Adolescent Research Agenda Committee

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Adolescent Research Agenda Committee

• Chair Pat Flynn, M.D.
• Vice-Chair Bret Rudy, M.D.

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Adolescents and HIV

• Adolescents and young adults account for 50 of
  new infections in the US
• Internationally, also age of highest risk for new
  infections

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Major Focus Areas

• HIV Prevention and Vaccine Preparedness
• Interventions to Prevent Disease Progression
• Minimize Co-Morbidities

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Major Focus 1 HIV Prevention and Vaccine
Preparedness

• To identify and define the HIV risk factors of
  seronegative youth within the families living
  with HIV and engaged in care at domestic and
  international PACTG sites
• To develop and implement HIV vaccine trials for
  at risk HIV-negative youth as part of a primary
  prevention program

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Pilot Projects in US and South Africa

• Family Mapping Project
• Recruited social network members of HIV-infected
  teens or women
• Delivered prevention message in 2 sessions and
  assessed willingness to participate in vaccine
  trial

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Pilot Projects in US and South Africa

• African Vaccine Preparedness Project
• Cape Town and Johannesburg
• Establish longitudinal cohort of HIV-at risk
  youth
• Assess community acceptance of HIV vaccine trials
  through focus groups and identification of
  community stakeholders
• Develop an HIV prevention program for this
  population

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Vaccine Preparedness Future

• Domestic
• Potential to expand Family Mapping Project to
  additional US sites
• International
• Planned two year follow up of African cohort
  (Cunningham, Vaccine Agenda)

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Major Focus 2 Interventions to Prevent Disease
Progression

• To determine the most effective ART regimen for
  HIV adolescents
• To determine optimal timing of therapy initiation
• To test the benefits of simplified regimens
• To define measures to improve adherence
• To define ART dosing guidelines based on pubertal
  development
• Treatment strategies for the patient with limited
  treatment options

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Determining Most Effective ART Regimen

• PACTG 1034 Adolescent PI vs. Efv
• Failed to accrue despite co-endorsement by ATN
• Are their biologic differences in treatment
  effectiveness in adolescents vs. adults vs.
  children?
• New treatment guidelines, healthy immune status
  of youth entering care, and concerns about
  treatment readiness make large trials prohibitive
• Small proof of concept may be more appropriate

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Determining Optimal Time of Treatment Initiation

• Adolescents have potential for greater immune
  recovery following HAART compared to adults.
• Poor treatment readiness and early failure plague
  adolescent therapy
• Early initiation to preserve immune function vs.
  delayed initiation to preserve treatment options
  conflict
• ATN protocol currently in development to begin to
  address

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Simplified Treatment Regimens For Adolescents

• ATN 015 4 days on, 3 days off PI based regimen
  following virologic control analysis underway
• PACTG 1040 Induction/Simplification to NRTI
  based therapy on-hold
• AACTG Promising results with once daily
  atazanavir/ritonavir may present a better option
• CD4 guided treatment interruption unlikely to be
  supported

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Define Measures to Improve Adherence

• Evidence supports most common reason for
  treatment failure is non-adherence to therapy
• Reasons for non-adherence multi-factorial (PACTG
  and ATN 023 b)
• PACTG 1036B Pilot Study of Directly Observed
  Therapy in Adolescents Infected Via High Risk
  Behaviors
• Potential to expand to perinatally infected
  adolescents
• Interventions combining DOT with other
  interventions

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Defining ART dosing based on pubertal development

• Mostly in the PI class of agents, data suggests
  that children and adolescents require higher
  doses to achieve targeted drug levels
• Should the practitioner dose beyond adult maximum
  without TDM?
• Does Tanner stage play a role in determining
  dosing?

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Major Focus 3 Minimize Co-Morbidities

• Infectious Co-Morbidities
• HPV
• Hepatitis B
• HSV
• Pregnancy
• Metabolic Abnormalities identified in PACTG 1045
• Behavioral Issues of Aging Up Perinatally
  Infected Adolescents

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Infectious Co-morbidities In HIV-infected
Adolescents

• HPV therapy and infection
• PACTG 1046 HPV therapeutic vaccine
• Availability of product and commitment to
  protocol unknown
• PACTG 1047 HPV prophylaxis vaccine
• Hepatitis B Prevention
• ATN 024, 48, 52 Hep B vaccine for HIV youth and
  companion studies to investigate immunologic and
  genetic factors influencing response

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Minimizing Metabolic Complications

• Metabolic
• Nutritional deficiencies
• Obesity
• Interventions addressing other abnormalities
  identified in PACTG 1045/ATN021

