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PMTCT New Approaches

PMTCT New Approaches. Nadine Johnson Consultant and Lecturer Department of Obstetrics and Gynaecology University Hospital of the West Indies. Objectives. Review the risk factors associated with transmission of HIV from a woman to her baby.

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PMTCT New Approaches

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  1. PMTCT New Approaches Nadine Johnson Consultant and Lecturer Department of Obstetrics and Gynaecology University Hospital of the West Indies Nadine Johnson

  2. Objectives • Review the risk factors associated with transmission of HIV from a woman to her baby. • Discuss interventions currently being used to prevent HIV mother-to-child transmission. • Discuss the new recommended MOH regimes for prevention of mother-to-child transmission. Nadine Johnson

  3. Kingston Paediatric and Perinatal HIV /AIDS Programme(KPAIDS)September 2002-August 2005 Nadine Johnson

  4. Results-KPAIDS Treatment Site N =369 Nadine Johnson

  5. Results - KPAIDS Nadine Johnson

  6. Prevention of Mother to Child Transmission.How? Nadine Johnson

  7. GOALS OF ANTENATAL CARE • Standard clinical evaluation • HIV disease stage • Evaluate degree of immunodeficiency • CD4+ count, • Assess risk of disease progression as determined by level of plasma HIV-RNA (viral load) • Document history of prior or current ARV use • Discuss known or unknown risks/benefits of therapy during pregnancy • Develop strategy for long term evaluation and management of mother and infant Nadine Johnson

  8. Timing of Perinatal HIV Transmission • In utero 25%–40% • Intrapartum 60%–75% • Addition risk with breastfeeding • 14% risk with established infection • 29%  risk with primary infection • Current evidence suggests most transmission occurs during the intrapartum period Nadine Johnson

  9. Factors Influencing Perinatal Transmission • Maternal Factors • HIV-1 RNA levels (viral load [VL]) • Low CD4 lymphocyte count • Other infections, Hepatitis C, CMV, bacterial vaginosis • Breastfeeding • Obstetrical Factors • Length of ruptured membranes/chorioamnionitis • Vaginal delivery • Invasive procedures • Infant Factors • Prematurity Nadine Johnson

  10. Measures to Reduce MTCT • During pregnancy: • Provide voluntary counseling and HIV testing plus psychosocial support • Diagnose and provide aggressive treatment of STDs and other infections as early as possible • Provide basic antenatal care including: • Iron Supplementation • Education about MTCT and infant feeding options • ART for MTCT • Risk reduction/safer sex measures Nadine Johnson

  11. Measures to Reduce MTCT • During Labor and Delivery: • Delay rupturing of membranes (ROM) • Do only minimal digital examinations after ROM • Reduce use of assisted delivery with forceps/ vacuum • Reduce use of episiotomy • Elective caesarean section has a more protective effect against MTCT than vaginal delivery Nadine Johnson

  12. Measures to Reduce MTCT • After Delivery: • Avoid mechanical nasal suction • Clean the newborn immediately of all maternal secretions and blood • Advise against breast feeding • If breastfeeding is chosen as an option: encourage exclusive breastfeeding and advise early cessation (up to 6 months) Nadine Johnson

  13. Measures to Reduce MTCT • Today, risk of perinatal transmission can be <2% with • Effective antiretroviral therapy (ART) • Elective cesarean section (C/S) as appropriate • No breastfeeding Nadine Johnson

  14. ARV Therapy and MTCT • Without antiretroviral (ARV) drugs during pregnancy, mother-to-child transmission (MTCT) has ranged from 16%–25% in North America and Europe • ARV therapy can produce a significant reduction in mother to child transmission of HIV • PACTG 076 (1994) showed that administration of AZT to women • from 14th week of pregnancy • during labour • to the newborn • Decreased the risk of MTCT by nearly 70% in the absence of breastfeeding Nadine Johnson

  15. ZDV Perinatal Transmission Prophylaxis Regimen: ACTG 076 Trial • Decreased Transmission From 25% to 8% Nadine Johnson

  16. Mechanism of Action - Zidovudine • Slight reduction in viral load • accounts for only 17 % of reduction in HIV transmission. • Reduces the concentration of HIV within cervico-vaginal secretions. • Unlike other HIV medications, ZDV becomes fully active within the placenta. Nadine Johnson

  17. SHORT COURSE ZDV PROPHYLAXIS REGIMENS • Regimens were designed and evaluated in clinical trials in resource-limited countries. • Following • Results of PACTG 076 • Data suggesting • most transmission occurs during delivery • in utero transmission predominantly occurs during the last two months of pregnancy Nadine Johnson

  18. Nadine Johnson

  19. HIVNET 012 • Single dose intrapartum/newborn Nevirapine • Non-nucleoside reverse transcriptase inhibitor • Reduce risk of transmission by 47% • Protocol is the most commonly used in low –resource settings because of its • demonstrated efficacy in clinical trials in reducing MTCT • low cost • ease of use in MTCT programs Nadine Johnson

