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Improving Outcomes for Children with HIV-1

Improving Outcomes for Children with HIV-1. Grace John-Stewart. Goals. Summarize ongoing pediatric HIV-1 studies and new directions Discuss some unique issues children face Introduce investigators with some specific focus interests to foster networking. Two Maps. e-MTCT Prevention Momentum.

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Improving Outcomes for Children with HIV-1

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  1. Improving Outcomes for Children with HIV-1 Grace John-Stewart

  2. Goals • Summarize ongoing pediatric HIV-1 studies and new directions • Discuss some unique issues children face • Introduce investigators with some specific focus interests to foster networking

  3. Two Maps

  4. e-MTCT Prevention Momentum • Global Target 1 • Reduce the number of new infections among children by 90% (<30,000 annually) and MTCT to <5% by 2015 • Global Target 2 • Reduce the number of AIDS related-maternal deaths by 50%

  5. Children with HIV-1 • High early mortality • Early ART survival OPH: can early ART enable a later ART break? • Frequently undetected • Late diagnosis PUSH: can urgent ART in hospital improve survival? CATCH: can we diagnose children earlier? • Unique issues in children • Growth PHM: Are there ways • Cognition to improve these markers? outcomes • Disclosure

  6. Optimizing Pediatric HIV-1 Therapy 03 OPH03

  7. OPH03 Early ART in Infants Survival benefit of early ART in infants (CHER) Early ART may preserve thymic function in infancy Is this sufficient to allow children to have a treatment interruption (TI)? 1Violari et al. (CHER) 2008

  8. Balancing Issues for Infant ART OPH03 ↑CD4, growth benefit ↑ resistance, failure, toxicity Lifelong ART ↑ treatment options ↑ VL, immune activation Interruption after CD4 reconstitution Potential treatment options for infant ART

  9. Methods OPH03 18 months Continue ART 0-13 months 24 months Birth Start ART ART Interrupt ART Randomize

  10. Study Flow Diagram OPH03 HIV treatment Clinic Infants on ART Newly diagnosed hospitalized infants PMTCT programs 18000 mother-infant Started ART < 13 months Eligible (n=121) On ART ≥24 mos (n=75) Randomized (n=42) Continued (n=21) Interrupted (n=21) Withdrawn* (n=1) Withdrawn (n=1) LTFU (n=1) http://pregnancy.amuchbetterway.com/files/2011/12/iStock_000002051524XSmall.jpg 18 mos FU (n=19) 18 mos FU (n=20) *temporarily withdrew from study protocol at 6 months

  11. Cohort Characteristics OPH03

  12. July 2011 DSMB Randomization discontinued, safe but too few with TI > 3 mos Caregivers were given option to restart OPH03 Restart of ART 21/21 restarted ART, 17 (81%) met study criteria

  13. Growth &SAE Similar Between Arms OPH03 Weight-for-age z-scores (Underweight) Height-for-age z-scores (Stunting) Weight-for-height z-scores (Wasting) One SAE in each arm: Continued (HIGH ALT) Interrupted (CELLULITIS)

  14. Post-randomization CD4 and Viral Load OPH03 Intent to Treat P<0.001 P=0.20 P=0.5 P=0.19 P=0.6 P=0.14 P=0.10 P=0.3 P=0.3 P=0.18 P=0.16 P<0.001

  15. Cofactors for Later Restart OPH03

  16. Summary High proportion of infants with early restart Growth and SAE incidence similar Infants with earlier restart had a lower CD4% at randomization but not pre-ART or nadir OPH03

  17. Conclusions and Context Interruption was not feasible for this population WHO guidelines CD4 25% vs. 20% in previous pediatric RCT- PENTA leading to earlier restart Successful PMTCT with fewer HIV infections detected in PMTCT programs and higher proportion identified when symptomatic Infants detected while asymptomatic or with higher CD4% at TI may be a better group for TI OPH03

