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Pediatric HIV and co-infection 25-26 July, 2013

แนวทางการดูแลรักษาเด็กและวัยรุ่นติดเชื้อเอช ไอ วี พ. ศ. 25 56. รศ พญ ธันยวีร์ ภูธนกิจ หน่วยโรคติดเชื้อ ภาควิชา กุมา ร เวช ศาสตร์ คณะแพทยศาสตร์ จุฬาลงกรณ์มหาวิทยาลัย HIVNAT, ศูนย์วิจัยโรคเอดส์ สภากาชาดไทย thanyawee.p@hivnat.org 02-256-4930. Pediatric HIV and co-infection 25-26 July, 2013.

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Pediatric HIV and co-infection 25-26 July, 2013

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  1. แนวทางการดูแลรักษาเด็กและวัยรุ่นติดเชื้อเอช ไอ วี พ. ศ. 2556 รศ พญ ธันยวีร์ ภูธนกิจหน่วยโรคติดเชื้อ ภาควิชากุมารเวชศาสตร์ คณะแพทยศาสตร์ จุฬาลงกรณ์มหาวิทยาลัย HIVNAT, ศูนย์วิจัยโรคเอดส์ สภากาชาดไทย thanyawee.p@hivnat.org02-256-4930 Pediatric HIV and co-infection 25-26 July, 2013
  2. แนวทางการดูแลเด็กและวัยรุ่นติดเชื้อเอชไอวี 2013 สถานการณ์ การรักษาผู้ติดเชื้อเอชไอวีทั่วโลก การเริ่มยาต้านไวรัส (When to start?) ในทารก-เด็ก-วัยรุ่น สูตรยาต้านไวรัส (What to start?) ในทารก-เด็ก-วัยรุ่น การติดตามหลังเริ่มยาต้านไวรัส (Treatment monitoring)
  3. People receiving ART: 2003-2012 WHO 2015 Target 15 million on Treatment WHO 3 by 5 campaign 9.7 million by 2012 630,000 children 4.2 million AIDS death averted from ART 0.3 million at 2002 WHO Global update on HIV treatment 2013
  4. Children (0-14 yr) receiving ART by 2012 WHO Global update on HIV treatment 2013
  5. New Pediatric HIV case: 1996-2012 2015 Target Elimination of HIV PMTCT > 90% of pregnant women received ART 800,000 new pediatric HIV has been averted during 2005-2012 2015 WHO Global update on HIV treatment 2013
  6. PMTCT coverage by WHO region WHO Global update on HIV treatment 2013
  7. Framework of HIV treatment and care 1 2 3 PED ARV CLINICS ENTRY POINTS UNDERSTAND DYNAMICS WHO Global update on HIV treatment 2013
  8. When to start ? Early infant diagnosis HIV functional cure: Mississippi Baby Update WHO treatment guideline 2013 Thai MOPH treatment guideline 2013
  9. HIV diagnosis: 1st step of linkage to care Entry Points: Infant born from HIV +ve mother Mother: 2 HIV tests at 1st, 3rd trimester Statistics 2012: Prevalence of HIV in pregnant ANC = 0.6% no ANC = 3.1% Father: couple counseling Statistics 2012: only 20% of father was tested Other entry points: severe infection, TB clinic, malnutrition, immunization clinic
  10. การวินิจฉัยการติดเชื้อเอชไอวีในทารก การวินิจฉัยการติดเชื้อเอชไอวีในทารก Laboratory for Early Infant Diagnosis HIV DNA PCR (ตรวจหาเชื้อไวรัสจากเม็ดเลือดขาว) +/- HIV RNA PCR (ตรวจหาปริมาณไวรัสในพลาสมา) copies/ml ควรเริ่มตรวจเมื่อไหร่ ความเสี่ยงสูง(มารดาได้รับยาต้าน < 4 สัปดาห์หรือHIV VL > 1000 c/ml) แนะนำเจาะเลือด 3 ครั้ง 1,2,4 เดือน (หากผลเลือดบวก จะได้ไม่ต้องหยุด ART) ความเสี่ยงต่ำ แนะนำเจาะเลือด 2 ครั้ง ครั้งแรกอายุ1-2 เดือน และซ้ำเมื่ออายุ ตั้งแต่ 4 เดือน ควรเจาะเลือดซ้ำเมื่อไหร่ (ต้องการผลยืนยัน 2 ครั้ง) หากผลPCRเมื่ออายุ 1-2 เดือนเป็นบวกควรรีบตรวจซ้ำทันที หากผล PCR เมื่ออายุ 1-2 เดือนเป็นลบควรตรวจซ้ำเมื่ออายุ 4 เดือน
