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PERINATAL GUIDELINES PANEL

PERINATAL GUIDELINES PANEL. Update July 31 2012. Perinatal Guidelines Update July 31 2012. Structured literature search on various sections conducted by staff of HIV/AIDS National Resource Center and used to review evidence.

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PERINATAL GUIDELINES PANEL

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  1. PERINATAL GUIDELINES PANEL Update July 31 2012

  2. Perinatal Guidelines Update July 31 2012 Structured literature search on various sections conducted by staff of HIV/AIDS National Resource Center and used to review evidence. More frequent updates of sections (without having to update entire document) planned for “live” document.

  3. Perinatal Guidelines Update July 31 2012 International Clinical Trials:Updated BAN through week 48

  4. Perinatal Guidelines Update July 31 2012 Preconception counseling: Table 4 on ARV-hormonal contraceptive interactions updated to include data on hormonal contraceptive interactions with rilpivirine and raltegravir.

  5. Perinatal Guidelines Update July 31 2012 Reproductive Options for HIV Seroconcordant and Serodiscordant Couples Based on HPTN 052 trial, for serodiscordant couples who want to conceive, use of antiretroviral therapy is now recommended for the HIV-infected partner, with the strength of the recommendation differing based on the CD4-cell count of the infected partner: AI for CD4 T-lymphocyte (CD4-cell) count ≤550 cells/mm3, BIII for CD4-cell count >550 cells/mm3 If therapy is initiated, maximal viral suppression is recommended before conception is attempted(AIII).

  6. Reproductive Options for HIV Seroconcordant and Serodiscordant Couples Discussion of pre-exposure prophylaxis (PrEP) studies in heterosexual couples, includes information on counseling, laboratory testing, and monitoring of individuals on PrEP and importance of reporting uninfected women who become pregnant on PrEP to the Antiretroviral Pregnancy Registry. Periconception administration of antiretroviral PrEP for HIV-uninfected partners may offer an additional tool to reduce the risk of sexual transmission(CIII). The utility of PrEP of the uninfected partner when the infected partner is receiving antiretroviral therapy has not been studied. Perinatal Guidelines Update July 31 2012

  7. Perinatal Guidelines Update July 31 2012 Preconception counseling:

  8. HPTN 052 Study Design Cohen M et al. NEJM 2011;365:493-505 Stable, healthy, serodiscordant couples, sexually-active; HIV+ partner with CD4 count: 350 to 550 cells/mm3 Immediate ART (N=886) Median follow-up: 1.7 years Deferred ART (CD4 <250 or AIDS) (N=877) Primary Transmission Endpoint Virologically-linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death

  9. HPTN 052 Baseline Characteristics Cohen M et al. NEJM 2011;365:493-505

  10. HPTN 052 Transmission Endpoints Cohen M et al. NEJM 2011;365:493-505 • * 18/28 (64%) transmissions from HIV+ participants with CD4 >350 cells/mm3 • * 23/28 (82%) transmissions occurred in sub-Saharan Africa couples • * 18/28 (64%) transmissions were from female to male partners

  11. HPTN 052: HIV-1 Transmissions (Linked and Overall) Cohen M et al. NEJM 2011;365:493-505

  12. Multivariate Analysis – Risk Factors Associated with Linked Transmission Events Cohen M et al. NEJM 2011;365:493-505

  13. PrEP Studies – Cochrane Review Okwundu CI et al. Cochrane Database Syst Rev 2012;7:CD007189

  14. PrEP Studies – Cochrane Review Okwundu CI et al. Cochrane Database Syst Rev 2012;7:CD007189

  15. PrEP Studies – Cochrane Review Okwundu CI et al. Cochrane Database Syst Rev 2012;7:CD007189

  16. Perinatal Guidelines ARV Choice in PregnancyUpdate July 31 2012 Antiretroviral drug recommendations: ddI and d4T moved from alternative NRTI for pregnant women to use in special circumstances. ATV/r moved from alternativePI choices to preferred. DRV/r moved from insufficient data to recommend to alternativePI choice Raltegravir moved from insufficient data to recommend to use in special circumstances.

  17. Perinatal Guidelines Update July 31 2012 ARV in Pregnancy Table: Continues to includes formulation and dosing information for each drug in addition to pregnancy-related information.

