What We Know About Perinatal HIV Transmission

1. What We Know About Perinatal HIV Transmission François-Xavier Bagnoud Center at UMDNJ

2. Scope of the Epidemic Among Women and Children • 130,000 AIDS cases in women reported through December 2000 • AIDS in women has risen from 7% early in the epidemic to 24% of adult cases today • 196 new AIDS cases reported in children in 2000 • 10,000 – 20,000 estimated children living with HIV infection • 300 – 400 babies continue to be born with HIV infection each year in the U.S. François-Xavier Bagnoud Center, UMDNJ, 2003

3. Scope of the Epidemic Among Women and Children in New Jersey • NJ is 5th in the U.S. in AIDS cases — 49,000 • Women are 28% — highest proportion in U.S. • 91% of pregnant women know their HIV status • ART use in pregnant women rose from 7% in 1993 to 70% in 1999 • Perinatal transmission fell from 21% in ’93 to 5.0% in ‘99 • But . . . 25% of HIV+ pregnant women have no prenatal care François-Xavier Bagnoud Center, UMDNJ, 2003

4. Perinatal Transmission of HIV • Without antiretroviral drugs during pregnancy, mother-to-child transmission has ranged from 16%–25% in North America and Europe • 21% transmission rate in the U.S. in 1994 before the standard recommendations of zidovudine (ZDV) in pregnancy • In 1995, transmission rate was 11% after the change in practice François-Xavier Bagnoud Center, UMDNJ, 2003

5. USPHS Guidelines for the Use of Antiretroviral Drugs in Pregnant Women for Maternal Health & Prevention of HIV Transmission • Developed in 1994 in response to ACTG 076 • Working Group reconvened in December 1999 and meets monthly • Updated recommendations available online at HIV/AIDS Treatment Information Service web site (www.hivatis.org) François-Xavier Bagnoud Center, UMDNJ, 2003

6. Timing of Perinatal HIV Transmission • 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 François-Xavier Bagnoud Center, UMDNJ, 2003

7. Breastfeeding and HIV Infection • Women with HIV infection in the U.S. should not breastfeed • Women considering breastfeeding should know their HIV status François-Xavier Bagnoud Center, UMDNJ, 2003

8. Influences on Perinatal Transmission: Maternal Factors • HIV-1 RNA levels (viral load) • Low CD4 lymphocyte count • Other infections, Hepatitis C, CMV, Bacterial Vaginosis • Maternal injection drug use • Lack of ZDV during pregnancy François-Xavier Bagnoud Center, UMDNJ, 2003

9. Influences on Perinatal Transmission: Obstetric and Infant Factors • Obstetrical Factors • Length of ruptured membranes/chorioamnionitis • Vaginal delivery • Invasive procedures • Infant Factors • Prematurity François-Xavier Bagnoud Center, UMDNJ, 2003

10. Maternal Viral Load (VL), ZDV Treatment and the Risk of Perinatal HIV Transmission • Correlation between high maternal VL and transmission • Transmission observed at every VL level, including undetectable levels • No HIV RNA threshold below which there was no risk of transmission • ZDV decreases transmission regardless of HIV RNA level • Recommendation: Initiate maternal ZDV regardless of plasma HIV RNA or CD4 counts François-Xavier Bagnoud Center, UMDNJ, 2003

11. What have we learned? Interrupting Perinatal HIV Transmission: Study Results

12. PACTG 076 • A phase III randomized placebo-controlled trial of zidovudine (ZDV) for the prevention of maternal-fetal HIV transmission • Treatment Regimen • Antepartum 100 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 until delivery • Postpartum/Infant Regimen2 mg/kg po q 6 hr for 6 weeks, to start 8 – 12 hours after birth François-Xavier Bagnoud Center, UMDNJ, 2003

13. Results of PACTG 076 30 This represents a 66% reduction in risk for transmission (P = <0.001) Efficacy was observed in all subgroups 20 22.6% Transmission Rate (%) 10 7.6% Placebo ZDV group François-Xavier Bagnoud Center, UMDNJ, 2003

14. Follow-up of Uninfected Infants and of Mothers in PACTG 076 • No significant differences in infant growth, development, or immune function in placebo v. ZDV. • No other safety abnormalities have been identified in infants • 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 • For mothers, no substantial differences in CD4 count, time to progression to AIDS, or death in women who received ZDV compared to those who received placebo François-Xavier Bagnoud Center, UMDNJ, 2003

