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Selected NIH-sponsored HIV Research Studies Involving Women, Adolescents, and Children

Selected NIH-sponsored HIV Research Studies Involving Women, Adolescents, and Children. Bill G. Kapogiannis , MD, FAAP Pediatric, Adolescent & Maternal AIDS (PAMA) Branch Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH Bethesda, MD.

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Selected NIH-sponsored HIV Research Studies Involving Women, Adolescents, and Children

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  1. Selected NIH-sponsored HIV Research Studies Involving Women, Adolescents, and Children Bill G. Kapogiannis, MD, FAAP Pediatric, Adolescent & Maternal AIDS (PAMA) Branch Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH Bethesda, MD

  2. Disclosures of Financial Relationships This speaker has no significant financial relationships with commercial entities to disclose. This speaker will not discuss off-label use or investigational product during the program. This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

  3. Learning Objectives • Recognize past and ongoing studies of the Adolescent Trials Network (ATN) • Identify past and ongoing studies of the Infant, Maternal, Pediatric, and Adolescent AIDS Clinical Trials group (IMPAACT) • Discuss future research directions

  4. Choose the correct answer about optimal timing of HAART initiation in HIV+ infants: • Initiation at 6-12 weeks of age results in a 3/4 reduction in early infant mortality • Deferral of therapy until infant CD4% < 20% does not impact neurodevelopmental outcomes • Among infants receiving early HAART, duration of therapy (1 vs 2 years) prior to interruption had little impact on how soon therapy had to be restarted • Significantly more infants in whom therapy was deferred required switch to 2nd-line ART on study than those initiating early

  5. CHER Schema HIV infection diagnosed before age 12 weeks and CD4 >25% (All get CTX and pneumococcal vaccine) ARM 1 ART* defer until needed N=125 ARM 2 Short-course 40 weeks of ART* (until ~1st birthday) N=125 ARM 3 Longer-course 96 weeks of ART* (until ~2nd birthday) N=125 ART* start (or restart) when CD4 <20%** or severe CDC Stage B or C disease occurs Follow-Up for Minimum 3.5 Years **August 2006 changed to <25% *ART = AZT/3TC/LPV/r

  6. CHER Schematic Representation of Study Treatment Strategies Arm 1: Delayed ART Until Meet Standard Criteria Continuous ART 1st Line 2nd Line ART Delay ART Until Needed Arm 2: Immediate ART at Age 6-12 Weeks until Age 1 Year (ART-40 weeks) Start 1st Line ART Continuous ART 1st Line 2nd Line ART ART Interruption Until Needed Arm 3: Immediate ART at Age 6-12 Weeks until Age 2 Years (ART-96 weeks) Start 1st Line ART 2nd Line ART Continuous ART 1st Line ART Interruption Until Needed

  7. CHER: Early HAART Significantly Reduces Mortality and Disease ProgressionViolari A et al. NEJM 2008;359:2233-44 Probability of Death Most deaths occurred within first 6 months P = 0.0002 76% Reduction in Mortality: 4% vs 16% for Early vs Deferred ART p<0.0001 16% 4% Probability of Death or CDC Severe B/C Disease p<0.0001 26% 6%

  8. Early HAART in HIV-Infected Infants Associated with Improved Neurodevelopmental Outcome: CHER and Control ChildrenLaughton B et al. AIDS. 2012;26(13):1685-1690. Griffiths Mental Development Scales given between age 10-15 months to deferred vs early patients, HIV-exposed uninfected, & HIV-unexposed children

  9. CHER: Time to Starting Continuous ART Cotton M et al. 19th CROI, Seattle, WA, March 2012 (Abs 28LB)

  10. CHER: Distribution of Primary Endpoints by Study ArmCotton M et al. 19th CROI, Seattle, WA, March 2012 (Abs 28LB)

  11. CHER: Time to Primary Outcome (Death or Failure 1st Line) ART-Deferred vs ART-40 wk and/or ART-96 wkCotton M et al. 19th CROI, Seattle, WA, March 2012 (Abs 28LB)

