U.S. Public Health Service Perinatal Guidelines

1. U.S. Public Health ServicePerinatal Guidelines Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States July 31, 2012

2. About This Presentation • These slides were developed from the July 31, 2012,revisions to the guidelines. • The goal of the guidelines is to provide guidance to HIV care practitioners. Because of the rapidly changing field of HIV care, users of this slide set are advised to check http://aidsinfor.nih.gov for updates. • 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 www.aidsetc.org

3. Table of Contents Topic Slide Number 4 7 12 20 40 67 77 83 106 Introduction Lessons Learned from Clinical Trials Pre-Conception Counseling Antiretroviral Drugs Antepartum Care Intrapartum Care Postpartum Care Care of the Neonate Special Considerations www.aidsetc.org

4. Introduction (1) • Providers considering the use of antiretrovirals (ARVs) for HIV-infected women during pregnancy must take into account: • ARV treatment (ART) for maternal HIV infection; and • ARV chemoprophylaxis to reduce the risk of perinatal transmission of HIV • With universal prenatal HIV counseling and testing, preconception care, ARV prophylaxis, scheduled C-section delivery (if indicated), and avoidance of breast-feeding, perinatal HIV infection has diminished to <2% in the United States. www.aidsetc.org

5. Introduction (2) • The members of the Panel for Use of ARV Drugs in Pregnant HIV-1-Infected Women are experts in the field of maternal HIV and prevention of perinatal HIV transmission. • Members meet monthly to review clinical trials results and update the guidelines, which are posted on www.aidsinfo.nih.gov. www.aidsetc.org

6. Introduction (3) Recommendations in these guidelines are based on scientific evidence and expert opinion. Each recommended statement is rated with a letter of A, B, or C that represents the strength of the recommendation and with a numeral I, II, or III, according to the quality of evidence. www.aidsetc.org

7. LESSONS LEARNED FROM CLINICAL TRIALS OF ANTIRETROVIRAL INTERVENTIONS TO REDUCE PERINATAL TRANSMISSION OF HIV

8. Overview • Pediatric AIDS Clinical Trials Group 076 • Major achievement in HIV research • Showed administration of zidovudine (ZDV) to pregnant women and their infants could reduce perinatal transmission by 70% • In addition, increased HIV testing in pregnancy and combination ARV prophylaxis during pregnancy has reduced perinatal transmission to <2%. • Every HIV-infected infant is a sentinel event representing missed opportunities. www.aidsetc.org

9. ARV Prophylaxis: Mechanisms of Action • Combined antepartum, intrapartum, and infant ARV prophylaxis is recommended to prevent perinatal transmission of HIV. (AI) • ARV drugs reduce perinatal transmission by several mechanisms, including: • Lowering maternal antepartum viral load (VL) • Providing infant pre- and postexposure prophylaxis www.aidsetc.org

10. Lessons from Trials of Short-Course ARV Regimens • Combination antenatal prophylaxis taken over longer duration is more effective then a short-course, single-drug regimen in reducing perinatal transmission. • Combination infant ARV prophylaxis is recommended in the United States for infants whose mothers have not received antenatal ARV drugs. • Adding single-dose intrapartumnevirapine (NVP) is not recommended for women in the United States who are receiving standard recommended antenatal ARV prophylaxis. • Breast-feeding by HIV-infected mothers is not recommended in the United States. www.aidsetc.org

11. Perinatal Transmission and HIV RNA Copy Number • All HIV-infected women should be counseled about and administered ARV drugs during pregnancy regardless of their HIV RNA levels. (AI) • Mother-to-child transmission has been observed at very low or undetectable maternal HIV RNA levels. • Discordance may occur between plasma RNA levels and amount of cervicovaginalviral shedding. • Particularly in the presence of genital tract coinfections www.aidsetc.org

12. PRECONCEPTION COUNSELING AND CARE FOR HIV-INFECTED WOMEN OF CHILDBEARING AGE

13. Preconception Counseling and Care (1) • Preconception care is part of routine primary care and is recommended by CDC, ACOG, and other national organizations. • Purpose: • Prevention of unintended pregnancies • Optimization of maternal health prior to pregnancy • Prevention of perinatal transmission • Prevention of HIV-transmission to an uninfected partner while trying to conceive www.aidsetc.org

14. Preconception Counseling and Care (2) Recommendations • Discuss childbearing intentions with all women of childbearing age on an ongoing basis throughout the course of their care. (AIII) • Include information about effective and appropriate contraceptive methods. (AI) • Preconception counseling: Include information on safer sex and elimination of alcohol, illicit drugs, and smoking. (AII) www.aidsetc.org

15. Preconception Counseling and Care (3) • Include assessment of HIV disease status and need for ART for the health of the woman. (AII) • Choose an ART regimen for HIV-infected women of childbearing age based on: • Efficacy • Hepatitis B status • Teratogenic potential • Possible adverse outcomes for mother and fetus (AII) www.aidsetc.org