  20. HIVNET 012 • Short-course ARV regimens, that do not fully suppress viral replication, may be associated with the development of ARV drug resistance • 19% of the women developed resistance postpartum. • Associated with HIV viral load and CD4 cell count at delivery • Detectable transient nevirapine resistance mutations were also observed at 6 - 8 weeks of age in 46% of infants who became infected despite NVP prophylaxis Nadine Johnson

  21. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. • Jourdain G, et alPerinatal HIV Prevention Trial Group. • Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, • CONCLUSION • Women who received intrapartum nevirapine were less likely to have virologic suppression after 6 months of postpartum treatment with a nevirapine-containing regimen. Nadine Johnson

  22. ? Zidovudine Resistance • Data from PACTG 076 indicate that a transient course of ZDV monotherapy during pregnancy appears safe and unlikely to induce resistance in a relatively healthy population of infected women. • Time-limited use of ZDV prophylaxis alone during pregnancy would be appropriate Nadine Johnson

  23. ? Role of Highly Active Antiretroviral Therapy (HAART) /Triple Therapy2NRTI + NNRTIor 2 NRTI + PI Nadine Johnson

  24. The Role of HAART • Women and Infants Transmission Study (WITS) 1990 • Collaborative, multi-site, longitudinal, natural history study of U.S. women with human immunodeficiency virus (HIV) infection and their offspring. • Confirmed rate of MTCT of HIV correlates with the maternal-serum HIV viral load at delivery: • Higher maternal viral load, greater chance of HIV transmission. • HAART effectively lower patients viral load and thus further reduce mother-to-child transmission • 1.2 % transmission rate • Very low transmission if viral load is <1000 copies/ml • However, no definite viral-load threshold below which mother-to-child transmission of HIV will not occur. Nadine Johnson

  25. START • Short-term antiretroviral therapy • Standard HAART regimens commencing in the 2nd trimester with the intention to achieve undetectable viral loads of <50 copies per ml prior to delivery. • Protease-inhibitor based combination is recommended. • PIs have a greater barrier to resistance development than NNRTIs and can be stopped concurrently with the nucleoside backbone. • PI pill burden and tolerance is improving with newer formulations • Low incidence of severe short-term side-effects. • If non-nucleosides are used, these must be discontinued 1-2 weeks prior to the nucleoside backbone to reduce the likelihood of the emergence of resistance Nadine Johnson

  26. Thai Perinatal HIV Prevention Trial (PHPT-2),Thailand • Antenatal: ZDV from 28 weeks. Intrapartum: ZDV alone or ZDV plus single-dose NVP at onset of labour • Postpartum ZDV for one week with or without single-dose NVP (infant) • Vertical transmission rate of 1.9% with addition of single dose Nevirapine to mother and infant. • Currently WHO recommended regime for low –resource settings Nadine Johnson

  27. Persistence of nevirapine exposure during the postpartum period after intrapartum single-dose nevirapine in addition to zidovudine prophylaxis for the prevention of mother-to-child transmission of HIV-1. • Cressey TR et al. J Acquir Immune Defic Syndr 2005 • CONCLUSIONS: Significant NVP concentrations remained for up to 20 days in these Thai women. • To ensure that coverage is maintained until NVP concentrations fall to non-suppressive levels, 1 month of additional antiretroviral treatment after delivery should be considered to prevent the emergence of resistant viruses. Nadine Johnson

  28. Not Just PMTCT • Many pregnant women infected with HIV will also be candidates for treatment of their own HIV infection. • Appropriate antiretroviral treatment of HIV must be provided to women who require it, irrespective of the decision to provide antiretroviral agents for prophylaxis. Nadine Johnson

  29. Jamaican Guidelines Ministry of Health Adaptation Nadine Johnson

  30. Criteria for Triple ARV Therapy • All women with clinical AIDS • Women with a CD4 count of ≤ 200/mm3 • Women with CD4 levels 200 - 350/mm3, • Doctor should assess when to start therapy, by looking at the presence of clinical features Nadine Johnson

  31. Women diagnosed in pregnancy • CD 4 count < 200/mm3 • Require antiretrovirals for own health • Should begin regime compatible with the PMTCT regime. • Women in the first trimester may consider delaying initiation of ART • Consider severity of maternal HIV disease and potential benefits and risks of delaying ART until after first trimester • For women who are severely ill, the benefit of early initiation may outweigh theoretical risk to fetus • If do not require ARV’s for own health then offer PMTCT prophylaxis Nadine Johnson

  32. Option A - CD4 Counts ≥ 350 • Offer PMTCT prophylaxis • Mother • Start • ZDV 300 mg bid at 28 weeks gestation (or as soon as possible thereafter) • From onset of labour until delivery;- • ZDV 300 mg PO every 3 hours • PLUS • Single dose Nevirapine at onset of labour. • Do not continue 3-hourly AZT dosing for longer than 24 hours. • Continue AZT for one week after delivery. Nadine Johnson