  18. ARV Recommendations: NRTIsWhat’s New? • Nucleoside reverse transcriptase inhibitors: • Didanosine and stavudine moved from alternative NRTI category to use in special circumstancescategory because they have more toxicity than the preferred and alternative NRTI drugs. 9/2011 AETC National Resource Center, www.aidsetc.org 18

  19. ARV Recommendations: NRTIs Class concerns for NRTIs: lactic acidosis, mitochondrial toxicity 9/2011 AETC National Resource Center, www.aidsetc.org 19

  20. ARV Recommendations: NRTIs (2) 9/2011 AETC National Resource Center, www.aidsetc.org

  21. ARV Recommendations: NRTIs (3) 9/2011 AETC National Resource Center, www.aidsetc.org

  22. ARV Recommendations: NNRTIs Class concerns for NNRTIs: rash, hypersensitivity, hepatic toxicity 9/2011 AETC National Resource Center, www.aidsetc.org 22

  23. ARV Recommendations: NNRTIs (2) 23 23

  24. ARV Recommendations: PIsWhat’s New? • Protease inhibitors: • Atazanavir with low-dose ritonavir boosting moved from an alternativeprotease inhibitor to a preferredprotease inhibitor for use in antiretroviral-naive pregnant women, along with lopinavir/ritonavir, because of increased information on safety in pregnancy. • Darunavir moved from insufficient data to recommend use to an alternativeprotease inhibitor for use in antiretroviral-naive pregnant women. 9/2011 AETC National Resource Center, www.aidsetc.org 24

  25. ARV Recommendations: PIs Class concerns for PIs: hyperglycemia, diabetes, question of increased risk of preterm delivery 9/2011 AETC National Resource Center, www.aidsetc.org * r = low-dose ritonavir 25

  26. ARV Recommendations: PIs (2) * r = low-dose ritonavir 9/2011 AETC National Resource Center, www.aidsetc.org 26

  27. ARV Recommendations: PIs (3) * r = low-dose ritonavir * r = low-dose ritonavir 9/2011 AETC National Resource Center, www.aidsetc.org 27

  28. ARV Recommendations: PIs (4) * r = low-dose ritonavir * r = low-dose ritonavir 9/2011 AETC National Resource Center, www.aidsetc.org 28

  29. ARV Recommendations: Entry Inhibitors 9/2011 AETC National Resource Center, www.aidsetc.org 29

  30. ARV Recommendations: Integrase InhibitorsWhat’s New? • Integrase inhibitors: • Raltegravir moved from insufficient data to recommend useto use in special circumstancesfor antiretroviral-naive pregnant women when preferred or alternative agents cannot be used. 9/2011 AETC National Resource Center, www.aidsetc.org 30

  31. Perinatal GuidelinesARV-Naive Pregnant WomenUpdate July 31 2012 • Increased discussion on when to initiate an antiretroviral drug regimen in pregnant women: • The decision as to whether to start the regimen in the first trimester or delay until 12 weeks’ gestation will depend on CD4-cell count, HIV RNA levels, and maternal conditions such as nausea and vomiting(AIII). • Earlier initiation of a combination antiretroviral regimen may be more effective in reducing transmission, but benefits must be weighed against potential fetal effects of first-trimester drug exposure.

  32. HIV-Infected ARV Naïve Pregnant Women

  33. Perinatal Guidelines- Pregnant Women Currently on ART Update July 31 2012 • Discussion of efavirenz use in the first trimester: • Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy and pregnancy is rarely recognized before 4 to 6 weeks of pregnancy, and unnecessary antiretroviral drug changes during pregnancy may be associated with loss of viral control and increased risk of perinatal transmission, efavirenz can be continued in pregnant women receiving an efavirenz-based regimen who present for antenatal care in the first trimester, provided the regimen produces virologic suppression (CIII).

  34. HIV-Infected Pregnant Women Currently on ART

  35. Teratogenicity Issues

  36. Meta-Analysis of Pregnancy Outcomes with First Trimester EFV ExposureFord N et al. AIDS 2011;25:2301-4 • Purpose: to identify observational cohorts reporting birth outcomes among women exposed to EFV during 1st trimester • Methods: search with key terms indicating birth defects and HIV/AIDS in multiple databases and conference abstracts 2009-July 2011, contacting large cohort studies and trials networks. • Primary endpoint: overall birth defects of any kind • Secondary endpoints: spontaneous abortions, termination of pregnancy, stillbirth, prematurity

  37. 19 Studies with Birth Defect Data with 1st Trimester EFV ExposureFord N et al. AIDS 2011;25:2301-4 *1 additional CNS defect (but not neural tube): anophthalmia, facial clefts, arm amniotic band

