Pmtct

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Pmtct

  1. 1. UPDATE PMTCT GUIDELINES 2010Nittaya Phanuphak, MDThai Red Cross AIDS Research Centre (TRC-ARC)and South East Asia Research Collaboration with Hawaii (SEARCH) The 9th TAS HIV/AIDS Treatment and Care Workshop 27 August 2010
  2. 2. Outline Changes in the most recent PMTCT Guidelines Rationale behind these changes 2010 Thai National PMTCT Guidelines Challenges in implementing the new guidelines in Thailand
  3. 3. Estimated number of children (<15 years) newly infected with HIV, 2008 Western & Eastern Europe Central Europe & Central Asia North America <100 3700 <100 [<100 – <200] ] [1700 – 6000] East Asia [<100 – <200] Middle East & North 3200 Caribbean Africa [2100 – 4500] 2300 4600 South & South-East Asia [1400 – 3400] [2300 – 7500] Sub-Saharan Africa 18 000 Latin America 390 000 [11Oceania 6900 [210 000 – 570 000] 000 – 25 000] <500 [4200 – 9700] [<500 – <1000] Total: 430 000 (240 000 – 610 000) = >1000 new infections in children each day December 2009
  4. 4. Coverage of ARVs for PMTCT, 2008An estimated 45% of HIV-infected pregnantwomen received some ARVs for PMTCT in2008, up from 35% in 2007 and 10% in 2004
  5. 5. WHO PMTCT Guidelines2006 Guidelines ART eligible if CD4 <200 or <350 cells/mm3 with WHO stage 3 or 4 AZT + sd-NVP as the most advanced PMTCT regimen recommended Start at 28 wk GA AZT syrup 1 week or 4 weeks depends on the length of maternal ARV No recommendation for maternal and infant’s ARV if breastfeeds
  6. 6. WHO PMTCT Guidelines2006 Guidelines Nov 2009 Rapid Advice ART eligible if CD4 <200 ART eligible if CD4 <350 or <350 cells/mm3 with cells/mm3 or WHO stage 3 WHO stage 3 or 4 or 4 AZT + sd-NVP as the most Maternal 3-drug regimen advanced PMTCT regimen as an equal option to AZT recommended (+ sd-NVP) Start at 28 wk GA Start earlier at 14 wk GA AZT syrup 1 week or 4 AZT (or NVP) syrup 4-6 weeks depends on the weeks for all length of maternal ARV No recommendation for Maternal and infant’s ARV maternal and infant’s ARV if breastfeeds if breastfeeds
  7. 7. WHO eligibility criteria for ART inpregnant women Start as soon as Preferred possible irrespective AZT+3TC+NVP or of GA AZT+3TC+EFV (not during the 1st trimester) Alternative TDF+3TC(FTC)+NVP or TDF+3TC(FTC)+EFV
  8. 8. When HAART is not yet indicatedWHO ANTIRETROVIRAL DRUGS FOR TREATING PREGNANT WOMENAND PREVENTING HIV INFECTION IN INFANTS – 2010 VERSION
  9. 9. DHHS PMTCT Guidelines29 April 2009 AZT+3TC+NVP (if CD4 <250), +EFV (if after 1st trimester), +LPV/r (preferred PI) ART not yet eligible: start after the 1st trimester and no later than 28 wk GA Breastfeeding is not recommended in the US (maternal or infant’s ARV reduce risk during breastfeeding) Ongoing PK study of LPV/r tablet Conflicting data on PI and preterm delivery Majority of data did not show increased hyperglycemia from PI during pregnancy
  10. 10. DHHS PMTCT Guidelines29 April 2009 24 May 2010 AZT+3TC+NVP (if CD4 <250), +EFV Breastfeeding is not recommended in (if after 1st trimester), +LPV/r the US (risk of resistance in infants (preferred PI) exposed to maternal or infant’s ARV during breastfeeding) ART not yet eligible: start after the 1st trimester and no later than 28 wk GA No new info on LPV/r tablet PK Breastfeeding is not recommended in Data on PI use and preterm delivery the US (maternal or infant’s ARV continued to be conflicting reduce risk during breastfeeding) No new info on PI and hyperglycemia Ongoing PK study of LPV/r tablet Common M184V/I and NNRTI Conflicting data on PI and preterm resistance after triple-drug prophylaxis delivery (rare PI mutation) Majority of data did not show Results from OCTANE increased hyperglycemia from PI during pregnancy NRTI tail (+PI) for 30 d esp. after stopping EFV
  11. 11. Rationale behind these changes Earlier CD4 count threshold for the initiation of HAART in non-pregnant adults Timing of transmission (with and without breastfeeding) and benefits of starting ARV earlier during pregnancy Importance of ARV regimens used during pregnancy to reduce transmission and prevent postpartum resistance Safety of 3-drug regimens (LPV/r, EFV) for use during pregnancy More countries ready to expand more effective PMTCT services
  12. 12. Rationale behind these changes Earlier CD4 count threshold for the initiation of HAART in non-pregnant adults Timing of transmission (with and without breastfeeding) and benefits of starting ARV earlier during pregnancy Importance of ARV regimens used during pregnancy to reduce transmission and prevent postpartum resistance Safety of 3-drug regimens (LPV/r, EFV) for use during pregnancy More countries ready to expand more effective PMTCT services
  13. 13. Timing of transmission to infant:Non-breastfeeding population Athens PK, et al. Lancet Infect Dis 2006; 6:726–32.
