Prevention of Perinatal Transmission of HIV

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Prevention of Perinatal Transmission of HIV

• Amanda Cotter MD MRCOG MRCPI MSPH
• Director of the Perinatal HIV Service
• Division of Maternal Fetal Medicine
• University of Miami

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Disclosure of Financial Relationships

• This speaker has no significant financial
  relationships with commercial entities to
  disclose.

This slide set has been peer-reviewed to ensure
that there are no conflicts of interest
represented in the presentation.
3
Learning Objectives

• Current pregnancy recommendations
• Preferred ART regimens
• Indications for cesarean delivery
• Complications of ART in pregnancy

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Pediatric AIDS Cases by Age Group and Year of
Diagnosis, Florida, 1990-2006
N1,304
5
United States
Pediatric (Ages lt13) AIDS Cases By
Race/Ethnicity Diagnosed through 2005 (N9,078)
2000 Population By Race/Ethnicity (Ages lt13)
(N52,190,294)
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Florida
2006 Florida Population Estimates (Ages
lt13) (N 2,941,177)
Pediatric HIV/AIDS Cases By Race/Ethnicity Report
ed through 2006 (N2,065)
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Perinatal HIV/AIDS Cases by Year of
Birth Florida, 1978-2006 (N1,958)
These data represent a 96 decline in
HIV-perinatally infected births from 1992 (N174)
to 2006 (N7). 116 perinatal AIDS cases were
diagnosed with AIDS after age 12. Note HIV
Infection Reporting Began 7/97. 2006 data are
provisional, data as of 02/01/07.
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HIV Rates per 100,000 Population (regardless of
AIDS status) among Women, Reported by County of
Residence, Florida, 2003
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HIV-Infected Newborns 2005-2007
HOLMES
ESCAMBIA
OKALOOSA
JACKSON
SANTA ROSA
WASHINGTON
GADSDEN
NASSAU
WALTON
HAMILTON
JEFFERSON
LEON
MADISON
CALHOUN
BAY
COLUMBIA
SUWANNEE
BAKER
DUVAL
LIBERTY
WAKULLA
TAYLOR
ST JOHNS
UNION
CLAY
GULF
LAFAYETTE
FRANKLIN
GILCHRIST
ALACHUA
PUTNAM
DIXIE
FLAGLER
LEVY
MARION
VOLUSIA
LAKE
CITRUS
SEMINOLE
SUMTER
BREVARD
HERNANDO
ORANGE
PASCO
OSCEOLA
HILLSBOROUGH
POLK
PINELLAS
INDIAN RIVER
MANATEE
OKEECHOBEE
HARDEE
ST LUCIE
HIGHLANDS
DESOTO
SARASOTA
MARTIN
2007 Births
GLADES
CHARLOTTE
HENDRY
LEE
PALM BEACH
COLLIER
BROWARD
MONROE
DADE
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Mother to Child HIV Transmission in the U.S.
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Preventing Perinatal Transmission

• Early identification
• Pregnancy management
• Maternal medical management
• Delivery/postpartum management
• Neonatal prophylaxis/treatment

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PACTG 076 Regimen Targeted Multiple Potential
Time Points of Transmission
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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 ()
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7.6
ZDV Group
Placebo
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How Does AZT Lower Perinatal HIV Transmission?

• Lowering viral load Median decrease in HIV RNA
  was only 0.28 log and change in RNA accounted for
  only 17 of observed AZT efficacy
• Two other important mechanisms through which AZT
  reduces transmission
• Pre-exposure prophylaxis of infant (through
  transplacental AZT passage)
• Post-exposure prophylaxis of infant (through
  continued AZT to the infant after birth)

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AZT Lowers Transmission Even with Very Low Viral
Load

• 44 cases transmission among 1,202 HIV women with
  delivery HIV RNA lt1,000
• Transmission differed by receipt of AZT
• Mothers receiving AZT 8/834 (1.0)
• Mothers not receiving AZT 36/368 (9.8)
• AZT independently reduced transmission

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• Follow-up of Uninfected Infants in ACTG 076 ZDV
  versus Placebo

• No significant difference in growth
• No difference in CD4/CD8 counts
• No other safety abnormalities identified
• No differences in developmental scores
• No cases of mitochondrial toxicity have been
  identified in USA

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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
• Death
• in women who received ZDV compared to those who
  received placebo