  11. Linkage into HIV care: Thailand NAP database: 30 Jun 2012
  12. Functional cure: a Mississippi baby HIV RNA Loss to follow up and stop ART at age 18 months 30 hours HIV DNA+ AZT/3TC/LPV/r from day 7 AZT/3TC/NVP started on day 1 Persaud D, 2013 Oral late breaker, Abstract 48LB
  13. When to start: WHO guideline 2013
  14. When to start: Thai guideline: 2013
  15. Infant < 3 mo: Early treatment lower AIDS/Death Death: 4% versus 16% (HR = 0.24, p <0.001) Cat C: 6.3% versus 25.6% ( HR = 0.25, p<0.001) CHER trial CIPRA South Africa; Violari A. NEJM 2008;359:2233-44.
  16. Children: when to start ? PREDICT trial1(1-12 years, RCT n=300) AIDS-free survival did not differ between deferred (CD4 <15%) and early treatment (CD4 15-24%) 144 week survival = 98.7% vs 97.9% IeDeaSA2(2-5 years, cohort n = 5,732) 3-year mortality rate was not difference in Rx all and using CD4 threshold All vs CD4 < 25% vs CD4 < 15%  4.5% vs 4.5% vs 5.3% 1 PuthanakitT. Lancet Infect Dis 2012:933-941. 2 Schomaker M. IeDEA Southern Africa Collaboration 2012
  17. Children: Effect of ART Growth outcomes South African cohort (N= 2,399) 2 year of HAART: only 81%, 64% achieved normal weight, height Risk factors of poor recovery: age > 3 year, baseline severe growth failure PREDICT study Early treatment has better growth parameter at 3 years of F/U Cognitive function outcomes No different in cognitive function at 3 years of F/U between early and deferred treatment in the PREDICT study Feinstien L et al. J Acquir Immune DeficSyndr 2012;61:235–242 Puthanakit T et al. PedInfect Dis J 2013:32:501-8.
  18. Adult: Treatment as Prevention (TasP) HAART initiation when CD4 350-550 cell/mm3 versus CD4 < 350 cell 96% reduction in HIV transmission to uninfected partners Cohen M et al. N Eng J Med 2011; 365:493-505.
  19. What to start- 1st line HAART ? Infant < 3 year : LPV/r is better than NVP : Switch strategies Children 3-10 year : EFV > NVP Adolescent > 10 year: TDF-based once daily regimen
  20. Approved antiretroviral drugs in children DHHS pediatric HIV treatment guideline Nov 1, 2012
  21. What to start ? WHO 2013
  22. What to start: Thai guideline 2013 (draft)
  23. Efficacy of LPV/r-based HAART in infants 6 mo-3 yr(P1060)Cohort I: Exposed to SD-NVP (N =164) Palumbo P et al. N Eng J Med 2010;363:1511-20.
  24. Efficacy of LPV/r-based HAART in infants 6 mo-3 yr(P1060)Cohort II: Not exposed to SD-NVP (N =288) Violari A et al. N Eng J Med 2012;366:2380-9.
