U'S' Public Health Service Perinatal Guidelines

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• 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

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• With support from the U.S. Centers for Disease
  Control and Prevention, Cooperative Agreement
  R62/CCR217856-03
• and
• Health Resources and Services Administration,
  HIV/AIDS Bureau H4A HA00063-01-01

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Background
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• Scope of the Epidemic in the U.S.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

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• Perinatal Transmission of HIV

• Without antiretroviral drugs during pregnancy,
  mother-to-child transmission has ranged from
  1625 in North America and Europe
• 21 transmission rate in the U.S. in 1994 before
  the standard recommendation of zidovudine (ZDV)
  in pregnancy
• With the change in practice, transmission was 11
  in 1995
• Today, risk of perinatal transmission can be lt 2
  with highly active antiretroviral therapy
  (HAART), elective C/S as appropriate and formula
  feeding

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• 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 women will
  be notified that they will be tested unless they
  decline
• 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, policies about HIV screening
  of pregnant women vary state to state

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• 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

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• Breastfeeding and HIV Infection

• Women with HIV infection in the U.S. should not
  breastfeed
• Women considering breastfeeding should know their
  HIV status

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• Factors Influencing 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
• Obstetrical Factors
• Length of ruptured membranes/chorioamnionitis
• Vaginal delivery
• Invasive procedures
• Infant Factors
• Prematurity

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• 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
  HIV/AIDS Treatment Information Service web site
  (www.aidsinfo.nih.gov)

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• Perinatal HIV Transmission
• and Maternal Viral Load (VL)

• Correlation between maternal HIV RNA level (VL)
  and risk of transmission, even in pregnant women
  treated with antiretroviral agents
• Risk of transmission in women with undetectable
  VL is extremely low, but transmission has
  occurred at all VL levels
• Other factors beside VL also 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

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• 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
  1434 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, start 812 hours after birth

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Results of ACTG 076
30
This represents a 66 reduction in risk for
transmission (P lt0.001) Efficacy was observed
in all subgroups
20
22.6
Transmission Rate ()
10
7.6
ZDV Group
Placebo
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• 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

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• 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

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• 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 6 ZDV/3TC vs 15 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

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• 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

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Preconception Counseling/Care for HIV Infected
Women of Childbearing Age

• GoalOptimal 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

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Preconception Care (cont)

• Begin or modify ARV therapy
• Avoid those with toxicities to developing fetus
• Choose those that reduce the risk of transmission
• Evaluate/control for therapy-associated side
  effects
• Evaluate and prophylax for O.I.s, give
  immunizations
• 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

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Treating Women with HIV Infection in Pregnancy

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• 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

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• When Should an Adult be Treated?

Clinical Category CD4 count HIV RNA
Recommendations
Symptomatic Asymptomatic, AIDS Asymptomatic As
ymptomatic Asymptomatic
Any value Any value CD4 T cells Any
value lt200/mm3 CD4 T cell Any value
gt200/mm3 but lt350 /mm3 CD4 T cells gt55,000
(bDNA gt350/mm3 or RT-PCR) CD4 T cells
lt55,000 (bDNA gt350/mm3 or RT-PCR)
Treat Treat Treatment should generally be
offered, though controversy exists Some experts
would recommend initiating therapy some would
defer and monitor CD4counts Many experts would
defer therapy observe
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• Guidelines for Care of 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

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• Guidelines for Antiretroviral Drugs 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 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

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Recommendations for ARV Prophylaxis to Reduce
Perinatal HIV Transmission
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• Clinical Scenario 1 Women without prior
  antiretroviral therapy

• Recommend
• 3-part ZDV regimen to reduce perinatal
  transmission for all HIV-infected pregnant
  women, regardless of antenatal viral load
• Combination ARV therapy that includes the 3-part
  ZDV regimen for women who require treatment or
  whose VL is gt1000, regardless of clinical or
  immunologic status
• Consider delaying therapy until after 10-12 weeks
  of gestation

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• Clinical Scenario 2Women currently on
  antiretroviral therapy

• 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
  based on gestational age (lt14 weeks)
• If therapy is stopped, stop and restart all ARV
  simultaneously
• Resistance testing for suboptimal viral
  suppression

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• Changing HIV Therapy During Pregnancy

• Poor CD4 response
• Drugs with potential teratogenicity
• Poor viral load response
• Poor adherence to regimen
• Evidence of viral resistance

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• Follow-Up of the Pregnant Woman with HIV

• CD4 and viral load to monitor the need for
• ARV therapy for maternal health
• Alteration in therapy
• Need for 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

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• Clinical Scenario 3
• HIV-infected woman in labor with no 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 to the newborn
• Single dose nevirapine for mother at onset of
  labor followed by single dose of nevirapine for
  the newborn at 4872 hrs of age
• The 2-dose nevirapine regimen as above combined
  with intrapartum IV ZDV and 6 week ZDV for the
  newborn

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• 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

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• Cesarean Section to Reduce Perinatal HIV
  Transmission

• Pregnant women with VL gt1000 should be counseled
  re potential benefit of scheduled C/S to reduce
  perinatal transmission
• 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
• Patients decision should be respected and honored

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Mode of Delivery Clinical Situation 1

• HIV woman not on ARVs, presents after 36
  weeks, VL and CD4 pending unlikely to be
  available before delivery.
• Discuss options for therapy
• Start ARVs at least the ZDV regimen
• 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

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Mode of Delivery Clinical Situation 2

• HIV woman began prenatal care in 3rd trimester
  responding to HAART, but VL is well over 1000
  at 36 weeks gestation.
• Continue therapy its working
• VL level falling but unlikely to be lt 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

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Mode of Delivery Clinical Situation 3

• 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 rapidly allow 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

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• Preterm Labor and Combination Antiretroviral
  Therapy

• 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

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Mitochondrial Toxicity and Nucleoside Analogue
Drugs

• Nucleoside analogs known to induce mitochondrial
  dysfunction
• Lactic acidosis/hepatic steatosis reported in 4
  women with HIV
• Pregnant women with HIV on nucleoside analogues
  should have liver enzymes and electrolytes
  monitored frequently in 3rd trimester
• d4T and ddI combination should be avoided during
  pregnancy

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• Antiretroviral Pregnancy Registry

• A 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., DuPont Pharmaceuticals Company,
  GlaxoSmithKline, F. Hoffmann-LaRoche Ltd., Merck
  Co., Inc.
• Purpose To assess safety of antiretroviral
  drugs during pregnancy
• Telephone [phone] Fax [phone]
  available at http//www.apregistry.com

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• 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

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• 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 follow-up of HIV- and ARV-exposed
  infants
• Support services for the family

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Case Studies
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Case Study 1

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

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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?

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Case Study 3

• Ellen, 32 y.o., 9 10 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
  HAART therapy and aC-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?

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Case Study 4

• Heather, 14 weeks gestation, HIV for 5 years,
  stage B2 (mild dysplasia), CD4 220 HIV-1 RNA is
  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?

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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 076 regimen to this
  woman?
• What alternative therapies can she choose to
  decrease perinatal transmission?
• What should follow-up care include?

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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 antiretroviral 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?