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U.S. Public Health Service Perinatal Guidelines

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  1. U.S. Public Health ServicePerinatal Guidelines Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and to Reduce Perinatal HIV-1 Transmission in the United States

  2. About This Presentation These slides were developed using the November 2005 guidelines. The intended audience is clinicians involved in the care of patients with HIV. The user is cautioned that due to the rapidly changing field of HIV care, this information could become out of date quickly. Finally, it is intended that these slides be used as prepared, without changes in either content or attribution. Users are asked to honor this intent. -AETC National Resource Center http://www.aidsetc.org

  3. Background

  4. Scope of the Epidemic in the United States among Women and Children • AIDS in women has risen from 7% early in the epidemic to 24% of adult cases today • 175 new AIDS cases reported in children in 2001 • 141,000 AIDS cases in women reported through June 2001 • 10,000–20,000 estimated children living with HIV infection • 280–370 babies continue to be born each year with HIV infection

  5. Without antiretroviral (ARV) drugs during pregnancy, mother-to-child transmission (MTCT) has ranged from 16%–25% in North America and Europe • 21% transmission rate in the U.S. in 1994 before the standard zidovudine (ZDV) recommendation during pregnancy • With the change in practice, transmission was 11% in 1995 • Today, risk of perinatal transmission can be <2% with • effective antiretroviral therapy (ART) • elective cesarean section (C/S) as appropriate • formula feeding Perinatal HIV Transmission

  6. National Recommendations for HIV Testing of Pregnant Women • CDC (USPHS) recommendations for HIV screening of pregnant women (4-22-03) • Prenatal: Routine HIV screening for all pregnant women using the “opt out” approach • Labor and delivery: Routine rapid testing for women whose HIV status is unknown • Postnatal: Rapid testing for all infants whose mother’s status is unknown • Regulations, laws, and policies about HIV screening of pregnant women vary state to state

  7. Cases documented intrauterine, intrapartum, and postpartum by breastfeeding • In utero 25%–40% of cases • Intrapartum 60%–75% of cases • Addition risk with breastfeeding • 14% risk with established infection • 29%  risk with primary infection • Current evidence suggests most transmission occurs during the intrapartum period Timing of Perinatal HIV Transmission

  8. Women with HIV infection in the United States should not breastfeed • Women considering breastfeeding should know their HIV status Breastfeeding and HIV Infection

  9. Maternal Factors HIV-1 RNA levels Low CD4 lymphocyte count Other infections(hepatitis C, CMV, bacterial vaginosis) Maternal injection drug use Lack of ZDV during pregnancy Obstetrical Factors Length of ruptured membranes/ chorioamnionitis Vaginal delivery Invasive procedures Infant Factors Prematurity Factors Influencing Perinatal Transmission

  10. Perinatal Guidelines • USPHS Task Force Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1 Infected Women for Maternal Health and to Reduce Perinatal HIV-1 Transmission in the United States • Developed in 1994 in response to ACTG 076 • Working Group reconvened in December 1999 and meets monthly • Updated recommendations available online at AIDSInfo website (www.aidsinfo.nih.gov)

  11. Perinatal HIV Transmission and Maternal HIV RNA Viral Load (VL) • Correlation between maternal VL and risk of transmission, even in pregnant women treated with ARV agents • Risk of transmission in women with undetectable VL is extremely low, but transmission has occurred at all VL levels • Other factors appear to play a role in transmission • ZDV decreases transmission regardless of VL level • ZDV prophylaxis should be given even to women with very low or undetectable VL levels

  12. A phase III randomized placebo-controlled trial of zidovudine (ZDV) for the prevention of maternal-fetal HIV transmission Treatment regimen • Antepartum100 mg ZDV po 5x day, started at 14-34 weeks gestation • IntrapartumDuring labor, 1-hour initial dose 2 mg/kg IV followed by continuous infusion of 1 mg/kg/hr until delivery • Postpartum/infant regimen2 mg/kg po q 6 hr for 6 weeks, start 8-12 hours after birth ACTG 076

  13. Results of ACTG 076 30 66% reduction in risk for transmission (P = <0.001) Efficacy observed in all subgroups 20 22.6% Transmission Rate (%) 10 7.6% Placebo ZDV Group

  14. Follow-up of Uninfected Infants in ACTG 076: ZDV versus Placebo • No significant difference in growth • No difference in CD4 and CD8 counts between groups • No other safety abnormalities have been identified • No differences in Bayley developmental scores in uninfected infants in ACTG 219 • Follow-up of infants with exposure to nucleoside analogues is ongoing due to the potential for mitochondrial toxicity • In the U.S., no cases of mitochondrial toxicity have been identified

  15. Follow-up of Women in ACTG 076 • Median follow-up 4.2 years • No substantial differences in CD4 count, time to progression to AIDS, or death in women who received ZDV compared to those who received placebo