  25. Treatment switch to NVP-based after initial VL suppression with LPV/r-based ART (NEVEREST) Cumulative probability of VL rebound > 1000 c/ml At week 72 = 10% vs 24% Can switch from LPV/r to NVP after VL < 50 copies/ml. Must perform at 24-48week after switch to detect one with VL rebound Continue LPV/r-based Switch to NPV-based Kuhn L. Lancet Infect Dis 2012:12:521-30.
  26. HAART in children: EFV, NVP, PI Efficacy of EFV versus NVP, EFV versus boosted PI Dosage of EFV in children 3 month to 3 years Dosage in adult 400 mg versus 600 mg (ENCORE study) Metaanalysis on risk of congenital malformation when use in women with child bearing age
  27. Children: EFV versus NVP-based ART Botswana-Baylor retrospective cohort HIV-infected children 3-16 years (N= 804) Median age 8 years, CD4 = 13%, Plasma HIV RNA = 5.3 log10copies/ml NRTI backbone: AZT/3TC 92% F/U time 69 months VL failure at 5 year EFV = 12.8% NVP = 25.1% Lowenthal ED. JAMA 2013;309:1803-9.
  28. Children: PI and NNRTI-based similar VL outcome NRTI RAM 1-2 > 3 6% 2% 22% 5% The PENPACT-1 Study Team. Lancet Infect Dis. 2011;11:273-83.
  29. Efavirenz:FDA approved for > 3 mo May 2013; EFV was approved for children 3-36 month Open capsule mixed with food Use within 30 min after mixing Avoid food 2 hours after http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/HIVandAIDSActivities/ucm350744.htm
  30. EFV: adult dose 400 mg vs 600 mg EFV 400 mg has non-inferior virological efficacy compare to EFV 600 mg and has lower rate of discontinuation due to adverse events Puls R, ENCORE1 Study Group: IAS 2013 WELBB01
  31. HAART in children: NRTIs backbone Start with non-thymidine analogue Once daily regimen Abacavir, Tenofovir
  32. ART Regimen Sequences Current practice New approach TDF (ABC) + 3TC + EFV (NVP) NRTIs + LPV/r or ATV/r AZT(d4T) + 3TC + EFV(NVP) TDF+ 3TC + Boosted PI
  33. Abacavir use in children PRO CON Cost, availablity Risk of ABC hypersensitivity, recommend for HLA-B*5701 screening prior to start Rx % HLA-B*5701 among Thais = 4.0% (95% CI: 1.6-8.0%) Few data in large scale program in children compare to AZT, d4T Use as a once daily Combination tablet: ABC/3TC (Kivexa) Low risk of metabolic complication Resistance mutation: K65R, M184V, L74V, Y115F Dosage (8 mg/kg/day) 14 to 21 kg 300 mg/day >21 to < 30 kg 450 mg/day > 30 kg 600 mg/day PuthanakitT. Ped Infect Dis J 2013;32:252-3.
  34. Abacabir in children; ARROW trial VL < 400 copies/ml week 24 week 144 A: ABC/3TC/NNRTI 77% 84% B: ABC/AZT/3TC/NNRTI  ABC/3TC/NNRTI 88% C: ABC/AZT/3TC/NNRTI  ABC/AZT/3TC (p= 0.009) 65% (p =0.009) ARROW Trial Lancet 2013; 381: 1391-1403
  35. Poorer VL outcome: ABC vs d4T Johannesburg observational cohort VL < 400 c/ml ABC d4T N 88 351 106 480 81 398 117 659 Technau KG, et al.Ped Infect Dis J 2013; 32:851-5.
  36. Tenofovirdisoproxilfumarate (TDF)in children Jan 18, 2012: US FDA approved tenofovir for treatment of HIV-infected children > 2 years LPV/r decrease tenofovir clearance Population PK among 93 children from 5-18 years of age with 283 samples 2012 DHHS guideline recommend TDF for children with Tanner stage 4-5 and consider in stage 3 and use as alternative in stage 1-2 2013: WHO guideline recommend TDF for age > 10 years and BW > 35 kg Bouazza N, et al. JAIDS 2011; 58: 283-8.
