1). The randomization was restricted so that the percentage of subjects with CD4 count 200 cells/mL or less would not exceed 15% of subjects on any arm. The study was not blinded.
The three treatment arms were: Arm 1-Engerix B, 20 μg; Arm 2-Engerix B, 40 μg; and Arm 3-Twinrix, 20 μg HBV surface antigen and 720 ELU HAV antigen. Vaccinations were administered in the deltoid muscle at entry, Week 4 and Week 24. Engerix B, 40 μg, was delivered as two injections of 20 μg. A negative pregnancy test was required from all female subjects within 7 days before each vaccination. Vaccination was delayed in subjects with acute febrile illness. Delayed administration of vaccine was allowed.
All subjects were observed for 20 minutes after vaccination and were contacted by telephone at Days 3 and 7 (± 24 hours) after vaccination to assess safety. Additionally, subjects were advised to contact study staff if concerned about any signs or symptoms or if any symptom appeared severe.
Toxicity was assessed using the Division of AIDS Table for Grading the Severity of Adverse Events (http://rcc.tech-res.com/safetyandpharmacyvigilance). If neurologic symptoms at any severity grade or nonneurologic symptoms Grade 3 or greater were reported, subjects were asked to return to the clinic within 48 hours for evaluation.
Subjects were evaluated at Week 28 for vaccine response (primary end point) and interval medical history. A vaccine response was defined as an HBsAb measurement of 10 IU/mL or greater. Subjects with a HBsAb response of less than 10 IU/mL (nonresponders) at Week 28 received a fourth dose of vaccine, Engerix B 40 μg. Nonresponders had repeat quantitative HBsAb assessed at least 4 weeks after the fourth dose, after which no further follow-up was performed. Vaccine responders had repeat assessment of HBV antibodies at Weeks 48 and 72 to assess duration of vaccine response.
Subjects did not receive additional vaccines if they became pregnant; developed a confirmed Grade 3 vaccine-related toxicity that persisted for more than 14 days, did not resolve, or recurred; or if they developed a Grade 4 toxicity and relationship to the study vaccine could not be ruled out.
Qualitative HBV and HAV serology, CD4 counts, HIV-1 viral load, and pregnancy tests were performed in local laboratories. Only subjects assigned to the Twinrix arm had HAV serology performed. Quantitative HBsAb assays were performed at a central testing laboratory (Abbott EIA or Ortho Vitros ECI performed by Quest Diagnostics, Baltimore, MD). The serologic assay changed during the study; however, sufficient samples were available to provide pre- and postimmunization test results with the Ortho Vitros ECI test for all but four (1.2%) of the subjects. In those cases, results from the Abbott EIA were used. To assure that HBV seroconversion represented response to vaccine rather than new HBV infection, all subjects with a vaccine response had HBcAb testing performed.
Statistical Considerations and Analysis
This study was designed to compare vaccine response at 28 weeks in two experimental regimens (Arms 2 and 3) with the standard regimen (Arm 1). From previous studies, the expected response to Arm 1 was 42%, whereas a response of 60% for either Arm 2 or 3 would constitute a clinically significant improvement. For α = 0.05 and power of 80%, 111 subjects per arm were needed. Anticipating 5% attrition, we targeted 123 subjects for each arm using the method of Lachin.30
All subjects who received vaccine were evaluated for safety. The primary planned efficacy analysis included all subjects with Week 28 serology results regardless of study vaccine receipt (modified intent to treat analysis, as specified in the study protocol); a per-protocol analysis was also done that included only subjects who met all eligibility and study requirements. We also planned and performed sensitivity analyses to determine the effect of missing end point data. Chi square tests were used to assess categorical variables and Student t test for continuous variables. Variables of interest included CD4 parameters (baseline count and percentage and historical nadir), baseline HIV-1 viral load, route of transmission, international location, ARV treatment, gender, ethnicity, body mass index (BMI), and cigarette smoking. Logistic regression analysis was used to evaluate the factors as predictors of initial vaccine response. Stepwise and best subsets methods were used to develop multivariate models for predicting vaccine response. Kaplan-Meier curves and proportional hazards modeling was used to evaluate predictors of duration of vaccine response. For responders at 28 weeks, duration was defined as the time to the first negative serology result using a response cutoff of 10 IU/mL; subjects with missing data were censored at the last available time point. Sensitivity analyses were performed to determine the effect of missing end point data. All analyses were conducted using SAS, Version 9.2 (SAS Corp, Cary, NC).