  16. Reducing Intrapartum HIV Transmission: Studies of Short Course Therapy • Oral ZDV in a non-breastfeeding population (Thailand) from 36 weeks and during labor • Transmission rate: 9.4 % ZDV vs 18.9 % placebo • Petra study–intrapartum/postpartum oral ZDV/3TC in a breastfeeding population (Uganda, S. Africa, Tanzania) • Transmission rate: 6% ZDV/3TC vs 15% placebo • HIVNet 012–intrapartum/postpartum/neonatal nevirapine (NVP) vs short course/neonatal ZDV in a breastfeeding population (Uganda) • Transmission rate: 12% NVP vs 21% ZDV

  17. Reducing HIV Transmission with Suboptimal Regimens • Partial ZDV regimens: (New York cohort) • Transmission rates • 6.1% with prenatal, intrapartum, and infant ZDV • 10% with only intrapartum ZDV • 9.3% if only infant ZDV started within first 48 hours • 26.6% with no ZDV

  18. Preconception Counseling/Care for HIV Infected Women of Childbearing Age • Goal: • Optimal maternal health for pregnancy • Stable, maximally suppressed VL • ACOG advocates preconception counseling for all women of childbearing age as a part of primary care • Effective contraception, if wanted, to reduce unintended pregnancy • Counsel about perinatal transmission risks, prevention strategies, potential effects of HIV treatment on pregnancy and infant • Screen for and treat infectious diseases, STDs

  19. Preconception Care (continued) • Begin or modify ARV therapy • Avoid ARV medications with toxicities to developing fetus • Choose those that reduce the risk of transmission • Evaluate/control for therapy-associated side effects • Evaluate and prophylax for OIs, give immunizations as needed • Optimize maternal nutritional status, start folic acid supplementation • Identify risk factors for adverse maternal or fetal outcome • Screen for maternal psychological and substance abuse disorders

  20. Treating Women with HIV Infection in Pregnancy

  21. Goals of ARV Therapy (ART) • To prolong life and improve quality of life • To suppress HIV to below the limits of detection or as low as possible, for as long as possible • To preserve or restore immune function

  22. When Should an Adult Be Treated?

  23. Care Guidelines for All Pregnant Women with HIV Infection • Provide standard clinical evaluation—HIV disease stage • Evaluate degree of immunodeficiency—CD4+ count, CD4% • Assess risk of disease progression as determined by level of plasma HIV-RNA • 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

  24. Guidelines for ART in Pregnancy: Concepts • Use optimal ARVs for the woman’s health; consider the potential impact on the fetus/infant • Offer 3-part ZDV regimen for reducing perinatal transmission, alone or in combination with other ARVs • Discuss preventable risk factors for perinatal transmission • Support decision-making by the woman following discussion of known and unknown benefits and risks • Acceptance or refusal of ARV or ZDV should not result in denial of care or punitive action

  25. Safety and Toxicity of ART in Pregnant Women: NRTIs • Clinical trial data in human pregnancy available for zidovudine, lamivudine, didanosine, stavudine • Mitochondrial toxicity possible with all NRTIs • Increased risk of lactic acidosis/hepatic steatosis with stavudine + didanosine* * This combination should be used only if no other alternatives are available.

  26. ART in Pregnant Women: NRTIs

  27. ART in Pregnant Women: NRTIs

  28. Safety and Toxicity of ART in Pregnant Women: NNRTIs • Clinical trial and pharmacokinetic (PK) data in human pregnancy available only for nevirapine • Prospective and retrospective reports for efavirenz; no clinical trials planned

  29. ART in Pregnant Women: NNRTIs

  30. ART in Pregnant Women: NNRTIs

  31. Safety and Toxicity of ART in Pregnant Women: PIs • PK and clinical trial data available for nelfinavir, saquinavir (soft gel capsules)/ritonavir • Limited data for indinavir and ritonavir • PK and clinical studies on indinavir/ritonavir and lopinavir/ritonavir are underway • Other PIs not yet studied • Concern for increased risk of hyperglycemia: monitor closely • Conflicting data re preterm delivery in women receiving PIs

  32. ART in Pregnant Women: PIs

  33. ART in Pregnant Women: PIs

  34. ART in Pregnant Women: PIs

  35. ART in Pregnant Women: Fusion Inhibitors

  36. Recommendations for ARV Prophylaxis to Reduce Perinatal HIV Transmission

  37. Clinical Scenario 1: Women w/o prior ARV therapy • Recommend • 3-part ZDV regimen to reduce perinatal transmission for all pregnant women with HIV infection, regardless of antenatal VL • Combination ART that includes the 3-part ZDV regimen for women who require treatment with VL>1000 copies/mL, regardless of clinical or immunologic status • Consider combination ART (as above) for women with VL<1000 copies/mL • Consider delaying therapy until after 10-12 weeks of gestation