  12. CHER: Time to Primary Outcome (Death or Failure 1st Line) ART-40 wkvs ART-96 wkCotton M et al. 19th CROI, Seattle, WA, March 2012 (Abs 28LB)

  13. CHER: Disease Progression (Severe B or C) or DeathART-Deferred vs ART-40 wkvs ART-96 wkCotton M et al. 19th CROI, Seattle, WA, March 2012 (Abs 28LB)

  14. CHER: SummaryCotton M et al. 19th CROI, Seattle, WA, March 2012 (Abs 28LB) • Early ART until 1st or 2nd birthday followed by interruption compared to deferred ART: • Appears safe in children with regular CD4 and clinical monitoring • Reduces mortality by ¾ and reduces disease progression • Has less ART exposure (potential cost-saving) • Early ART for 2 years compared to 1 year results in: • Similar ART exposure • Longer subsequent interruption • Trend toward fewer clinical events • Few children required switch to 2nd line ART. • Further analysis needed to evaluate viral suppression, resistance and immune response after ART restart.

  15. The International Maternal Pediatric Adolescent AIDS Clinical Trials Group • Mission/Aims • Develop and evaluate safe, cost effective approaches to interrupt mother-to-child transmission (MTCT) • Evaluate treatments for HIV-infected children, adolescents, and pregnant women, including treatment and prevention of co-infections and co-morbidities • Evaluate vaccines for prevention of MTCT and sexual transmission among adolescents, and for therapeutic use

  16. IMPAACT Leadership Group • IMPAACT has a leadership group consisting of 5 scientific committees that develop and prioritize the science/protocols which are then implemented by 39 domestic and 34 international clinical trial units • PMTCT • Primary Therapy • Complications • Vaccine/IBT • Women’s Health • IMPAACT is supported by SDMC, Operations Center, and Central Lab Group (4 virology, 4 immunology, 4 pharmacology, 1 genetics specialty labs) and approximately $65 million/yr total in funding

  17. IMPAACT National Institute of Allergy and Infectious Disease (NIAID) Funded Sites 13 Domestic, 25 International Clinical Research Sites

  18. IMPAACT Eunice Kennedy Shriver National Institute of Child Health Development (NICHD) Funded Sites23 Domestic, 10 International Clinical Research Sites

  19. Choose the FALSE statement about global mortality in children under 5 during 2008: • Approximately half of the nearly 9 million deaths occurred in Africa • Rotavirus is the leading cause among diarrheal-related mortality • Malaria accounts for approximately 1/3 of deaths in Africa among this group • Respiratory illness is the leading cause of mortality

  20. Global Childhood Mortality in 2008 • 8.795 million estimated deaths in children <5 yr of age (half in Africa) • 18% or 1.575 million deaths due to pneumonia (S. Pneumoniae, TB, RSV) • 15% or 1.336 million deaths due to diarrhea (rotavirus is leading cause) • 8% or 732 thousand deaths due to malaria (16% in Africa) Black RE et al Lancet 2010;375:1969-1987

  21. Burden of HIV • WHO estimates that 367,000 infants were infected with HIV in 2009 • 40% of new “adult” infections occur in youth 15 - 24 yrs • If we meet WHO goals (90% women/infants receive VCT and ARV prophylaxis with regimens capable of reducing MTCT to <5%), still 138,000 new infections yearly in 25 countries

  22. Infants and Children Differ from Adults • Well characterized timing of acute infant infection • Immune responses not fully developed in infants • Disease progression; HIV - 40% survival at 2 yr, w/o Rx • Functional thymus – immune reconstitution • Pharmacokinetics – absorption, distribution, clearance • Ontogeny of renal and hepatic function • Growth and development – including neurodevelopment; still unknown impact of HIV, ARVs • Potential duration of ARV need, 70-80 years • Challenges of TB diagnosis • Increased severity of malaria