Three hundred-seventy-one subjects were enrolled and randomized and 336 (90.6%) had HBV serology performed at Week 28 and were considered evaluable (Fig. 1). The evaluable group differed from the randomized group as shown in Table 1. Demographic, historical, and HIV disease and treatment characteristics for the latter group are shown in Table 1. Subjects in the three arms were similar with the exception of more evaluable subjects who never smoked cigarettes in Arm 3.
At Week 28, the experimental arms demonstrated greater vaccine response than the control arm (Engerix B, 20 μg). The increased dose arm (Engerix B, 40 μg) had a response rate of 73.2% (95% confidence interval [CI], 65-81.4%) compared with 60% (95% CI, 50.8-69.2%) in the standard dose (Engerix B, 20 μg) arm (P = 0.04). Similarly, the Twinrix arm showed an improved response rate of 75.4% (95% CI, 67.7-83.2%) compared with the standard dose (P = 0.02). Other predictors of vaccine response in univariate analyses included female gender, higher nadir CD4, higher baseline CD4 and percentage, lower baseline viral load, and enrollment at a US site (Table 2). Ethnicity, BMI, smoking, and use or type of ARV were not related to response. Route of infection was also not related to response (P = 0.12). In addition, when perinatally infected subjects were compared with all others, no differences in response were observed (P = 0.07). However, when perinatally infected subjects were compared with those infected by high-risk behaviors (excluding missing, unknown, and transfusion categories), those infected perinatally had poorer response to vaccination (60.0% versus 73.3%, P = 0.047).
Vaccination with Twinrix resulted in higher mean levels of HBsAb (97.7 IU/mL) compared with the Engerix B, 20-μg arm (52.5 IU/mL, P = 0.03). The difference between the two Engerix B arms was not statistically significant (52.5 versus 77.6 IU/mL, P = 0.17).
In a multivariate analysis, treatment arm and baseline CD4 count remained statistically significant (Table 2) along with an interaction term that reflects how subjects in the increased dose Engerix B arm responded differently depending on their CD4 count. This model indicates that the odds of responding to study vaccine are 1.99 times higher for subjects in the Twinrix arm compared with the Engerix B, 20-μg arm, regardless of CD4 count. Subjects receiving the Engerix B, 40-μg vaccine with CD4 counts at the lowest quartile (305) had odds of 1.34 for vaccine response when compared with the Engerix B, 20-μg arm; this odds ratio increases to 2.91 for the median CD4 count (460) and to 8.23 at the third quartile (668). Further analysis indicated that male gender, international location, and perinatal infection all had significant associations with low CD4 counts (data not shown), thus further justifying CD4 count as the strongest predictor of vaccine response.
Results were similar when sensitivity analyses for missing data and per-protocol analyses were conducted. Analyses were performed using two scenarios: all missing data indicating response and all missing data indicating lack of response. Specifically, the logistic regression analysis was repeated assuming that missing response data at Week 28 indicated nonresponse; results for the adjusted analysis were similar to results shown in Table 2.
Among the 118 subjects in the Twinrix arm, 53% had positive HAV qualitative serology at baseline and 98% at Week 28. HBV response after Twinrix administration was independent of baseline HAV antibody status (P = 0.2).
Two hundred twenty vaccine responders were analyzed for duration of HBV response using both the nominal study visit week and actual time lapse since completion of vaccination series. After 72 weeks, 41.4% (standard deviation [SD] 4.9%), 52.4% (SD 4.7%), and 50.4% (SD 4.8%) of the subjects Arms 1, 2, and 3, respectively, had HBsAb levels 10 IU/mL or greater (Fig. 2); the differences between the standard of care (Arm 1) and the experimental arms (2 and 3) were not statistically significant. Similarly, the overall differences between Kaplan-Meier curves for response duration in Figure 2 were not statistically significant (P = 0.10). Thus, the difference in duration of response based on treatment arm was not statistically significant. Using proportional hazard modeling, only age and baseline CD4 count were associated with duration of vaccine response (data not shown).
No vaccine responder had evidence of new-onset HBV infection. A fourth vaccine dose of Engerix B, 40 μg, was administered to 82 subjects who were vaccine nonresponders. Only 23% demonstrated antibody level of 10 IU/mL or greater after this fourth vaccination.
All vaccine regimens were well tolerated and safe. No severe adverse events were observed. Vaccine-associated events included headache (six), asthenia (one), arthralgia (two), somnolence (one), syncope (one), injection site pain (three), and myalgia (three) and most were mild in severity (Grade 1 or 2). Only one Grade 3 adverse event, arthralgia, was possibly related to study vaccine. There were no differences in events between vaccine arms.