  18. 2013 • Mississippi baby • Very early ART followed by unscheduled TI with viral control • CHER follow-up (Lancet Aug 22, 2013) • 377 infants CD4 >25% asymptomatic <12 wks • Early then TI at 40 or 96 wks • Restart at CD4 20% • 40W TI 33 wks, 19% remained off ART at end of study • 96W TI 70 wks, 36% remained off ART at end of study • Visconti trial • ~15% post-treatment controllers (starting within 10 wks acute infection) • Viral control for median 89 months • New directions • Replicate early detection and rapid ART • Therapeutic vaccines or other strategies in cure agenda

  19. Where are children diagnosed? • PMTCT programs • <5% transmission risk • EID • 15% • 6 wks, 9 mos, 18 mos • Older children infected before PMTCT scale-up • 28% ART in ART-eligible children • Symptomatic presentation

  20. Pediatric Urgent Start of HAART (PUSH)

  21. Late diagnosis in children with HIV-1 associated with high mortality CHER Cohort (empiric ART, diagnosed early) OPH03 Cohort (empiric ART, diagnosed late) CTL Cohort (untreated) OPH03 - 6 month mortality: 32% - median time to ART was 14 days - 12 deaths occurred before ART at a median of 11 days

  22. Early ART during OI Useful • Early/deferred OI (ACTG A1564) • 14 days vs. deferred HR = 0.53 Early versus Deferred ART [95%CI 0.30–0.92 p = 0.023] ZolopaPLoS ONE 4(5): e5575

  23. Early ART in TB Beneficial • 56% reduction in mortality in early ART group (p=0.003) • Early 4 weeks

  24. Will Urgent ART Benefit Hospitalized Children? • Potential Pros: • Faster immune reconstitution • Faster viral suppression • Survival • Potential Cons: • IRIS • Drug toxicity • Implementation Urgent ART

  25. Late diagnosis has high mortality CHER Cohort (empiric ART, diagnosed early) OPH03 Cohort (empiric ART, diagnosed late) CTL Cohort (untreated) OPH03 - 6 month mortality: 32% - median time to ART was 14 days - 12 deaths occurred before ART at a median of 11 days

  26. Study Design Hospitalized children • Un-blinded RCT • Key Inclusion Criteria • Age 0 to 12 years • HIV-1 positive • No prior ART • Eligible for ART • Key Exclusion Criteria • Suspected CNS infection • Visit schedule • Enrollment • 1, 2, 4, 8, 12, 16, 20, 24 weeks post-ART HIV-1 negative Recruitment and Screening: HIV-1 positive Enrollment (N=360) DAY 0 Randomization Urgent ART (N=180) ART at < 48 hours Early ART(N=180) ART at 7-14 days Follow-up: 6 Months Monitor for mortality, IRIS, drug toxicity

  27. Study Sites http://www.destination360.com/africa/kenya/map • Kenyatta National Hospital (KNH) • JaramogiOgingaOdinga Teaching & Referral Hospital (JOOTRH) [Kisumu Provincial General Hospital] • Kisumu East District Hospital (KEDH)

  28. Issues in the study • Quick turnaround for diagnosis • Family diagnosis and disclosure • Costs of HIV diagnosis in hospital • Belief in ART/HIV efficacy

  29. Early Detection of HIV: CATCHAnjuli Wagner, JennSlyker, Irene Njuguna • Adults with HIV: test children • Clinic • Home • Ethical issues

  30. Disclosure of HIV diagnosisGrace Wariua, Kristin Beima-Sofie, Maureen Kelley • Practitioners • Time to disclose • Revealing process • Risks of current messages • Children • Caregivers

  31. Growth and cognitionChristine McGrath, Sarah Benki-Nugent, Claudia Crowell, Dalton Wamalwa • Early ART improves growth • Role of nutritional supplementation • PI-ART faster milestones

  32. Improving Outcomes for Children with HIV-1 • Early ART • Preserve regimens • Improve survival forthose diagnosed late • Find undiagnosed • Comprehensive approach • Social, growth, cognitive, disclosure, co-infection issues

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