  37. Tenofovir use in children: Monitoring for toxicity Renal toxicity Risk for acute renal failure or eGFR < 60 /ml/min:0.2-1.7% Proximal tubular dysfunction – hypophosphatemia: 2-4% Longer exposure – increase risk More risk of toxicity when combine with boosted PI > NNRTI Bone mineral density Decline in BMD from baseline, usually occur during first 6-12 months of treatment, stable thereafter Adult: risk of osetoporotic fracture 1.12 compare to non-tenofovir regimen Children: clinical significance of low BMD is unknown GS-7340 (TAF)specific uptakes in the lymphoid cells; 25 mg compare to 300 mg TDF
  38. Single tablet regimens for children Tenofovir 300/emtricitabine 200 /efavirenz 600(Atripla) Age > 12 years and BW > 40 kg Tenofovir 300 /emtricitabine 200 /rilpivirine 25(Complera) Age > 18 years Tenofovir/emtricitabine/elvitegravir/cobicistat (Quad 1/ Stribild) Age > 18 years Cobicistat = a pharmacoenhancer, inhibitor P450 3A enzymes, = boosts intestinal absorption of atazanavir, darunavir, GS7340
  39. Drug development: monthly injectable ART GSK 744 HIV integrase inhibitor/ dolutegravir analogue Injectable nanosuspension; IM SC Achieve plasma concentration > 4 times IC90 in healthy adults TMC-278 LA Long-acting nanosuspension of rilpivirine (NNRTI) IM loading 1200 mg then maintenance 600 mg q 4 week Plasma level comparable to oral rilpivirine 25 mg/day Spreen W. IAS 2013 WEAB0103
  40. Treatment monitoring Point of care testing CD4 Point of care testing plasma HIV RNA “International drug purchasing facility” established in 2006 To improve access to treatment and diagnositics for HIV TB Malaria in low-income countries.
  41. Laboratory monitoring: CD4 CD4 test Point of care testing will help for linkage to HIV treatment 25 ul of whole blood CD4 cell count report in 20 min AlereTM Prima CD4 http://alerehiv.com/hiv-monitoring/alere-pima-cd4/
  42. CD4 Product Pipeline BD Zyomyx Alere Pima CD4 HumaCount mBio Omega Diagnostics Partec Mini Daktari 2014 2009 2010 2011 2013 2012 Instruments Disposable Murtagh slide collection *Estimated - timeline and sequence may change
  43. CD4 monitoring Less important after immune recovery to threshold level and have HIV virological suppression Adult patient who had CD4 > 300 cell/mm3 and HIV RNA < 200 copies/ml are unlikely to have CD4 drop < 200 cell/mm3, Only 3% in 4 years of follow-up How to break the habit ? Gale et al.Clin Infect Dis 2013; 56:1340-3.
  44. Laboratory monitoring: Viral load Plasma HIV Viral load Recommended for treatment monitoring Base on NHSO data; only 60% of children have annual VL testing WHO threshold for switching regimen: VL > 1000 copies/ml Point of care testing for HIV Viral load Liat Platform 200 Ul plasma or 50 ulfingerstick blood Turn around time 30-55 min
  45. Pipeline: HIV Viral Load and Early Infant diagnosis (EID) Micronics Liat AlereQ WAVE 80 EOSCAPE ALL Cavidi AMP Lynx EID Biohelix SAMBA EID SAMBA VL Gene XPert NWGHF VL Lumora 2013 2016 2015 2014 2012 Murtagh slide collection
  46. Recommend further readings http://www.jiasociety.org/index.php/jias/pages /view/thematicadolescents http://www.who.int/hiv/pub/guidelines/arv2013/en/index.html

  47. Thank you for your attention

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