16. Reproductive Options for HIV-Concordant and Serodiscordant Couples (1) All couples: • Both partners should be screened for genital tract infections. (AII) • Semen analysis is recommended for HIV-infected men. HIV, and possibly ART, may be associated with a higher prevalence of abnormalities. www.aidsetc.org

17. Reproductive Options for HIV-Concordant and Serodiscordant Couples (2) Serodiscordant couples: • Expert consultation is recommended. (AIII) • No single method of safer conception is fully protective against transmission of HIV. • Initiation of ART for the HIV-infected partner is recommended (AI for CD4 count ≤550 cells/µL and BIII for CD4 count >550 cells/µL). • Maximal viral suppression is recommended before attempting conception. (AIII) • HPTN 052 trial showed ART can significantly decrease HIV transmission to uninfected partners. www.aidsetc.org

18. Reproductive Options for HIV-Concordant and Serodiscordant Couples (3) • HIV-infected female with uninfected male partner: The safest option is artificial insemination, including the option of self-insemination, during the periovulatory period. (AIII) • HIV-infected man with uninfected female: Sperm preparation techniques + either intrauterine insemination or in vitro fertilization should be considered if using donor sperm from an uninfected male is unacceptable. (AII) www.aidsetc.org

19. Reproductive Options for HIV-Concordant and Serodiscordant Couples (4) • Periconception administration of 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 ART has not been studied. • Outcome studies are needed to examine adverse events, including risk of congenital abnormalities. www.aidsetc.org

20. ANTIRETROVIRAL DRUGS INTHE PERINATAL PERIOD

21. Use of ARV Drugs by HIV-Infected Pregnant Women and Their Infants • Considerations for choice of ARV drugs for pregnant women include: • Possible changes in dosing requirements resulting from physiologic changes associated with pregnancy • Potential exacerbation of ARV drug toxicities • Pharmacokinetics and toxicity of transplacentally transferred drugs • Potential short- and long-term effects of ARV drugs on fetuses and newborns www.aidsetc.org

22. Combination ART and Pregnancy Outcome • Possible small increased risk of preterm birth in pregnant women receiving protease inhibitor (PI)-based ART; however, given the clear benefits, PIs should not be withheld for fear of altering pregnancy outcome. (AII) www.aidsetc.org

23. Pharmacokinetic Changes • Altered dosing during pregnancy may be required for some protease inhibitors, such as lopinavir/ritonavir (AII) • Concentrations of the following drugs are reduced during the 2nd and/or 3rd trimesters • Lopinavir/ritonavir (LPV/r) • Atazanavir (ATV) • Darunavir (DRV) • Nelfinavir (NFV) • The need for dosage adjustment depends on the patient’s treatment experience and use ofconcomitant medications www.aidsetc.org

24. Teratogenicity • Women of childbearing potential should undergo pregnancy testing before initiating efavirenz(EFV) and receive counseling about the potential risk to the fetus and desirability of avoiding pregnancy while on EFV. (AIII) • Consider non-EFV regimens in patients who are: (BIII) • Planning to become pregnant • Sexually active and not using effective contraception www.aidsetc.org

25. Report all cases of ARV use in pregnant women to the Antiretroviral Pregnancy Registry: http://www.APRegistry.com(AIII) The registry collects observational, nonexperimental data regarding ARV exposure during pregnancy to assess potential teratogenicity. www.aidsetc.org August 2012

26. Nevirapine and Hepatic/Rash Toxicity • Avoid initiating NVP in women with CD4 counts >250 cells/µLunless the benefits outweigh the risks. (AII) • Risk of hepatotoxicity/hypersensitivity reaction • Women who are tolerating NVP-containing regimens and become pregnant can continue regardless of CD4 count. (AII) www.aidsetc.org

27. NRTI Drugs and Mitochondrial Toxicity • The combination of stavudine (d4T) and didanosine (ddl) should not be prescribed during pregnancy because of reports of lactic acidosis and maternal/neonatal mortality with prolonged use in pregnancy. (AII) • Mitochondrial dysfunction should be considered in uninfected children with perinatal exposure to ARV drugs who present with severe clinical findings, particularly neurological. (AII) • Long-term clinical follow-up is recommended for any child with in utero exposure to ARV drugs. (AIII) www.aidsetc.org

28. Protease Inhibitors and Hyperglycemia • HIV-infected women taking ARV regimens during pregnancy should undergo standard glucose screening at 24-28 weeks’ gestation. (AIII) • Owing to linkage with hyperglycemia • Consider earlier glucose screening in women receiving PI-based regimens initiated before pregnancy. (BIII) www.aidsetc.org

29. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (1) www.aidsetc.org

30. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (2) www.aidsetc.org

31. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (3) www.aidsetc.org

32. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (4) www.aidsetc.org

33. Nonnucleoside Reverse Transcriptase Inhibitors (NRTIs) (1) www.aidsetc.org

34. NonnucleosideReverse Transcriptase Inhibitors (NRTIs) (2) www.aidsetc.org

35. NonnucleosideReverse Transcriptase Inhibitors (NRTIs) (3) www.aidsetc.org

36. Protease Inhibitors (1) Class concerns for PIs: hyperglycemia, diabetes, question of increased risk of preterm delivery www.aidsetc.org