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Behavioral Issues in Ageing-Up Perinatally
Infected Adolescents

• Transferring responsibility for medication
  adherence
• Disclosure to friends and potential sexual
  partners
• Transition to adult care
• Rebellion

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Challenges

• Availability of HIV-infected adolescents at CTS
  not know
• Reality check Ages 12 24 enrolled 03-04

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Opportunities

• Focus on available populations
• Domestically aging-up perinatally infected
  youth
• Internationally HIV-infected via high risk
  behaviors and HIV-negative at-risk
• Collaboration instead of overlap with other
  Networks ATN and AACTG

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Interactions with AACTG

• Previously limited to co-endorsement of studies
  focusing on womens health and pregnancy
• New DAIDS structure should increase availability
  of initial treatment studies open to adolescents
  infected via high risk behavior
• Refer our adolescents to AACTG treatment trials

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Interactions with ATN

• Established process for co-endorsement and
  co-development of protocol for both domestic and
  international protocols PACTG 1034, ATN 015,
  023b, 024, 048, 052
• Considerable overlap between individuals and
  clinical sites cities (but not necessarily
  clinics)

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Adolescent Trials Network
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Collaborations with ATN

• Encourage co-development of appropriate protocols
  of the Therapeutics Leadership Group
• Define better ways to interact/consult with the
  Behavioral Leadership Group (focused on chronic
  disease of perinatal HIV infection and adherence)
  
• Avoid duplication of efforts of Community
  Prevention Leadership Group (defining domestic
  HIV-at risk cohort for vaccine studies)

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Focus of ADRAC 2006-07

• Major Focus HIV Prevention and Vaccine
  Preparedness
• Domestic consider expansion of Family Mapping
  Project in consultation with ATN CPLG
• International Develop observational cohort as
  described in Vaccine Agenda

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Focus of ADRAC 2006-07

• Major Focus Interventions to Prevent Disease
  Progression
• Domestic
• Resolve recommendations for PI dosing
• Does data exist from other studies to answer this
  question?
• Development of 1026-like study of aging up youth
  on PI therapy to inform dosing guidelines through
  puberty
• Compare dosing based on weight vs. Tanner staging
• Establish relationship with AACTG for primary
  treatment trials, possible salvage trials

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Focus of ADRAC 2006-07

• Major Focus Interventions to Prevent Disease
  Progression
• Domestic
• Complete 1036B, consider amendment for enrolling
  perinatally infected aging up adolescent
• Co-endorsement/Co-development of ATN early vs.
  delayed therapy trial
• Reconsider development of PACTG 1040 vs
  co-enrollment in AACTG atazanavir/ritonavir trial

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Focus of ADRAC 2006-07

• Major Focus Interventions to Prevent Disease
  Progression
• International Yet to be defined
• Establishment of adolescent cohorts
• Pediatrics vs. Adult providers

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Focus of ADRAC 2006-07

• Major Focus Minimize Co-Morbidities
• Domestic
• 1046 Therapeutic HPV vaccine
• Hepatitis B protocols
• Pregnancy outcome of ageing-up perinatally
  infected adolescents
• Behavioral aspects of ageing-up perinatally
  infected adolescents

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Top Priorities

• Domestic
• Recommendations for PI dosing for Ageing-Up
  Perinatally Infected Adolescents
• Vaccine Management of HPV disease
• Behavioral Interventions in Ageing-Up Perinatally
  Infected Adolescents- HIV as a Chronic Disease
• International
• Vaccine Preparedness
• Development of Adolescent Treatment Research
  Agenda (?)

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Future Directions

• Continuation of ADRAC vs splitting agenda across
  other committees
• Enhance relationships with ATN and AACTG to
  reduce overlap resulting in cost reductions
• Recruitment of individuals experienced in
  behavioral research to lead these investigations

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Top Priorities

• Domestic
• Resolve Recommendations for PI dosing (Primary
  Therapy)
• Vaccine Management of HPV disease (Complications)
• Behavioral Interventions in Ageing-Up Perinatally
  Infected Adolescents- HIV as a Chronic Disease
  (Complications)
• International
• Vaccine Preparedness (Vaccine)
• Development of Adolescent Treatment Research
  Agenda (?) (Primary Therapy)

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Future Directions

• Decision about continuation of ADRAC vs splitting
  agenda across other committees
• Enhance relationships with ATN and AACTG to
  reduce duplication of effort resulting in cost
  savings for all
• Define the structure of these interactions
• Recruitment of individuals experienced in
  behavioral research to lead these
  investigations/mechanism for consultation with
  ATN
• Recruitment of international expertise