In this study of HIV-infected youth, 70% of HBV vaccine recipients demonstrated vaccine response 28 days after completing the series, a substantial improvement over rates in prior reports. Only one study of patients in Thailand, aged 21 to 45 years and receiving highly active antiretroviral therapy with undetectable HIV-1 viral loads, demonstrated a similar response rate of 71% after vaccination with Engerix B, 20 μg.21 The improved response among our subjects may be the result of younger age (mean = 20 years) or higher CD4 counts. In adult trials, younger age has been associated with improved vaccine response,22,31 whereas the median CD4 count of 460 cells/mL in our population (only 13% of our subjects had CD4 less than 200 cells/mL) is greater than that in many of the adult studies of HBV vaccination.12,14,16,18,20,21,22,24
A key finding of this study is that vaccination with increased dose of HBV antigen is an independent predictor of short-term vaccine response, modified by CD4 count. This result supports previous studies in adults. Fonseca evaluated 210 HIV-infected adults randomized to receive Engerix B, either 20 μg or 40 μg per dose, in a three-dose series.18 Overall, they report a 34% response rate with the 20-μg dose compared with a 47% response rate with the 40-μg dose (P = 0.07), but they found a statistically significant difference between doses when the analysis was limited to subjects with CD4 350 cells/mL or greater or to subjects with HIV-1 viral loads less than 10,000 copies/mL. Our study also found better response for the 40-μg arm at higher CD4 counts. Similarly, Cornejo-Juarez demonstrated improved response to higher dose vaccines but only in patients with CD4 200 cell/mL or greater.3,24 Our results support these findings by establishing the interaction between vaccine response and CD4 level with the odds ratio for vaccine response rising from 1.34 for CD4 of 305 (first quartile for our participants) to 8.23 for CD4 of 668 (third quartile).
We also demonstrated improved vaccine response and higher levels of HBsAb to 20 μg of HBV antigen when it was combined with HAV antigen in Twinrix. Knoll et al and Ambrosch et al both demonstrated a trend toward higher levels of HBsAb when the combination vaccine was used compared with monovalent HBV vaccine in HIV-uninfected youth.27-29 We believe this is the first study to compare Twinrix with monovalent HBV vaccine in an HIV-infected population. In a study of 97 HIV-infected adults reported by Kim, one third of the subjects received Twinrix. However, no analysis of response in these subjects compared with monovalent HBV vaccine was performed.22 Twinrix could potentially be used routinely in a clinic setting because it can be safely administered to HAV-seropositive individuals. Therefore, it would not be necessary to assess HAV immune status before vaccination. Also of interest, although an improved response was seen with combination vaccination, pre-existing antibody to HAV did not predict HBV response in subjects receiving Twinrix.
Factors previously reported to affect immunogenicity of HBV vaccine were explored, but only treatment arm and higher baseline CD4 count were independent predictors of response. BMI and smoking status did not influence immunogenicity. These factors are important predictors among immunocompetent patients but have not emerged as important factors in HIV-infected individuals,32,33 probably because immune status, evidenced by CD4 counts, HIV-1 viral loads, and highly active antiretroviral therapy, are stronger predictors of vaccine response in HIV-infected populations.
Route of infection was explored as a factor related to immune response. We observed no differences in response rates among perinatally infected youth compared with nonperinatally infected youth (P = 0.07). However, we did observe marginally statistically significant response rates when perinatally infected youth were compared with those infected through high-risk behaviors (P = 0.047). We suggest that the status of the immune system as manifested by the CD4 count rather than the mode of infection underlies these findings.
Management of patients lacking immune response after vaccination remains controversial. Booster vaccines, using both standard and increased amounts of antigen, have been evaluated with highly variable success (5-78%).4,10,12,14,19,31,34,35 Our poor rate of seroconversion, 23%, after an additional dose of HBV vaccine was similar to Tayal14 and Bloom34 in which one to three additional doses of vaccine in nonresponders after standard dose regimens resulted in seroconversion of 25% and 29%, respectively. Boosters with one to three double doses of vaccine has also been reported to be effective after initial failure of a standard dose of antigen but again with highly variable results.4,19,31,35 In adult studies, one to three additional boosters resulted in 51% and 73% seroconversion.19,31 In perinatally infected children, one to two doses resulted in 14% and 73% seroconversion.4,35 Unfortunately, the findings of this study do not further inform this controversy.
