Faculty Bibliography

Adolescents and youth aged 15-24 are one of the populations most impacted by the global HIV epidemic with an estimated 50% of new infections occurring in this age group. They are thus one of the prime populations for targeting behavioral and biomedical preventions. However, the dynamics of the HIV epidemic in youth vary widely by geographic region and risk behavior profiles. There are also biological and neurodevelopmental considerations that must be considered in the development, testing, and ultimate dissemination of HIV prevention interventions. These concepts are broadly discussed here

BACKGROUND: Multiple studies have shown excellent response rates after hepatitis B immunization in youth; however, one previous study conducted in urban youth demonstrated poor responses. METHODS: Urban youth, ages 12 to 17 years, at participating Adolescent Medicine Trials Network for HIV/AIDS Interventions Clinical/Research sites were randomized to receive either 2 doses of Recombivax HB (10 microg hepatitis B surface antigen) or Twinrix (20 microg hepatitis B surface antigen and 720 EL.U hepatitis A antigen) at 0 and 24 weeks. Safety data were collected and antibody measures performed at 0, 28, and 76 weeks. RESULTS: A total of 123 subjects were enrolled and 102 had week 28 serum samples available for antibody measure. A positive response (serum antibody > or =10 mIU/mL) to hepatitis B antigen was documented in 41 of 47 (87.2%; 95% confidence interval [CI] 74.3%-95.2%) Recombivax HB recipients and in 52 of 55 (94.6%; 95% CI, 84.9%-98.9%) Twinrix recipients (P = 0.295). In an adjusted analysis, those identified as Hispanic ethnicity (N = 86) were more likely to have a positive response (odds ratio 7.38, 95% CI, 1.56-34.95; P = 0.0018); whereas those who identified as not heterosexual (N = 9) were less likely to respond (odds ratio = 0.12, 95% CI, 0.02-0.74). The majority of youth in the Twinrix arm were hepatitis A antibody positive at baseline (26/51; 51%); however, 24 of 25 hepatitis A antibody negative youth responded to the hepatitis A component. Both vaccines were safe. CONCLUSIONS: Response rate to 2 doses of Recombivax HB in urban youth is lower than previous studies suggest. The factors associated with diminished response are not known.

Abstract Adherence to antiretroviral regimens continues to be a significant problem in HIV-infected individuals facing a lifetime of therapy. Youth who were infected through perinatal transmission enter into adolescence often with a history of multiple medication regimens. Thus, adherence can be a particularly important issue in these young people, as medication options can often be limited. This was a cross-sectional, observational study to determine the prevalence of personal barriers to adherence and to identify associations among the following barriers in subjects 12 to 24 years old: mental health barriers, self-efficacy and outcome expectancy, and structural barriers. Among the 368 study participants, 274 (74.5%) were adherent and 94 (25.5%) were nonadherent to highly active antiretroviral therapy (HAART). No significant differences were found between adherent and nonadherent subjects according to mental health disorders. Adherence was associated with some but not all structural barriers. Both self-efficacy and outcome expectancy were significantly higher in adherent versus nonadherent subjects (p < 0.0001). In subjects with low self-efficacy and outcome expectancy, adherence differed according to the presence or absence of either mental health or structural barriers, similar to findings in behaviorally- infected adolescents. Interventions that address the breadth and clustering of adherence barriers in adolescents are needed to have the maximum chance for positive effects

This was a proof-of-principle study to evaluate the impact of short cycle therapy (SCT; 4 days on/3 days off) in adolescents and young adults with good viral suppression on a protease inhibitor-based antiretroviral regimen. Subjects were recruited by the Adolescent Trials Network for HIV/AIDS Interventions and the Pediatric AIDS Clinical Trials Group. Subjects were infected either through perinatal/early childhood transmission or later via risk behaviors. All subjects were required to have at least 6 months of documented viral suppression below 400 copies/ml plus a preentry value below 200 copies/ml and an entry CD4+ T cell count above 350 cells/mm3. Of the 32 subjects enrolled, 12 (37.5%) had confirmed viral load rebound >400 copies, with 18 subjects (56%) coming off for any reason. The majority of subjects resuppressed when placed back onto continuous therapy using the same agents. Although no difference was found in virologic rebound rates between the early and later transmission groups, those infected early in life had higher rates of coming off SCT for any reason. There was no impact of SCT on the CD4+ T cell counts in those who remained on study or those who came off SCT for any reason. Subjects demonstrated good adherence to the SCT regimen. This study suggests that further evaluation of SCT may be warranted in some groups of adolescents and young adults infected with HIV

Adherence continues to be a major barrier to successful treatment with highly active antiretroviral therapy (HAART) for HIV-infected individuals. HIV-infected adolescents and young adults face a lifetime of treatment with HAART. Often, individuals who struggle with adherence to HAART face multiple barriers that would therefore impact on the success of any single modality intervention. Thus, we conducted a cross-sectional, observational study to determine the prevalence of personal barriers to adherence and to identify associations between these barriers in HIV-infected subjects, 12 to 24. We studied the following personal barriers to adherence: mental health barriers, high/low self-efficacy and outcome expectancy, and the presence of specific structural barriers. There were 396 subjects infected after age 9 recruited from sites from the Adolescent Trials Network for HIV/AIDS Interventions or the Pediatric AIDS Clinical Trials Group. Of the 396 subjects, 148 (37.4%) self-identified as nonadherent. No significant differences were found between adherent and nonadherent subjects for the presence of mental health disorders. Adherence was significantly associated with all but one structural barrier. Both self-efficacy and outcome expectancy were higher among adherent versus nonadherent subjects (p < 0.0001). Grouping subjects according to low self-efficacy and outcome expectancy for adherence, adherence differed according to the presence or absence of mental health disorders and structural barriers (p < 0.0001). Our data suggest that adolescents have significant rates of non-adherence and face multiple personal barriers. Adherence interventions must address multiple barriers to have the maximum chance for positive effects.