  23. Adolescents and Pregnant Women Differ from Non-Pregnant Adults Adolescents • Pubertal development; impact of HIV-1 and ARVs • Risk-taking behavior; behavioral disinhibition • Adherence to medications Pregnant Women • Increased risk of acquisition and transmission of HIV-1 • Pharmacokinetics; absorption, distribution, clearance, binding • Adverse events; preeclampsia, fetal loss, congenital anomalies • Alterations in immune function, transplacental antibodies • Higher risk of severe disease and mortality (H1N1, malaria)

  24. Past Accomplishments of the Pediatric/Maternal HIV-1 Networks • Preventing vertical transmission of HIV-1 • Providing data for licensure of drugs for infants, children and adolescents with HIV and dosing recommendations for pregnant women • Developed and validated diagnostic testing for infant HIV infection • Evaluating vaccine safety and immunogenicity in HIV infected pregnant woman, adolescents and children and other pediatric populations

  25. Antiretroviral Drugs Approved in Adults Efficacy data provided

  26. Which of the following antiretroviral agents is NOT approved for children under 12 yrs: • Abacavir • Tenofovir • Efavirenz • Maraviroc • Etravirine

  27. ARV Pediatric Labeling Influenced by IMPAACT Studies Approval or label dosing Efficacy data provided Under study in IMPAACT * for pMTCT

  28. MMR* Varicella Pneumococcal* DTaP HPV (girls and boys) Hep A Hep B Vaccines in Children, Adolescents and Pregnant Women in IMPAACT Studies Rotavirus* H1N1 Seasonal Influenza Meningococcal HPIV3* TB* HIV-1* Red font indicates vaccines also studied in pregnant women * Indicates vaccine studied in children less than 2 years old

  29. Current IMPAACT Studies Pathogenesis Translational Phase I/II Phase II Phase III IRIS Microbialtranslocation Genomics Reservoirs Etravirine GSK 572 Raltegravir Tenofovir/newborn Efavirenz/infants/TB Atazanavir Pregnancy PK Viral decay late pregnancy ARV PK interactions Weight band dosing LPV ARVs malnutrition FTC monotx bridge Simplification/adols NVP vs LPV/r infants NVP/breastfeeding PROMISE* Infant prophylaxis ARV Bone Δs PIs malaria HIV TherVx (adol) Alendronate Bedaquiline MDR-TB H1N1 vaccine kids H1N1 pregnancy HPIV-3 infants/kids Atorvastatin Pneumococcal Vx preg HPV Vx kids ARV/anti-malarial interact ARV/anti-TB interact ARV/psychotropic interact INH/pregnancy Rotavirus Vx Meningococcal Vx HBV Vxadols HPV Vxadols Complications * indicates study with greater than 8000 subjects

  30. PROMISE – Addresses 4 key questions • What is the optimal intervention for the prevention of antepartum and intrapartum transmission of HIV? (Antepartum Component) • What is the optimal intervention for the prevention of HIV transmission in breastfeeding infants? (Postpartum Component) • What is the optimal intervention for the preservation of maternal health after the risk period for MTCT ends (either at delivery or cessation of BF)? (Maternal Health Component) • What is the optimal intervention for the prevention of the infant morbidity and mortality associated with BF cessation? (Infant Health Component)

  31. Triple ARV Prophylaxis Triple ARV Prophylaxis AZT AZT+ sdNVP+ TRV tail Promoting Maternal and Infant Survival Everywhere AP 14 wks-termIPPP for Duration BFWeaning Infant uninfected at birth R a n d o m i z e CD4>350 Continue Triple ARV Regimen R a n d o m i z e R a n d o m i z e Mother Triple ARV Prophylaxis Stop All ARVs Infant NVP Prophylaxis AZT+ sdNVP+ TRV tail Implemented Q1 2010: 1700 enrolled Late presenters