  14. 14. Timing of transmission to infant:Breastfeeding population Athens PK, et al. Lancet Infect Dis 2006; 6:726–32.
  15. 15. Risk factors for perinatal HIV transmission High maternal viral load Low maternal CD4 count Vaginal delivery Premature rupture of membrane Preterm delivery, low birth weightNewell ML, et al. AIDS 1996; 10:1675-1681.Magder LS, et al. JAIDS 2005; 38:87-95.Joao E, et al. CROI 2010, abstract 897.
  16. 16. PMTCT during antepartum period Antepartum Antepartum ARV for pregnant womenTo reduce maternal HIV RNA level to the lowest level as quick as possible To increase maternal CD4 count to the highest level To improve maternal health and reduce pre-term and LBW delivery
  17. 17. When should HAART be initiated in pregnancy to achieve undetectable VL?Read P, et al. CROI 2010, Abstract 896.
  18. 18. Read P, et al. CROI 2010, Abstract 896.
  19. 19. Rationale behind these changes Earlier CD4 count threshold for the initiation of HAART in non-pregnant adults Timing of transmission (with and without breastfeeding) and benefits of starting ARV earlier during pregnancy Importance of ARV regimens used during pregnancy to reduce transmission and prevent postpartum resistance Safety of 3-drug regimens (LPV/r, EFV) for use during pregnancy More countries ready to expand more effective PMTCT services
  20. 20. Perinatal HIV transmission in the UK and Ireland whenHAART is recommended for all pregnant women,2000-2006 (N = 5131) TR % •Overall transmission rate = 1.2% 30 •TR reduced 1% for every additional    25 25 week of HAART  •TR 0.1% if HAART and VL < 50 20 16.7 Elective C/S N=637 N=143 Emergency C/S 15 11.1 Planned VD Unplanned VD 10 N=4107 N=125 5.85.9 5 3.3 2.7 0.71.70.7 1.4 0 0 0 0 0 0 HAART DualRx MonoRx UntreatedTownsend CL, et al. AIDS 2008;22:973-981.
  21. 21. Efficacy in reducing perinatal HIV transmission AZT from 28 wk GA plus single-dose NVP (when maternal therapy is not indicated) 2% from PHPT-2 5.8% from Dept. of Health report 2007 (Thailand) HAART for PMTCT <1-2% in developed and developing countries 2.4% from Thai Red Cross cohort (women with CD4>200 80%, CD4 <200 20%) Kesho Bora study Women with CD4 200−500, randomized between 28-36 weeks GA 1.8% with HAART versus 2.2% with AZT plus sd-NVP (not significant)Lallemant M, et al. N Engl J Med 2004;351:217-228.Cooper ER, et al. JAIDS 2002;29:484-494.European Collaborative Study. CID 2005;40:458-465.De Vincenzi I, et al. 5th IAS 2009, Abstract LBPEC0.