We observed high levels of vaccine response after completion of the vaccinations series along with statistically significant differences between standard of care (Arm 1) and the experimental Arms (2 and 3). However, the differences between arms were not statistically significant at Week 72, and antibody levels waned over this period. At Week 72, approximately half of the subjects had HBsAb levels thought to be protective. This result is similar to the REACH cohort in which approximately 40% of HIV-infected youth who had ever received HBV vaccination had protective antibody levels. Declining antibody levels may increase risk for HBV infections in this population.36
Despite a history of prior HAV vaccination in only 5% of the evaluable subjects receiving Twinrix, 53% were seropositive at baseline. Response to HAV immunization was excellent with 98% seropositive at Week 28. This finding is consistent with prior studies that reported seroresponse rates of 84.5% in HIV-infected children and adolescents after two doses of vaccine and 88.4% in HIV-infected adults after a three-dose series.37,38 Higher CD4% and lower viral loads have been correlated with HAV response in HIV-infected children and adolescents.37,39 In HIV-infected adults, CD4 greater than 350 cells/mL was associated with improved response, although not statistically significant.38
In summary, vaccination with Engerix B, 40 μg, or Twinrix resulted in greater HBV vaccine response compared with standard-dose Engerix B, 20 μg, at Week 28. Because vaccination with both HBV and HAV is recommended in HIV-infected patients, protection for both infections may be achieved using one vaccine series with Twinrix, potentially improving patient acceptance and reducing cost. In addition, because higher CD4 count was an independent predictor of vaccine response, consideration may be given to stabilizing patients on highly active antiretroviral therapy and increasing CD4 counts before initiating HBV vaccination, although the risk and benefit of delaying vaccination must be considered and the patient educated about transmission routes for HBV and avoidance of infection risk.
Additional protocol team members included Audrey Smith Rogers, PhD, MPH, and Leslie Serchuck, MD, Pediatric, Adolescent and Maternal AIDS Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD; Patrick Jean-Phillippe, MD, Henry Jackson Foundation, Rockville, MD; Jonas H. Ellenberg, PhD, Westat Corp; George Seage, DSc, MPH, Harvard School of Public Health; and Linda Levin, MD, Mount Sinai Medical Center, New York, NY.
The study was scientifically reviewed by the ATN's Therapeutic Leadership Group. Network, scientific, and logistic support was provided by the ATN Coordinating Center (C. Wilson, C. Partlow) at the University of Alabama at Birmingham. Network operations and analytic support were provided by the ATN Data and Operations Center at Westat (J. Korelitz, B. Driver).
We acknowledge the contribution of the investigators and staff at the following sites that participated and enrolled subjects into this study: Children's Diagnostic and Treatment Center, Fort Lauderdale, FL (Anna Puga, MD, Esmine Leonard, RN, Zulma Eysallanne, RN, Amy Inman, BS); Children's Hospital of Los Angeles, Los Angeles, CA (Marvin Belzer, MD, Diane Tucker, RN, MSN); Children's Memorial Hospital, Chicago, IL (Robert Garofolo, MD, Julia Brennan, RN, MSN, ANP-C, Jennifer Kershaw, CPNP); Children's National Medical Center, Washington, DC (Lawrence J. D'Angelo, MD, Connie Trexler, RN, CPN, BSN, Rita Hagler, CPNP, Amy Klamberg, CPNP); John H. Stroger Jr Hospital of Cook County and the Ruth M. Rothstein CORE Center, Chicago, IL (Jaime Martinez, MD, Lisa Henry-Reid, MD, Kelly Bojan, DNP, RN, CFNP, Rachel Jackson, MSN, APN, CFNP); Montefiore Medical Center, Bronx, NY (Donna Futterman, MD, Elizabeth Enriquez-Bruce, MD, Maria