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Infant AZT Started Within 24 Hours Reduces
Transmission Even if No Maternal AP/IP AZT
APIPPP IPPP PPlt24 hr PPgt48 hr No AZT
Importance of Infant Pre- /or Post-Exposure
Prophylaxis
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Possible Routes of Transmission
In-utero
At Birth
During Breastfeeding
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• Timing of Perinatal Transmission

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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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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Risk Factors for Transmission in Era of
Antiretroviral Therapy Viral Load Type of
Antiretroviral Therapy Mode of Delivery
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• Perinatal HIV Transmission and Maternal HIV RNA
  Viral Load

• Correlation between maternal VL and risk of
  transmission even in pregnant women treated with
  ARV agents
• Risk of transmission with VL ND is extremely low
  but transmission has occurred at all VL levels
• ZDV decreases transmission regardless of VL level

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Delivery VL Perinatal Transmission
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More Potent Antiretroviral Regimens associated
with Lower Perinatal Transmission
Women Infants Transmission Study, 1990-1999
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• Care Guidelines for All Pregnant Women with HIV
  Infection

• Clinical evaluation HIV disease stage
• Evaluate 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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ART in Pregnancy

• Reduce perinatal transmission
• Improve maternal health

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ART in Pregnancy at UM/JMH
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Effects of ART in Pregnancy

• Pregnant woman
• Fetus
• Newborn

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Stek et al AIDS 2006
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When to treat?

• After 1st trimester
• When the patient is ready
• When the patient can tolerate
• To keep the viral load lt 1000

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• Guidelines for ART in Pregnancy

• Use optimal ARVs for the womans health consider
  the potential impact on the fetus/infant
• Offer 3-part ZDV regimen
• Discuss preventable risk factors for PNT
• Support decision-making by the woman following
  discussion of known/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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ART Concerns

• Multi drug resistance
• Mitochondrial toxicity
• Teratogenicity
• OI prophylaxis
• Adverse pregnancy outcome

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Safety Toxicity 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

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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
• 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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Mitochondrial Toxicity and Nucleoside Analogue
Drugs

• Nucleoside analogs known to induce mitochondrial
  dysfunction
• Lactic acidosis/hepatic steatosis reported
• Pregnant women with HIV infection on nucleoside
  analogues should have liver enzymes and
  electrolytes monitored in T3
• Avoid d4T ddI combination during pregnancy

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Recommendations for ARV Prophylaxis to Reduce
Perinatal HIV Transmission
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• Women Without Prior ART

• Recommend
• Combination ART including the 3-part ZDV regimen
  for women who require treatment with VLgt1000
  copies/mL regardless of clinical or immunologic
  status
• Consider combination ART for women with VLlt1000
  copies/mL
• Consider delaying therapy until after 10-12 weeks
  of gestation

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• Women Currently on ART

• Discuss benefits potential risks of her regimen
• Add or substitute ZDV after 1st trimester if
  possible
• Discontinue teratogenic drugs
• Consider stopping current therapy during 1st
  trimester
• Stop and restart all ART simultaneously
• Resistance testing for suboptimal viral
  suppression

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• In Labor Without ART

Intrapartum IV ZDV followed by 6 weeks ZDV for
newborn Oral ZDV/3TC for mother at onset
during labor followed by 1 week oral ZDV/3TC for
newborn Single dose NVP for mother at labor
onset followed by single dose NVP for newborn at
4872 hrs of age The 2-dose NVP regimen as
above combined with intrapartum IV ZDV 6 weeks
ZDV for newborn
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• 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 for her ARV treatment needs

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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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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-lives, 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
• For NNRTI-containing combination regimens,
  consider continuing NRTIs for 4-7 days after
  stopping NNRTI

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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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Adverse Pregnancy Outcome

• Combination therapy was associated with a 33
  risk of premature delivery
• 
  Lorenzi et al, AIDS 1998

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Adverse Pregnancy Outcome

• No increase in preterm delivery, low birth weight
  or stillbirth
• 5 on PI versus 2 had VLBW
• 
  
• Tuomala et al, NEJM 2002

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Objective

• Is antiretroviral therapy associated with
  adverse pregnancy outcome at a single site
  managed by MFM specialists according to strict
  protocols ?