Treatment failure and drug resistance create obstacles to long-term management of HIV-1 infection. Nearly 60% of infected persons fail their first highly active antiretroviral therapy (HAART) regimen, partially because of nonadherence, requiring a switch to a second regimen to prevent drug resistance. Among HIV-infected youth, a group with rising infection rates, treatment switch is often delayed; virologic and immunologic consequences of this delay are unknown. We conducted a retrospective, longitudinal study of drug resistance outcomes of initial HAART in U.S. youth enrolled between 1999-2001 in a multicenter, observational study and experiencing delayed switch in their first nonsuppressive treatment regimen for up to 3 years. HIV-1 genotyping was performed on plasma samples collected longitudinally, and changes in drug resistance mutations, CD4+ T cell numbers and viral replication capacity were assessed. Forty-four percent (n = 18) of youth in the parent study experiencing virologic nonsuppression were maintained on their initial HAART regimen for a median of 144 weeks. Drug resistance was detected in 61% (11/18) of subjects during the study. Subjects on non-nucleoside reverse transcriptase inhibitor (NNRTI) regimens developed more (8/10) drug resistance mutations than those on protease-inhibitor (PI) regimens (2/7) (p = 0.058). Subjects developing NNRTI-resistance (NNRTI-R), showed a trend toward lower CD4+ T cell gains (median: -6 cells/mm(3) per year) than those without detectable NNRTI-R (median: +149 cells/mm(3) per year) (p = 0.16). HIV-1-infected youth maintained on initial nonsuppressive NNRTI-based HAART regimens are more likely to develop drug-resistant viremia than with PI-based HAART. This finding may have implications for initial treatment regimens and transmission risk in HIV-infected youth, a group with rising infection rates

Several emergency department (ED)-based HIV screening programs have been described. However, the majority of these programs have been aimed at adults and older adolescents, and few have taken place in a dedicated pediatric ED. Given that many adolescents seek care in hospital EDs, and that the ED may be an adolescent's only contact with the health care system, we decided to implement an HIV-counseling and testing program in the ED of an urban children's hospital. The program included a dedicated health educator who provided sexual health counseling in a 30-minute session as well as optional HIV testing and test results to patients aged 14-24 years, and arranged necessary follow-up care for adolescents who tested positive for HIV. We collected aggregate data on the number of youth counseled, tested, and followed up. A total of 1287 patients were approached for potential counseling and testing during the first 3 years of the project. Of these, 643 (50.0%) agreed to meet with the health educator and were counseled. Three hundred eighteen (49.5%) of these patients agreed to HIV testing. One hundred eighty-seven (58.8%) patients returned for follow-up. Two patients (0.6%) whose previous HIV status was unknown tested positive for HIV; both of these patients were successfully linked to care. Fifty-six health care providers (17.3% of ED providers) were surveyed about their opinions of the program; although 93% were supportive of the program, several respondents were concerned about the appropriateness of HIV testing in the ED setting. This project suggests that, if appropriate resources are available, a dedicated HIV counseling and testing program can be successfully implemented in a busy, urban, pediatric ED. Providing access to these services to high-risk adolescents has the potential to significantly impact their health.

The PACTG 381 cohort included 120 adolescents infected via high-risk behaviors and treated with at least two NRTIs plus either a protease inhibitor or an efavirenz-containing HAART regimen. After 24 weeks of therapy, only 69 of 118 (59%) evaluable subjects had undetectable viral loads. We now present findings of the study after 3 years of follow-up. Virologic, immunologic, and treatment information were collected from subjects every 12 weeks beyond the first 24 weeks of therapy through 156 weeks. Of the 120 subjects starting HAART, 44 (37%) stayed on study treatment for the 3 years of observation. Twenty-nine (24%) subjects reached and maintained undetectable viral loads. Poorer adherence (p = 0.016), higher baseline viral load (p = 0.010), and CD8 naive counts (p = 0.034) predicted virologic failure. Immunologic measurements improved from entry to the end of follow-up in the subjects with undetectable viral loads. CD4 counts at the end of study were not significantly different from HIV-uninfected youth, but CD4%, CD8 counts and percent, and CD8 activation markers remained significantly different. Adolescents infected with HIV via high-risk behaviors have less than optimal responses to HAART therapy with only 24% achieving and maintaining undetectable viral loads over 3 years. Immunologic improvement was demonstrated and CD4 counts in subjects with virologic control reached levels in HIV-uninfected adolescents. Interventions, especially those focused on adherence, are necessary to improve HAART outcomes in adolescents

This study examined trauma history and posttraumatic stress in a sample of 30 adolescents and young adults with HIV/AIDS, recruited from December 14, 2004 through May 3, 2005. Overall, participants reported a mean of 5.63 traumatic events, with 93% of the sample reporting that receiving a diagnosis of HIV was experienced as traumatic. Of these, 13.3% met criteria for posttraumatic stress disorder in response to HIV diagnosis, while an additional 20% showed significant post-traumatic stress symptoms. Even greater rates of posttraumatic stress were reported in response to other trauma, with 47% of youth surveyed reporting symptoms of posttraumatic stress in response to such traumatic events as being a victim of a personal attack, sexual abuse, or being abandoned by a caregiver. These findings may inform professionals about the potential impact of the HIV diagnosis on adolescents and young adults, particularly as this may impact participation in medical care and need for mental health support