  32. IMPAACT Future Research Priorities • Pediatric vaccine studies (HIV infected and other pediatric populations) • Aeras recombinant BCGs and adeno-vector vaccines for TB; safe and immunogenic? • HPIV3, RSV, HSV vaccines in development; safe and immunogenic? • Malaria vaccines in development; e.g. irradiated sporozoites • Safety/PK of new ARVs/formulations, TB, other drugs in children & pregnant women; drug-drug interactions • Improved diagnostic tests for infants and children • Assays to diagnose TB in children using accessible body fluids such as blood, urine, stool. • Innovative point of care diagnostics for other pathogens. • HIV prevention strategies in adolescents internationally • What are optimal strategies for PrEP in adolescents?

  33. IMPAACT Future Research Priorities • Prevention/treatment of Co-infections (HCV, HBV, TB) • Treatment of co-morbidities and effects of chronic ARV use in children • Safety/PK and efficacy of Atorvastatin to treat lipodystrophy? • Drug-drug interactions between ARVs and psychotropic meds? • Prevention of MTCT and treatment of pregnant women • Pathogenesis-based evaluation of failures of prophylaxis • Prevention of incident infection during pregnancy and breastfeeding • Immune/inflammatory response • Pathogenesis research in acutely infected newborns that can lead to development of a cure strategy. • Define and ameliorate the inflammatory response that causes morbidity such as IRIS, non-AIDS events in children & pregnancy.

  34. NIH Scientific Priority Areas for HIV Peds and Maternal Health • Prevention of HIV Acquisition • Cure and/or Functional Cure • Pharmacology, Drug Formulation and Novel Interventions • Co-infections, Co-morbidities and ART Consequences • Vaccines of High Priority to these Populations

  35. Prevention of HIV Acquisition • Collaborate on bridging studies in adolescents to evaluate the safety, feasibility and efficacy of microbicides, PrEP and HIV vaccines: • Protocols on safety/efficacy of tenofovir gel and other microbicides (e.g. VRC monoclonal Ab) in young women • Evaluate testing strategies and interventions for incident infection in pregnant and breastfeeding women to prevent transmission to their infants: • Protocols to evaluate safety and efficacy of oral/microbicidePrEP in pregnant and lactating women • Evaluate any high priority emerging questions related to mother-to-child transmission: • Prevention MTCT of TB, HCV, HBV and drug safety in pregnant women/fetus in HIV infected pregnant women.

  36. Cure and/or Functional Cure • Evaluate novel strategies to prevent development of viral reservoirs specially in the unique context of the known timing of intrapartum transmission Within the context of clinical trials: • Quantify viral reservoirs • Especially in newborns (in utero & perinatal infection) • Investigate host, viral or other factors that influence the size and development of viral reservoirs • In recently infected newborns • Evaluate tools to investigate reservoirs • Viral, immunological, genetic assays to assess body compartments using body fluids, biopsy and autopsy

  37. Pharmacology, Drug Formulation and Novel Interventions • Determine the safety and optimal dosing of new ARVs and drugs for related infections • Especially in pregnant women, young children and infants • Elucidate drug-drug interactions involving ARVs and medications to treat co-infections and co-morbidities • TB, malaria, hepatitis in children and pregnant women • Evaluate highly innovative drug formulations and delivery platforms • e.g. Sprinkles and medication patches in infants and young children • Evaluate novel anti-HIV compounds, therapeutic vaccines and other interventions aimed at ameliorating the effects of HIV infection