  22. 22. Efficacy in reducing perinatal HIV transmission AZT from 28 wk GA plus single-dose NVP (when maternal therapy is not indicated) 2% from PHPT-2 5.8% from Dept. of Healthmust aim to reduce Thailand report 2007 (Thailand) HAART for PMTCT pediatric “new HIV cases” from <1-2% in developed and developing countries 500 (5.8%) to <100 cases/year (1%) 2.4% from Thai Red Cross cohort (women with CD4>200 80%, CD4 = 80% reduction in the whole country’s <200 20%) Kesho Bora studypediatric HIV burden. Women with CD4 200−500, randomized between 28-36 weeks GA 1.8% with HAART versus 2.2% with AZT plus sd-NVP (not significant)Lallemant M, et al. N Engl J Med 2004;351:217-228.Cooper ER, et al. JAIDS 2002;29:484-494.European Collaborative Study. CID 2005;40:458-465.De Vincenzi I, et al. 5th IAS 2009, Abstract LBPEC0.
  23. 23. NVP resistance after sd-NVPNVP has long half-life and has low genetic barrierNNRTI resistance after exposure to sd-NVP has varied from 15%to 75%, especially when virus is not fully suppresibleNVP resistance in plasma and cellular provirus can still bedetected at 12 months after exposure1-week AZT/3TC after delivery decreased NVP resistance (from60% to 10%) but did not eliminate the riskTreatment outcome with NNRTI-based HAART in postpartumwomen exposed to sd-NVP is impaired and associated withNNRTI resistance (both standard and allele-specific genotype)Loubser S, et al. AIDS 2006;20:995-1002.McIntyre JA, et al. 3rd IAS Conference 2005.McIntyre JA, et al. CROI 2010, Abstract 153LB.Boltz V, et al. CROI 2010, Abstract 154.
  24. 24. OCTANE/A5208 OCTANE 1: Women exposed to sd-NVP TDF/FTC/NVP (n=120): VF or death 26% TDF/FTC/LPV/r (n=120): VF or death 8% (p=0.0004) DSMB recommended in Oct 08 to release data as soon as possible OCTANE 2: Women without sd-NVP exposure TDF/FTC/NVP (n=249): VF or death 17% TDF/FTC/LPV/r (n=251): VF or death 20% (ITT HR 0.85, 0.56-1.29)
  25. 25. Women and Infants Transmission Study (WITS): postpartum resistance substudy Postpartum samples from women exposed antepartum to AZT+3TC+NVP (n=8) AZT+3TC+NFV (n=87) AZT+3TC (n=20) Dual therapy (VS triple-drug therapy) Significantly higher rate of M184V/I (19/20, 95%) Risk factor for M184 V/I and NNRTI resistance Triple-drug therapy High rate of M184V/I (47/94, 51.6% High rate of NNRTI resistance (3/8, 37.5%) Rare PI resistance (1/87, 1.1%)Paredes R, et al. AIDS 2010;24:45-53.
  26. 26. Rationale behind these changes Earlier CD4 count threshold for the initiation of HAART in non-pregnant adults Timing of transmission (with and without breastfeeding) and benefits of starting ARV earlier during pregnancy Importance of ARV regimens used during pregnancy to reduce transmission and prevent postpartum resistance Safety of 3-drug regimens (LPV/r, EFV) for use during pregnancy More countries ready to expand more effective PMTCT services
  27. 27. Use in pregnant women with high CD4 count (>250 or >350) to avoid serious hepatotoxicity from NVP-based regimen LPV/rtv is the preferred PI Overall side effects: dyslipidemia, nausea, vomiting, loose stools, hyperglycemia and hepatitis Inconclusive data on preterm delivery and hyperglycemia associated with PI No concern regarding drug resistance if discontinue after delivery LPV/rtv exposure during the third trimester is reduced but dose modification is not needed in Thai pregnant womenHitti J, et al. Am J Obstet Gynecol 2007;196:331–337.Kourtis AP, et al. AIDS 2007;21:607–615.
  28. 28. Aluvia® tablet Cressey T, et al. CROI 2010, Abstract 906.GPO LPV/r (200/50) tabletRamautarsing R, et al. The 11th Workshop on ClinicalPharmacology of HIV Therapy, Poster#9.