37. Protease Inhibitors (2) www.aidsetc.org

38. Protease Inhibitors (3) www.aidsetc.org

39. Additional Recommendations by Class Integrase Inhibitors Entry Inhibitors www.aidsetc.org

40. ANTEPARTUM CARE

41. Pregnant Women Who Are ARV Naive (1) • Pregnant women with HIV infection should receive standard clinical, immunologic and virologic evaluation. • Including hepatitis C and tuberculosis screening • All HIV-infected pregnant women should receive a potent combination ARV regimen to reduce the risk of perinatal transmission. (AI) • Reducing HIV RNA to undetectable levels lowers the risk of perinatal transmission, lessens the need for elective C-section to reduce risk of HIV transmission, and reduces risk of ARV drug resistance in the mother. www.aidsetc.org

42. Pregnant Women Who Are ARV Naive (2) • The choice of regimen should take into account current adult treatment guidelines, what is known about the use of the drugs during pregnancy, and the risk of teratogenicity. (see Guidelines, Table 5) • Use a dual-NRTI backbone; 1 or more NRTIs should have high levels of transplacental passage: (AIII) • ZDV, 3TC, FTC, TFV, ABC • NVP can be used as a component of the regimen in pregnant women with CD4 counts <250 cells/µL. But NVP should only be used if the benefit clearly outweighs the risk of hepatic toxicity. (AII) www.aidsetc.org

43. Pregnant Women Who Are ARV Naive (3) • The decision as to whether to start the regimen in the 1st trimester vsdelay until 12 weeks’ gestation will depend on CD4 count, VL, and maternal conditions such as nausea and vomiting. (AIII) • Earlier initiation may be more effective in reducing risk of transmission, but benefits must be weighed against potential fetal effects. • Fetuses are most susceptible to potential teratogenic effects in the 1st trimester. • Although most transmission occurs late in pregnancy or during delivery, recent analyses suggest that early control of viral replication may be important. www.aidsetc.org

44. Pregnant Women Who Are ARV Naive (4) • Conduct drug resistance testing before starting ARVs. • However, if HIV is diagnosed or the woman presents later in pregnancy, start the ARV regimen promptly and adjust, as needed, after resistance testing results are available. www.aidsetc.org

45. Pregnant Women Who Are ARV Naive (5) • RAL has been suggested for women with a high VL late in pregnancy because of its ability to rapidly suppress VL. But the safety and efficacy of RAL in this setting have not been evaluated. • Use of ZDV alone for prophylaxis is not optimal, but could be an option, combined with C-section delivery, for women with VL <1,000 copies/mL who wish to reduce fetal exposure to ARVs. www.aidsetc.org

46. Pregnant Women Who Are ARV Naive (6) • The regimen initiated during pregnancy can be modified after delivery to a simplified regimen with ARVs that are not used during pregnancy because of insufficient pregnancy safety data. • Drugs may be stopped after delivery in women who do not feel prepared to continue lifelong treatment. • Consult with the HIV care provider. www.aidsetc.org

47. HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Therapy (1) • HIV-infected women who present for care in the 1st trimester should continue any effective ARV regimen. (AII) • Including: • Effective EFV-based regimens (CIII) • Effective NVP-based regimens (AIII) • Resistance testing should be performed on women with detectable viremia. (AI) • >500-1,000 copies/mL www.aidsetc.org

48. HIV-Infected Pregnant Women Who Are Currently Receiving Antiretroviral Therapy (2) • Rationale for continuing EFV in pregnancy: • 1st trimester exposure is not associated with a large increase in the risk of neural tube defects. • The risk of neural tube defects is limited to the first 5-6 weeks of pregnancy, before most pregnancies are recognized. • Treatment changes during pregnancy increase the risk of incomplete viral suppression at the end of pregnancy. www.aidsetc.org

49. Pregnant Women Who Are ARV-Experienced (1) • Pregnant women with HIV infection who have received ARVs previously for prevention of perinatal transmission: • Rates of resistance appear to be low after prophylaxis with combination ART. But interpretation of resistance testing after treatment discontinuation is complex; resistance testing is most accurate if done while on ARVs or within 4 weeks of discontinuing ARVs. • Treatment failure has not been demonstrated with reinitiation of ART following prophylactic use in pregnancy. www.aidsetc.org

50. Pregnant Women Who Are ARV-Experienced (2) • Pregnant women with HIV infection who have received ARVs previously for their own health: • Choice of ARV regimen is challenging and will vary by: • History of ART • Indication for stopping treatment • Efficacy of previous ART • Results of past and current resistance testing • Testing for HLA-B*5701 www.aidsetc.org