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Title: U'S' Public Health Service Perinatal Guidelines


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 December
2004 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information could become out of date quickly.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.aids-etc.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
  • 10,00020,000 estimated children living with HIV
    infection
  • 280370 babies continue to be born each year with
    HIV infection

5
  • Perinatal HIV Transmission
  • Without antiretroviral (ARV) drugs during
    pregnancy, mother-to-child transmission (MTCT)
    has ranged from 1625 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 lt2
    with
  • effective antiretroviral therapy (ART)
  • elective cesarean section (C/S) as appropriate
  • formula feeding

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
    mothers status is unknown
  • Regulations, laws, and policies about HIV
    screening of pregnant women vary state to state

7
  • Timing of Perinatal HIV Transmission
  • Cases documented intrauterine, intrapartum, and
    postpartum by breastfeeding
  • In utero 2540 of cases
  • Intrapartum 6075 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

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

9
Factors Influencing Perinatal Transmission
  • 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

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
  • ACTG 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/hr until delivery
  • Postpartum/infant regimen2 mg/kg po q 6 hr for 6
    weeks, start 8-12 hours after birth

13
Results of ACTG 076
30
66 reduction in risk for transmission (P
lt0.001) Efficacy observed in all subgroups
20
22.6
Transmission Rate ()
10
7.6
ZDV Group
Placebo
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 studyintrapartum/postpartum oral ZDV/3TC
    in a breastfeeding population (Uganda, S.
    Africa, Tanzania)
  • Transmission rate 6 ZDV/3TC vs 15 placebo
  • HIVNet 012intrapartum/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 evaluationHIV disease
    stage
  • Evaluate degree of immunodeficiencyCD4 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 womans 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

29
ART in Pregnant Women NNRTIs
30
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

31
ART in Pregnant Women PIs
32
ART in Pregnant Women PIs
33
ART in Pregnant Women PIs
34
ART in Pregnant Women Fusion Inhibitors
35
Recommendations for ARV Prophylaxis to Reduce
Perinatal HIV Transmission
36
  • 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
    VLgt1000 copies/mL, regardless of clinical or
    immunologic status
  • Consider combination ART (as above) for women
    with VLlt1000 copies/mL
  • Consider delaying therapy until after 10-12 weeks
    of gestation

37
  • 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

38
  • Changing ART During Pregnancy
  • Poor CD4 response
  • Drugs with potential teratogenicity
  • Poor viral load response
  • Poor adherence to regimen
  • Evidence of viral resistance

39
  • 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

40
  • Clinical Scenario 3
  • 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
  • Single dose NVP for mother at onset of labor
    followed by single dose of NVP for the newborn at
    4872 hrs of age
  • The 2-dose NVP regimen as above combined with
    intrapartum IV ZDV and 6 week ZDV for the newborn

41
  • 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 612 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

42
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)

43
  • 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 VLgt1000 copies/mL
    unproven benefit in women on ART

44
Cesarean Section to Reduce Perinatal HIV
Transmission
  • Unclear whether scheduled C/S offers any benefit
    to women on ART with VL lt1000 VL copies/mL, given
    the low transmission rate
  • Complications of C/S somewhat more frequent than
    in HIV-uninfected women
  • Patients decision should be respected

45
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

46
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 therapyits working
  • VL level falling but unlikely to be lt1000 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

47
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

48
Mode of Delivery Clinical Situation 4
  • HIV woman scheduled for elective C/S, presents
    in early labor or shortly after rupture of
    membranes.
  • IV ZDV should be started immediately
  • If labor is progressing rapidlyallow for vaginal
    delivery
  • If minimal cervical dilatation, some clinicians
    would administer loading dose of ZDV and proceed
    with C/S
  • Other options pitocin augmentation to expedite
    vaginal delivery
  • During labor, avoid use of scalp electrodes,
    other invasive monitoring/procedures

49
  • Preterm Labor and Combination ART
  • A Swiss study reported a possible association
    between combination ARV therapy and preterm
    births
  • Meta-analysis of 7 clinical studies found use of
    multiple drugs v. no ARVs or one drug was not
    associated with preterm labor, low birth weight,
    low Apgar or stillbirth
  • Patients should be educated and cautioned about
    signs of premature labor

50
Prophylaxis for Neonates
  • If HIV mother did not receive antenatal or
    intrapartum treatment
  • Optimal regimen not known some evidence for ZDV
    x 6 weeks, single-dose nevirapine, and ZDV
    single-dose nevirapine
  • Further research needed

51
Stopping ART
  • Discontinue all drugs simultaneously, unless
    significant differences in half-life
  • Resistance may develop if virus replicates in the
    presence of 1-2 ARVs
  • NNRTIs have long half-lifes, low genetic barrier
    to resistance
  • Resistance to NNRTIs may develop quickly after
    single-dose nevirapine or discontinuation of
    nevirapine-containing regimens
  • Avoid using single-dose nevirapine alone
    (monotherapy)
  • For NNRTI-containing combination regimens,
    consider continuing NRTIs for 4-7 days after
    stopping NNRTI
  • Need research to guide discontinuation strategies

