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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Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
HIV; hepatitis B vaccination; adolescents; Engerix B; Twinrix