  29. 29. Hepatitis and rash can occur 5 retrospective cases and 1 prospective case of neural tube defects in human exposed to EFV during the first trimester Neural tube closes by around day 28 of gestation Meta-analysis of 11 prospective cohorts and 5 retrospective reviews of 1st trimester exposure to EFV 1132 exposed to EFV vs 7163 exposed to non-EFV RR 0.87 (0.61-1.24, p=0.45) 2.9% overall birth defects 0.08% neural tube defects (1/1256) Discontinue EFV before the other drugs in the regimen due to long half-life (probably longer than NVP)Ford N, et al. AIDS 2010;24:1461-1470.
  30. 30. Rationale behind these changes Earlier CD4 count threshold for the initiation of HAART in non-pregnant adults Timing of transmission (with and without breastfeeding) and benefits of starting ARV earlier during pregnancy Importance of ARV regimens used during pregnancy to reduce transmission and prevent postpartum resistance Safety of 3-drug regimens (LPV/r, EFV) for use during pregnancy More countries ready to expand more effective PMTCT services
  31. 31. 2010 Thai National PMTCT Guidelinesกรณีหญิงตั้งครรภยังไมเคยไดรับยาตานไวรัสมากอน แนะนํา LPV/r ทุกราย เพื่อใหงายตอการปฏิบัติ หลีกเลียงโอกาสเกิดตับอักเสบหาก CD4 count >250 cells/mm3 ่ เริ่มยาไดเลยตั้งแตอายุครรภ 14 สัปดาห โดยไมตองรอผล CD4 count หยุดยาไดพรอมกันทุกตัวหลังคลอด หาก CD4 count >350 cells/mm3 ไมตองปรับขนาดยาในไตรมาสที่ 3
  32. 32. 2010 Thai National PMTCT Guidelinesการใหยาปองกันโรคติดเชือฉวยโอกาสในหญิงตั้งครรภ ้
  33. 33. 2010 Thai National PMTCT Guidelinesกรณีตงครรภขึ้นมาระหวางกําลังกินยาตานไวรัสอยู ั้ ไมตองหยุดยา ใหพิจารณาผลการรักษาโดยเร็วจากคา CD4 และ VL
  34. 34. PMTCT during intrapartum anddelivery period Intrapartum and delivery Intrapartum ARV or ARV before delivery To prepare adequate plasma ARV level in the infant for “pre-exposure prophylaxis” Elective Caesarian Section Avoid invasive procedure and prolonged rupture of membrane
  35. 35. 2010 Thai National PMTCT Guidelinesการดูแลระหวางเจ็บครรภคลอด
  36. 36. Mode of delivery in the HAART era Overall transmission rate among women with VL<1,000 copies/mL is low (but can occur even at very low VL) From UK and Ireland 0.1% if <50 copies/mL (3/2,309) 1.2% if 50-999 copies/mL (12/1,023) Unclear if cesarean delivery confers any additional benefit C/S reduced risk (aOR 0.3, p=0.022) among women with VL<1,000 copies/mL (when AZT was primarily used) Not clear if there is any benefit among women receiving triple- drug therapy for several weeks (TR 0.8% if >14 days)Townsend CL, et al. AIDS 2008;22:973-981.Ioannidis JP, et al. J Infect Dis 2001;183:539-545.