15. 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 breast-feeding population (Uganda, S. Africa, Tanzania) • Transmission rate: 10% ZDV/3TC vs 17% placebo • HIVNet 012 – intrapartum/postpartum/neonatal nevirapine (NVP) vs short course/neonatal ZDV in a breast-feeding population (Uganda) • Transmission rate: 12% NVP vs 21% ZDV François-Xavier Bagnoud Center, UMDNJ, 2003

16. Reducing Intrapartum HIV Transmission:Studies of Short Course ARV Therapy François-Xavier Bagnoud Center, UMDNJ, 2003

17. Reducing HIV Transmission with Suboptimal Regimens • HIV transmission rates with partial ZDV regimens (New York cohort): • 6.1% with prenatal, intrapartum, and infant ZDV • 10% with only intrapartum ZDV • 9.3% with only infant ZDV started within first 48 hours • 26.6% with no ZDV François-Xavier Bagnoud Center, UMDNJ, 2003

18. Reducing HIV Transmission with Suboptimal Regimens: The New York Cohort François-Xavier Bagnoud Center, UMDNJ, 2003

19. Treating Women with HIV Infection in Pregnancy

20. Goals of Antiretroviral Therapy • 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 François-Xavier Bagnoud Center, UMDNJ, 2003

21. Guidelines for Antiretroviral Drugs During Pregnancy • Use optimal ARV for the woman’s health • Add ZDV regimen for reducing perinatal HIV transmission • Discuss preventable risk factors for perinatal transmission • Counsel on cesarean delivery • Support decision-making by 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 François-Xavier Bagnoud Center, UMDNJ, 2003

22. Women without prior antiretroviral therapy: Guidelines for Antiretroviral Drugs in Pregnancy:Clinical Scenario 1 • Recommend: • Standard combination therapy for women with high viral load, low CD4 count • Combination therapy for women with viral load 1,000 regardless of clinical or immunologic status • 3-part ZDV regimen to reduce perinatal transmission for all HIV-infected pregnant women, regardless of antenatal VL • Consider delaying therapy until completion of first trimester • Offer scheduled cesarean delivery for women with viral loads >1000 (based on most recent VL results) François-Xavier Bagnoud Center, UMDNJ, 2003

23. Clinical Scenario 2: Women currently on antiretroviral therapy: • Discuss benefits and potential risks of her current regimen during pregnancy • Add or substitute ZDV at 14 weeks • Recommend intrapartum and neonatal ZDV • Discontinue teratogenic drugs • Consider continuing or stopping current therapy based on gestational age (<14 weeks) • If therapy is stopped, stop and restart all ARV simultaneously • Resistance testing for suboptimal viral suppression or failure François-Xavier Bagnoud Center, UMDNJ, 2003

24. Clinical Scenario 3: Women with HIV infection who present in labor with no previous treatment • Discuss benefits of treatment during intrapartum and neonatal period • Four treatment options • Single dose nevirapine for mother at onset of labor followed by single dose of nevirapine for the newborn at age 48–72 hrs • Oral ZDV/3TC for mother during labor followed by one week oral ZDV/3TC to the newborn • Intrapartum IV ZDV followed by six weeks ZDV for the newborn • The two-dose nevirapine regimen as above combined with intrapartum IV ZDV and six week ZDV for the newborn François-Xavier Bagnoud Center, UMDNJ, 2003

25. 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 François-Xavier Bagnoud Center, UMDNJ, 2003

26. Cesarean Section to Reduce Perinatal HIV Transmission • Scheduled C/S offers potential benefit to reduce perinatal transmission for pregnant women with VL >1000 • Unknown whether scheduled C/S offers any benefit to women on HAART with low or undetectable VL given the low transmission rate • Complications of C/S similar to HIV uninfected women • Patient’s decision should be respected and honored • No known benefit of C/S if labor has begun François-Xavier Bagnoud Center, UMDNJ, 2003

27. Postpartum Follow-up of the Woman with HIV Infection • Referral for medical management • Referral for psychosocial care and case management • Refer infant to experienced pediatric HIV providers for follow-up • Educate mom about newborn’s need for • Prophylactic ARV (ZDV x 6 weeks) • Diagnostic testing and follow-up • PCP prophylaxis at 6 wks of age François-Xavier Bagnoud Center, UMDNJ, 2003