  38. Clinical Scenario 2Women currently on ART • Discuss benefits and potential risks of her regimen during pregnancy • Add or substitute ZDV after the 1st trimester if possible • Recommend intrapartum and neonatal ZDV • Discontinue teratogenic drugs • Consider continuing or stopping current therapy during first trimester • If therapy is stopped, stop and restart all ARV simultaneously • Resistance testing for suboptimal viral suppression

  39. Changing ART During Pregnancy • Poor CD4+ response • Drugs with potential teratogenicity • Poor viral load response • Poor adherence to regimen • Evidence of viral resistance

  40. Follow-up of the Pregnant Woman with HIV Infection • CD4+ and VL to monitor the need for • ART for maternal health • Alteration in therapy • PCP prophylaxis • New onset of symptoms • Side effects or toxicities • Adherence to therapy • Fetal assessment based on gestational age • Long-range planning for continuity of medical care

  41. Clinical Scenario 3 (1) HIV-infected woman in labor w/o prior treatment • Discuss benefits of treatment during labor and for the neonatal period • Four treatment options: • Intrapartum IV ZDV followed by 6 weeks ZDV for the newborn • Oral ZDV/3TC for mother at onset and during labor followed by 1 week oral ZDV/3TC for the newborn

  42. Clinical Scenario 3 (2) HIV-infected woman in labor w/o prior treatment • Four treatment options (continued) 3. Single dose NVP* for mother at onset of labor followed by single dose of NVP for the newborn at 48–72 hrs of age 4. The single dose maternal/fetal NVP* regimen as above combined with intrapartum IV ZDV and 6 week ZDV for the newborn *High rate of NVP resistance mutations in women who receive single dose NVP

  43. Clinical Scenario 3 (3) HIV-infected woman in labor w/o prior treatment • High rate of NVP resistance mutations in women who receive single dose NVP • If single-dose NVP is given to the mother, alone or in combination with ZDV, consider adding maternal ZDV/3TC starting as soon as possible (intrapartum or immediately postpartum) and continuing for 3 to 7 days. This may reduce development of NVP resistance.

  44. Clinical Scenario 4 Infant whose mother did not receive prenatal or intrapartum ZDV • Offer the six-week neonatal ZDV component • Initiate therapy as soon as possible after maternal consent (preferably within 6–12 hours of birth) • Begin diagnostic testing of the infant • Refer to pediatric HIV specialist for long-term care • Maternal assessment in immediate postpartum period (e.g. CD4+, VL) for her ARV treatment needs

  45. Rapid Testing at Delivery toLate-Presenting Women • High risk of perinatal transmission in women without antenatal care and without HIV counseling and testing • Rapid testing during labor can it possible to initiate ARV prophylaxis and to refer the woman for care • ARV prophylaxis should be initiated as soon as possible after a positive rapid HIV test (before confirmatory test results are available)

  46. Cesarean Section to Reduce Perinatal HIV Transmission • Pregnant women should be counseled re: potential benefits and risks of scheduled C/S to reduce perinatal transmission • C/S reduces transmission in women with unknown VL who are not on ART or are receiving only ZDV • May be effective in women with VL>1000 copies/mL; unproven benefit in women on ART

  47. Cesarean Section to Reduce Perinatal HIV Transmission • Unclear whether scheduled C/S offers any benefit to women on ART with VL <1000 copies/mL, given the low transmission rate • Complications of C/S somewhat more frequent than in HIV-uninfected women • Patient’s decision should be respected

  48. Mode of Delivery: Clinical Situation 1 HIV+ woman not on ART, presents after ~36 weeks, VL and CD4+ pending, unlikely to be available before delivery. • Discuss options for therapy • Start ARVs, at minimum the ZDV regimen, consider ART • Counsel about scheduled C/S • If C/S, schedule for 38 weeks; start IV ZDV 3 hours before surgery • Infant should receive 6 weeks ZDV after birth • Discuss options for continuing/starting combination therapy as soon as VL, CD4+ count available

  49. Mode of Delivery: Clinical Situation 2 HIV+ woman, began prenatal care in 3rd trimester, responding to ART, but VL is well over 1000 at 36 weeks gestation. • Continue ARV therapy—it’s working • VL level falling but unlikely to be <1000 before delivery • Scheduled C/S may reduce risk of intrapartum transmission • Schedule C/S for 38 weeks; start IV ZDV 3 hours before surgery; continue other ARVs • Infant should receive 6 weeks ZDV after birth • Stress importance of adherence to therapy after delivery

  50. Mode of Delivery: Clinical Situation 3 HIV+ woman on ART with undetectable VL at 36 weeks gestation • Inform woman that her risk of perinatal transmission is low (approximately 2%), even with vaginal delivery • Few data on whether C/S will lower risk further in women with undetectable VL • Risks of C/S should be balanced against unknown benefit of C/S in this case