  37. 37. 2010 Thai National PMTCT Guidelinesการคลอดทางชองคลอดการผาทองคลอดกอนการเจ็บครรภ
  38. 38. PMTCT after delivery After delivery ARV for infant after delivery As post-exposure prophylaxis for the infant Formula feeding To prevent HIV acquisition through breast feeding
  39. 39. 2010 Thai National PMTCT Guidelinesการใหยาในทารก
  40. 40. 2010 Thai National PMTCT Guidelinesการใหยาหญิงตั้งครรภในระหวางเจ็บครรภคลอด “กรณี No ANC”
  41. 41. 2010 Thai National PMTCT Guidelinesการใหยาทารก “กรณี No ANC”
  42. 42. 2010 Thai National PMTCT Guidelinesการตรวจทาง กอนเริ่มยา ระหวางไดรับยาหองปฏิบัติการCD4 count - ตรวจทันทีหลังทราบวาติดเชื้อเอชไอวี - ตรวจ 6 เดือนหลังเริ่มยาViral load - ไมจําเปนตองตรวจ - ตรวจที่ 36 สัปดาหCBC - ตรวจกอนเริ่มยาทุกราย - ตรวจซ้ําหลังไดรับ AZT 4-8 สัปดาห - หาก Hb <8 g/dl หรือ Hct <24% ไม - หาก Hb <8 g/dl หรือ Hct <24% ใหเปลี่ยน AZT เปน d4T ควรเริ่มยา AZT ใหใช d4T แทน แตชวงคลอด ยังตองให AZT ทุก 3 ชั่วโมงเชนเดิมALT - ตรวจกอนเริ่มยาทุกราย - ตรวจซ้ําหากมีอาการสงสัยตับอักเสบ - หากผลสูงกวา 2.5 เทาของคาปกติสงสุด ู - หากผลสูงกวา 2.5 เทาของคาปกติสงสุด ควรเปลี่ยนเปน ู ไมควรใช NVP EFV หรือ LPV/r หากกําลังไดรับยา NVP อยูUrine sugar - ตรวจกอนเริ่มยาทุกราย - ทุกครั้งที่มาตรวจครรภคุณภาพGlucose - ตรวจกอนเริ่มยาสูตร LPV/r ทุกราย - ผูที่ไดยาสูตร LPV/r ทุกรายตรวจที่ 24-28 สัปดาห หรือchallenge test หากมีความเสี่ยง หลังเริ่มยา LPV/r อยางนอย 4 สัปดาหขึ้นไป หากไดผล(GCT) 50 gm ** blood sugar ที่ 1 ชม. สูงกวา 140 mg% ใหทํา OGTT *** ตอหรือปรึกษาสูติแพทย
  43. 43. Management of HIV-exposed infants AZT syrup 4mg/kg every 12 hrs for 4-6 weeks (as post-exposure prophylaxis), start as soon as possible after delivery Do not give single-dose NVP except high risk mother (does not receive 3 drugs or no ANC) Start cotrimoxazole syrup (after discontinue AZT) 10mg/kg/d, divided into 2 doses, 3 days/wk until 6 months of age or earlier if HIV-negative status can be assured from blood tests Breast feeding is not recommended, do not use mixed feeding Vaccination can be given for healthy infants
  44. 44. Laboratory tests to determineinfant’s HIV status DNA-PCR x 2 First DNA-PCR at 1(-2) months of age If 1st DNA-PCR is positive, repeat immediately, if 2nd DNA- PCR is positive “HIV-positive” If 1st DNA-PCR is negative, repeat at 4 months of age, if 2nd DNA-PCR is negative “HIV-negative”, can discontinue cotrimoxazole syrup If 2 DNA-PCR give inconsistent results, repeat 3rd DNA-PCR immediately and interpret the result according to the 3rd test result
  45. 45. Laboratory tests to determineinfant’s HIV status Anti-HIV at 12 months of age If anti-HIV negative “HIV-negative” If anti-HIV positive, could still be maternal antibody repeat anti-HIV at 18 months of age If anti-HIV positive at 18 months and does not go along with 2 DNA-PCR test results repeat anti-HIV using non-Ag-Ab test or repeat at 24 months of age
  46. 46. Challenges in implementing the newThai National PMTCT guidelines Pilot implementation in Regional Health Center 7 (7 provinces, 97 hospitals) during March – May 2010 Meetings with regional/provincial/hospital administrators Trainings for health care workers in the field, “nurse” in particular Guidelines/policy documentation Necessary for doctors in short-term rotation
  47. 47. Challenges in implementing the newThai National PMTCT guidelines VMI system for PMTCT drugs regardless of treatment access programs Stock on-hand in each hospital/Regional Health Center Needs for real-time consultation by phone/email Manuals/IEC materials for health care workers, peer educators, pregnant women CD, pocket book, leaflet Frequently asked questions
  48. 48. SummarySignificant changes in PMTCT guidelines were made in thepast year with trend towards triple-drug regimen for allHIV-positive pregnant womenRegimen selection depends on gestational age, CD4 count,HIV-related symptoms (and viral load) at an individuallevel but greatly depends on practical purposes at thecountry levelFor breastfeeding population, maternal and/or infant’sARV greatly reduce, although not eliminate, transmissionrisk during breastfeedingChallenges are expected during the transitional period butsupports are ready both technically and logistically inThailand

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