  38. Co-infections, Co-morbidities and ART Consequences • Investigate interventions to treat and prevent co-morbidities, co-infections and ART consequences • Prevention and treatment of co-morbidities and effects of long-term ARV use in children (neurodevelopmental, growth, psych, renal, lipodystrophy) • Novel vaccines and drugs to prevent TB, PK studies of new TB drugs, evaluation and treatment of MDR TB • Evaluate non-invasive and reliable strategies to diagnose TB and other infections in children • e.g. Cepheid Xpert (NAAT-based) TB assay • Evaluate strategies to prevent mother-to-child transmission of HIV related infections such as TB and hepatitis • e.g. Newly licensed anti-HCV drugs

  39. Co-infections, Co-morbidities and ART Consequences Within the context of interventional research, address the impact on HIV pathogenesis and disease progression of • Immune activation, inflammation, and immune senescence and strategies to reconstitute immunity • Role of microbial translocation, IRIS, immune development/senescence and CVS disease (children vs adults), ARVs and immunomodulators in children • Other chronic viral infections • HBV, HCV, HPV and EBV • Genetics and other host factors • Pharmacogenomics, HIV susceptibility

  40. Vaccines of High Priority to HIV-infected Children and Pregnant Women • Determine the safety and immunogenicity of licensed and other high priority vaccines in HIV-infected children • TB, HCV, HBV, HPV, HSV, RSV, malaria and influenza • Determine the safety of licensed and other high priority vaccines in HIV-infected pregnant women and investigate transplacental infant protection • e.g. PCV

  41. Summary • The pediatric and maternal HIV networks have accomplished significant milestones in PMTCT, advanced ARV management for HIV-infected children and pregnant women and spearheaded vaccine safety and immunogenicity efforts for these populations • Much research remains to be done in pediatric and maternal HIV and other infectious diseases affecting these populations • IMPAACT is uniquely poised with its clinical infrastructure, access to site populations and leadership/site expertise to address and advance key aspects of pediatric and maternal health

  42. The Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN)

  43. ATN’s Scientific Leadership and Agenda

  44. Select the TRUE statement regarding domestic HIV epidemiology in 2009: • The incidence of HIV infections among Hispanic males is similar to that of White males • The largest proportion of new HIV infections occurred among 13-29 year olds • New HIV cases among African Americans were equally high between males and females • The proportion of new HIV infections among youth 13-29 who were unaware of their infection status was 21%

  45. Domestic Burden of HIV *Centers for Disease Control and Prevention, 2011

  46. Domestic Burden of HIV *Centers for Disease Control and Prevention, 2011

  47. Adolescents≠ Adults or Children

  48. Adolescents≠ Adults or Children • Can’t simply scale up/down dosing of meds • Physical changes in adolescence can result in unpredictable parameters that may not change consistently with age, developmental stage or metabolic function • Medication dosage may be • adequate and not require adjustment • toxic • sub-therapeutic • Only through carefully controlled clinical research among youth can appropriate regimens/doses of a variety of medications and treatment strategies be determined

  49. Adolescents≠ Adults or Children • Barriers to care and participation in research involve • Behavioral issues and adherence challenges due to • Eating disorders • mood disorders • substance use • other risk-taking behaviors • poor psychosocial support systems/coping behaviors • instability of home environment/housing • Adherence issues can present barriers in a variety of settings • Medical/Research visits • Medications/Study Interventions • Non-pharmacologic/biomedical treatment interventions • Psychotherapy • Substance use rehabilitation • Risk reduction counseling • Inability to pay for services and products without inadvertent parental disclosure

  50. Under which of the following circumstances is it MOST APPROPRIATE to disclose a youth’s PHI to their parent/guardian? • The new diagnosis of HIV infection and AIDS in a 17 year old boy who you are concerned may not follow up for care, placing his health in jeopardy and risking a secondary transmission to his new boyfriend • The provision of HIV PEP to a 16 year old young woman, whose 1st date forced sexual activity the evening prior • The diagnosis of major depression in a 16 year old young man who has been recently diagnosed with HIV infection • The provision of HIV PrEP to an 18 year old young man who is on his father’s health insurance policy and has admitted to several casual anonymous encounters of UAI in the past 3 months

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