52
Mitochondrial Toxicity and Nucleoside Analogue
Drugs
  • Nucleoside analogs known to induce mitochondrial
    dysfunction conflicting data on mitochondrial
    toxicity in infants exposed to ARVs
  • Lactic acidosis/hepatic steatosis reported in 4
    women with HIV infection
  • Pregnant women with HIV infection on nucleoside
    analogues should have liver enzymes and
    electrolytes monitored frequently in 3rd
    trimester
  • d4T ddI combination should be avoided during
    pregnancy

53
Nevirapine Rash and Hepatotoxicity
  • Risk of nevirapine-associated hepatotoxicity and
    rash is higher in women particularly if CD4 gt250
    cells/mm3
  • Pregnant women who take nevirapine should have
    frequent measures of transaminase levels,
    especially in the first 18 weeks of treatment
  • Use with caution in ARV-naive pregnant women who
    are starting ART

54
  • Antiretroviral Pregnancy Registry
  • Collaborative project managed by PharmaResearch
    Corporation on behalf of an advisory committee
    (specialists in OB/GYN, ID, teratology,
    epidemiology, and CDC and NIH members) and
    sponsored by
  • Abbott Laboratories, Agouron Pharmaceuticals,
    Inc., Boehringer Ingelheim Company, Bristol-Myers
    Squibb, Co., Gilead Sciences, Inc.,
    GlaxoSmithKline, F. Hoffmann-LaRoche Ltd., Merck
    Co., Inc. and PharmaResearch.
  • Purpose To assess safety of ARVs during
    pregnancy
  • Telephone (800) 258-4263 Fax (800) 800-1052
    available at http//www.apregistry.com

55
  • Comprehensive Care of Women Postpartum
  • Primary and HIV specialty care
  • Ob/GYN and family planning services
  • Mental health and substance abuse treatment as
    needed
  • Coordination of care through case management for
    the woman and her family
  • Support services for the family

56
  • Evaluation and Follow-up of Infants
  • Support for ZDV prophylaxis for 6 weeks
  • HIV diagnostic testing to establish or rule out
    HIV infection as early as possible
  • Referral to an HIV specialist
  • PCP prophylaxis initiated at 6 weeks of age
  • Long-term followup of HIV- and ARV-exposed
    infants
  • Support services for the family

57
Case Studies
58
Case Study 1
  • Angela, 41 y.o., first prenatal visit,
    approximately 19 weeks gestation, tested HIV 2
    months ago. CD4 725 cells/mm3, HIV-1 RNA 600
    copies/ml. This is her 4th pregnancy, she has no
    children.
  • What recommendations for ARV therapy apply in
    this case?
  • What questions will you ask what options to
    present?
  • What OB condition may complicate this case?
  • What is the follow-up after delivery for the
    woman and infant?

59
Case Study 2
  • Maria, 27 y.o., at 35 weeks gestation, requested
    HIV test. Former boyfriend died of AIDS. Test is
    positive, CD4 350, HIV-1 RNA 120,000 husband and
    child test negative. Refuses ZDV. It made my
    boyfriend worse. Wants the cocktail that Magic
    Johnson uses.
  • What are the recommendations for this woman?
  • Psychological issues? Related to community
    beliefs?
  • What counseling will you do?

60
Case Study 3
  • Ellen, 32 y.o., 910 weeks gestation, tested
    positive on voluntary prenatal screening. A
    former heroin user, she is now on methadone. CD4
    198. HIV-1 RNA is 100,000. Under stress. Wants
    ART and a C-section. Wants to know what else she
    can do to stay well. Heard that ritonavir is a
    good drug.
  • What are the recommendations for this woman?
  • Screening for other infectious complications?
  • Options for reducing perinatal transmission?
  • What management issues does this case present?

61
Case Study 4
  • Heather, 14 weeks gestation, HIV for 5 years,
    stage B2 (mild dysplasia), CD4 220 HIV-1 RNA
    5,000. Shes on ZDV, ddI, and nelfinavir. Shes
    anemic. Husband has AIDS. This is a planned
    pregnancy. Office staff feel this couple is
    irresponsible for having a baby.
  • What are the recommendations for this woman?
  • What information does this couple need?
  • What are other options for this woman? Should she
    be referred?
  • How are you going to deal with the office staff?

62
Case Study 5
  • Joan, G8P3, HIV for 3 years, admitted with
    ruptured membranes. No prenatal care. Lost 2
    children to HIV. Urine for cocaine, GB strep
    (urine, cervix), other STDs negative. CD4 845.
  • What are the recommendations for this mother and
    infant?
  • How will you present the ACTG 076 regimen to this
    woman?
  • What alternative therapies can she choose to
    decrease perinatal transmission?
  • What should follow-up care include?

63
Case Study 6
  • Twelve hours after the birth of her infant,
    Angela Gs HIV test comes back positive. She
    tested negative early in her pregnancy but the
    test was repeated on admission to L D because
    she reported that her husband was back to using
    IV drugs. She did not have any antenatal or
    intrapartum ARV therapy.
  • What are the recommendations for this mother and
    infant?
  • How will you present the 076 regimen to this
    woman and what are the options?
  • What follow-up care is needed for Angela and her
    baby?

64
Acknowledgements
  • Slide set prepared for the AETC National Resource
    Center by the François-Xavier Bagnoud Center
    UMDNJ, Newark, NJ
  • Reviewed and revised by Susa Coffey, MD
  • Published text posted on www.aidsinfo.nih.gov
  • Current slide set posted on www.aidsetc.org
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