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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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information could become out of date quickly.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
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Background
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• 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

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• 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

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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
• 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

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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 United States
  should not breastfeed
• Women considering breastfeeding should know their
  HIV status

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Factors Influencing Perinatal Transmission

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

• 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

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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
  AIDSInfo website (www.aidsinfo.nih.gov)

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• 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

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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
  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

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Results of ACTG 076
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66 reduction in risk for transmission (P
lt0.001) Efficacy observed in all subgroups
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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 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

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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

• 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

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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

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Treating Women with HIV Infection in Pregnancy

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• 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

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When Should an Adult Be Treated?
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• 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

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• 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

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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.
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ART in Pregnant Women NRTIs
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ART in Pregnant Women NRTIs
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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

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ART in Pregnant Women NNRTIs
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ART in Pregnant Women NNRTIs
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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

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ART in Pregnant Women PIs
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ART in Pregnant Women PIs
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ART in Pregnant Women PIs
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ART in Pregnant Women Fusion Inhibitors
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Recommendations for ARV Prophylaxis to Reduce
Perinatal HIV Transmission
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• 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

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• 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

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• Changing ART 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 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

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• 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

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• 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
  4872 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
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• 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.

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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 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

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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)

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• 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

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Cesarean Section to Reduce Perinatal HIV
Transmission

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

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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

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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

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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

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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

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• 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

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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

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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

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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

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Nevirapine Rash and Hepatotoxicity

• Risk of nevirapine-associated hepatotoxicity and
  rash is higher in women particularly if CD4 gt250
  cells/mm³
• In women with CD4 gt250 cells/mm³,
  nevirapine-based regimens should be used only if
  benefit outweighs risk
• Women with CD4 lt250 cells/mm³ may receive
  nevirapine
• Women who enter pregnancy on a well-tolerated
  nevirapine-based regimen may continue nevirapine
• Pregnant women who take nevirapine should have
  frequent measures of transaminase levels,
  especially in the first 18 weeks of treatment

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Efavirenz Teratogenicity

• Now classified as FDA pregnancy category D
• Teratogenic in primates
• Retrospective case reports of CNS defects in
  infants of women who received efavirenz at
  conception and during the first trimester (neural
  tube defects in 3, Dandy-Walker malformation in
  1)
• Efavirenz should be avoided during the first
  trimester, and in women at risk of becoming
  pregnant
• Pregnancy should be avoided in women receiving
  efavirenz
• Certain hormonal contraceptives have higher
  failure rates because of drug interactions with
  efavirenz barrier contraception should be used

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• 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 [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 followup 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 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?

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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., 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?

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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?

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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 ACTG 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 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?

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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