Campos, RN); Mount Sinai Medical Center, New York, NY (Linda Levin-Carmine, MD, Mary Geiger, RN, Angela Lee, PA-C); St Jude Children's Research Hospital, Memphis, TN (Sarah Stender, MD, Kristen Branum, BS, Mary Dillard, RN, Tina Culley, BS, Carla McKinley, FNP, Thomas Wride, MS); Tulane University Health Sciences Center, New Orleans, LA (Sue Ellen Abdalian, MD, Alyne Baker, RN, MN, Leslie Kozina, RN, Trina Jeanjacques, BA); University of California at San Francisco, San Francisco, CA (Barbara Moscicki, MD, Coco Auerswald, MD, J.B. Molaghan, CRNP); University of Maryland, Baltimore, MD (Ligia Peralta, MD, Leonel Flores, MD, Reshma S. Gorle, MPH); University of Puerto Rico, San Juan, PR (Irma L. Febo, MD, Hazel T. Ayala-Flores, BSN, Anne T. F. Gomez, BA); and the University of South Florida, Tampa, FL (Patricia Emmanuel, MD, Jorge Lujan-Zilbermann, MD, Diane M. Straub, MD, MPH, Silvia Callejas, BSN, ACRN, Priscilla C. Julian, RN, Amayvis Rebolledo, MAD). The following PACTG/IMPAACT sites also participated and enrolled subjects into this study: Children's Hospital of Boston, Boston, MA (Cathryn Samples, MD, MPH, Susan Sommer, MSN, RNC, Helen Mahoney West, MSN, CPNP, Martha Cavallo, MS, WHNP); University of California at San Diego, San Diego, CA (Stephen A. Spector, MD, Ronaldo M. Vianni, MD, Kimberly A. Norris, RN, Lisa Stangl, FNP); University of Alabama, Birmingham, AL (Robert Pass, MD, Marilyn Crain, MD, Newana Beatty, BA); Duke University (Felicia Wiley, RN); University of Florida College of Medicine, Jacksonville, FL (Mobeen H. Rathore, MD, Ayesha Mirza, MD, Nizar Maraqa, MD, Ann Usitalo, PhD); Children's Hospital of Michigan (Ellen Moore, MD, Elizabeth Secord, MD, Ulyssa Hancock, BSN); Boston Medical Center, Boston, MA (Ellen R. Cooper, MD, Barbara Damon Marinaccio, CPNP, Desiree Jones-Eaves, RN, Debra A. McLaud, RN); The Children's Hospital, Denver, CO (Mark J. Abzug, MD, Myron J. Levin, MD, Emily A. Barr, PNP, CNM, Jody Maes, MD, Elizabeth McFarland, MD, Suzanne Paul, FNP-C, Carol Salbenblatt, MSN, Adriana Weinberg, MD); Princess Margaret Hospital, Nassau (Michael Gomez, MD, Percy McNeil, MD, Robert Orlander, MD, Marva Jervis, MS, Chanelle Diggins, RN); San Juan Hospital, San Juan, Puerto Rico (Midnela Acevedo, MD, Milagros Gonzalez, MD, Thalita F. Abreu, MD, Lourdes Angeli, RN, MPH, Wanda Marrero, RN, Elvia Perez, MEd, MA); IPPMG-UFRJ, Rio de Janeiro, RJ, Brazil (Ricardo Hugo Oliveira, MD, Maria C. Sapia, MD, Christina B. Hofer, Elizabeth Machado, MD, PhD); Hospital dos Servidores do Estado, Rio de Janeiro, Brazil (Maria Leticia S. Cruz, MD, Esaú C. João Filho, MD, Angela Beatriz N. Carvalho, MD, Claudette A. Cardoso, MD, Eduarda Gusmão, MD, Elaine Santos, RN); Federal University of Minas Gerais, Belo Horizonte, Brazil (Jorge Pinto, MD, Flávia Gomes Faleiro Ferreira, MD, Mónica D. Brandáio, RN); Instituto de Infectologia Emilio Ribas, São Paulo, Brazil (Marinella Della Negra, MD, Wladimir Queiroz, MD, Yu Ching Lian, MD); Hospital das Clinicas da Faculdade de Medicina de Ribeirão Preto/USP, Ribeirão Preto, Brazil (Marisa Márcia M. Mussi-Pinhata, MD, Geraldo Duarte, MD, Carolina S. Vieira, MD, Conrado M. Continho, MD, Tatiana C. Matsubara, RN); Harriet Shezi Children's Hospital, Soweto, South Africa (Tammy Meyers, MD, Hermien Gous, PharmD, Janet Grab, Pharm, Lee Kleynhaus, MD, Sally Naidoo, RN, Merleesa Naidoo, Angela Oosthuizen, BS, Megan Palmer, MD); and all the site pharmacists.
We also thank Jacqueline Loeb (Westat) for protocol support and William Meyer, Lawrence Hirsch and James Hong (Quest Diagnostics, Inc, Baltimore, MD) for laboratory guidance and support.
The investigators are grateful to the members of the local youth Community Advisory Boards for their insight and counsel and are particularly indebted to the youth who participated in this study.
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