  38. Use of raltegravir in late pregnancy in women with high viral loads to decrease viral load discussed but not endorsed. The efficacy and safety of this approach have not been evaluated and only anecdotal reports are available. In the setting of a failing regimen related to nonadherence and/or resistance, there are concerns that the addition of a single agent may further increase risk of resistance and potential loss of future effectiveness with raltegravir. Until more data become available on the safety of raltegravir use in pregnancy, this approach cannot be recommended. Perinatal Guidelines- Special Situations – Failure Viral Suppression July 31 2012

  39. Perinatal Guidelines July 31 2012 Hepatitis B/HIV coinfection in pregnancy – no changes diagnosis/management Hepatitis C/HIV coinfection in pregnancy – no changes diagnosis/management HIV-2 infection in pregnancy – no changes diagnosis/management. Expanded testing information. Acute HIV infection during pregnancy – no changes diagnosis/ management.

  40. New Table on Results of Studies Assessing Association Between ART and Preterm Delivery • ARV Drug Regimens and Pregnancy Outcomes • Addition of a new table summarizes the results of studies assessing the association between antiretroviral regimens and preterm delivery.

  41. Perinatal GuidelinesResistance TestingJuly 31, 2012 • Recommended if HIV RNA > 500-1000 copies/mL. • Do not delay initiation of antiretrovirals in later pregnancy while awaiting results. • When discontinuing NNRTI regimen, continue NRTI’s for 7-30 days to cover prolonged NNRTI levels or switch NNRTI to PI before stopping.

  42. Resistance Testing

  43. Use of IV AZT during labor and maternal viral load: IV AZT is no longer required for HIV-infected women receiving combination antiretroviral regimens who have HIV RNA <400 copies/mL near delivery (BII). HIV-infected women with HIV RNA ≥400 copies/mL (or unknown HIV RNA) near delivery should be administered IV AZT during labor, regardless of antepartum regimen or mode of delivery (AI). Based on pharmacokinetic data, in women with HIV RNA ≥400 copies/mL near delivery for whom AZT is recommended, IV would be preferred to oral administration in the United States; in situations where IV administration is not possible, oral administration can be considered. Perinatal Guidelines Intrapartum ARV Update July 31 2012

  44. MTCT, Intrapartum AZT, and RNA at DeliveryWarszawski J, et al. AIDS 2008;22:289-99 • 5,271 mother-child pairs delivered between 1997-2004; 19% got single ARV, 33% dual ARV, 48% HAART. • 96% received intrapartum IV AZT. • Overall, IV AZT was associated with lower MTCT (1.2% [59/5,006] with IV AZT vs. 3.1% [7/230] without, P =.025) but this association was related to HIV RNA level at delivery • In 364 women with HIV RNA >10,000 copies/mL at delivery, IV AZT was strongly associated with a lower MTCT: 5.3% (18/339) with IV AZT versus 22.7% (5/22) without (P =.009). • However, intrapartum prophylaxis was not associated with transmission in 2,845 women with HIV RNA <400 copies/mL at delivery: 0.6% (17/2,750) with IV AZT versus 0% (0/95) without. • Data not provided for women with viral load 400-9,999 copies/mL.

  45. Perinatal Guidelines Update July 31 2012 • Intrapartum ARV Use:

  46. Perinatal Guidelines Update July 31 2012 • Intrapartum - Mode of Delivery:No significant changes.

  47. Perinatal Guidelines Update July 31 2012 • Postpartum Follow-Up of Mother:No significant changes.

  48. Perinatal Guidelines Update July 31 2012 Neonatal ARV Prophylaxis: Twice daily dosing of AZT when used for the 6-week AZT prophylaxis is recommended for full-term infants. The recommended dose of AZT for post-exposure prophylaxis in full-term neonates is 4 mg/kg twice daily for the first 6 weeks of life, beginning as soon after birth as possible and preferably within 6-12 hours of delivery Preterm dosing information updated

  49. Perinatal Guidelines Update July 31 2012 Neonatal ARV Prophylaxis: Table 9 revised to reflect neonatal dosing only of zidovudine (in term and preterm infants) and nevirapine in the regimen used in the NICHD-HPTN 040 study. Choice of neonatal antiretroviral drug prophylaxis includes discussion of the NICHD-HPTN 040 study and concerns regarding use of lopinavir/ritonavir in neonates. Addition of new pharmacokinetic data on nevirapine in preterm infants.

  50. Perinatal Guidelines Update July 31 2012

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