  33. Option A - CD4 Counts ≥ 350 • To Infants AZT • ZDV 4 mg/kg (0.4 ml/kg) p.o every 12 hours for one week • And a single dose of 2mg/kg of Nevirapine suspension at birth • Premature (<34 wk EGA) infant dosage: 2 mg/kg Po q 12 hr for 2 weeks then 3 mg/kg Po q 12 hr for four weeks Nadine Johnson

  34. Option B - CD4 levels 200 - 350/mm3 • Remember this is a special category of patient. • Asymptomatic - give PMTCT prophylaxis • Symptomatic, then patient requires HAART therapy. • NOTE WELL - NEVIRAPINE must not be used for HAART in women with CD4 count >/250mm3 Nadine Johnson

  35. Option C - Late Presentation • After 38 weeks or during labour • has not received AZT • Mother • Single dose 200 mg of Nevirapine tablet at onset of labour. Nadine Johnson

  36. Option C • Newborn infant • AZT for 1 week • Nevirapine suspension 2mg/kg • within 72 hours after birth but preferably within 24 hours • If AZT unavailable and Mother received Nevirapine < 2 hours before delivery • 2 doses of Nevirapine 24 hours apart within 72 hours after birth . Nadine Johnson

  37. Option D - CD4 count < 200 • Commence ARV triple therapy at end of first trimester • Zidovudine/Lamivudine plus (Nelfinavir/ Kaletra or Nevirapine ) • Continues meds intra-partum • To Infants • ZDV 4 mg/kg (0.4 ml/kg) Po every 12 hours for one week • And a single dose of 2mg/kg of Nevirapine suspension at birth. Nadine Johnson

  38. UNKNOWN HIV STATUS AT TIME OF LABOUR • All opportunity for intervention is not lost • Diagnosis at the time of labour and delivery is still important point of entry for both preventive and treatment services Nadine Johnson

  39. UNKNOWN HIV STATUS AT TIME OF LABOUR • Counselling and rapid testing during labour • Women testing positive • Offer maternal single dose nevirapine prophylaxis • AZT to infant x 6 weeks. • Imminent delivery • Omit maternal dose • AZT to infant for 6 weeks ( ideally) or • Administer infant nevirapine dose as soon as possible after birth. • Already Delivered • Offer counselling and rapid testing shortly after delivery • Mother positive • Postpartum AZT x 6 weeks to the infant Nadine Johnson

  40. As access to ARV treatment becomes more widely available women not only live longer, but take advantage of their reproductive potential. Two further Clinical Scenarios Nadine Johnson

  41. HIV-INFECTED WOMEN on ARV’s WHO BECOME PREGNANT • Existing concerns relating to potential effects of ARV drugs on the developing fetus • Suspending treatment during the first trimester not recommended • Avoid EFV in first trimester • Replace with NFV or Lopinovir/r, NVP, because of a possible risk of CNS birth defects. Nadine Johnson

  42. HIV-INFECTED WOMEN on ARV’s WHO BECOME PREGNANT • Nausea and vomiting common in early pregnancy • Weeks 6 and 16 • Continue 2nd and 3rd trimester in ~ 20 % • Incidence may be increased in women taking ART • May affect adherence and occasionally require temporary discontinuation. • If treatment discontinued, stop all ARV drugs simultaneously and restart together to decrease risk of developing drug resistance. • Continue ARV treatment with the full regimen during labour. • Infant AZT for 1 week Nadine Johnson

  43. HIV-INFECTED WOMEN WITHINDICATIONS FOR INITIATING ARV’SWHO MAY BECOME PREGNANT • Choice of ARV regimen for women with potential to become pregnant must consider • Possibility that drugs may be received during the first trimester: • During the period of organogenesis • Before pregnancy recognized • Efavirenz • Potentially teratogenic • Avoid if effective contraception cannot be ensured Nadine Johnson

  44. HIV-INFECTED WOMEN WITHINDICATIONS FOR INITIATING ARV’SWHO MAY BECOME PREGNANT • Recommended first - line ARV regimens • ZDV +3TC +(NVP/Nelfinavir/Kaletra) • d4T +3TC +(NVP/Nelfinavir/Kaletra) Nadine Johnson

  45. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs) • NRTIs associated with • lactic acidosis • hepatic steatosis • body fat redistribution (lipodystrophy Nadine Johnson

  46. Nadine Johnson

  47. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) • All NNRTIs may have significant interactions with other drugs; dosage adjustment of interacting agents may be required Nadine Johnson

  48. Nadine Johnson

  49. Protease Inhibitors • All PIs are associated with metabolic abnormalities • dyslipidemia, • hyperglycemia, • insulin resistance, • and lipodystrophy. • Need to screen for Gestational Diabetes • May increase the risk of bleeding in hemophiliacs and • May have significant interactions with other drugs • dosage adjustments may be required. Nadine Johnson

  50. Nadine Johnson

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