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Methods

• Perinatal database
• 1990-2002

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Inclusion Criteria

• Singleton pregnancy
• At least one prenatal visit
• Delivered at JMH 1990-2002

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ARV Therapy

• Combination therapy PI
• Combination therapy PI
• Monotherapy

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Outcome Variables

• Preterm delivery
• 37 weeks
• 32 weeks
• Low birthweight
• lt2500 grams
• lt1500 grams
• Stillbirth

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Results

• Total n 1337
• Any Antiretroviral therapy n 999
• No Antiretroviral therapy n 338

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Results

• Monotherapy n 492
• Combination therapy without PI n 373
• Combination therapy with PI n 134

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Preterm Delivery
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Birth Weight
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Stillbirth
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Logistic Regression Model

• Race / Ethnicity
• Cigarettes
• Alcohol
• Substance abuse
• Gonorrhoea
• Chlamydia
• Trichomonas

• Herpes
• Hepatitis B
• Hx PTD
• Weeks on ARV
• Lowest CD4 count
• CDC stage
• ARV

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Conclusion

• Combination therapy with a PI is associated
  with an increased rate of preterm delivery
  (p0.0001)
• OR 2.4, 95 CI 1.3 - 4.4

Cotter et al, JID 2006
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Implications

• Risk of prematurity
• Risk of perinatal transmission
• Toxicity of protease inhibitors

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Implications

• Trial of combination therapy without a protease
  inhibitor

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Implications

• Counseling re risks

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What is the optimal ART regimen for the
prevention of perinatal transmission?
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Cotter et al, AJOG 2007
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Cotter et al, AJOG 2007
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Mode of Delivery?
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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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Clinical Situation 2

• HIV woman began prenatal care in 3rd trimester,
  responding to ART, but VL gt 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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Clinical Situation 3

• HIV woman on ART with undetectable VL at 36
  weeks gestation
• Inform woman that her risk of perinatal
  transmission is lt2 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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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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• 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 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

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Post C/S Morbidity

• Emergency cesarean 12 (4.17)
• Elective cesarean 6.4 (1.85)
• NSVD 4.0
• Postpartum fever
• DVT/PE
• Transfusion
• Postpartum procedures

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How can MTCT be further reduced?

• Early prenatal care
• Re-test women at 32 weeks, especially high risk
  women
• Rapid HIV testing of all pregnant women
  presenting to the hospital without documented HIV
  status

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Missed Opportunities for HIV Perinatal
Prevention in the USA

• Review of 5054 HIV-exposed deliveries at 6 sites
  in the USA from 19962000
• 423 HIV-infected infants
• Perinatal HIV transmission rate
• 2.5 for maternal combination therapy
• 5.4 for maternal AZT alone (both with
  intrapartum and neonatal AZT)
• 28 with no treatment

Peters VB et al. XIV IAC Barcelona, 2002
Abstract 1429.
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57 missed opportunities
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Prenatal HIV Testing Among Women Delivering a
Live Birth in Florida (1996-2002)
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Rapid Testing at Delivery toLate-Presenting Women

• High risk of perinatal transmission in women
  without antenatal care
• Rapid testing in labor can make it possible to
  initiate ARV prophylaxis
• ARV prophylaxis should be initiated as soon as
  possible after a positive rapid HIV test

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Rapid Testing The Last Frontier

• Undocumented HIV status in labor
• No prenatal care
• Prenatal care but no lab result
• Patients word ??
• Late presenters gt34 weeks

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Rapid Testing Advantages

• Cost lt10
• Results in 20-30 minutes
• Positive probably infected
• Oraquick high sensitivity specificity
• Confirmation 24 hours - weeks

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Rapid HIV Testing at Labor Delivery the MIRIAD
Study

• 24 hr counseling rapid testing
• 16 hospitals in 6 US cities
• Nov 2001 - Nov 2003
• 84 consented
• 34 HIV (7/1000)

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The MIRIAD Study

• OraQuick
• Sensitivity/Specificity 100 / 99.9
• PPV 90
• Median turn around time 70 mins
• 70 mothers received intrapartum ZDV within 30-45
  minutes
• 34 infants received ZDVNVP
• 3/32 infants seroconverted

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Rapid Testing MIRIAD

• Median time from blood draw to patient
  notification of results 66 minutes (45-120)
• Median to EIA results 28hrs
• Less than 2 hrs on LD results often postpartum
• All infants received ZDV _at_ median of 3.8 hrs

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Rapid Testing MIRIAD

• 34 HIV infected women
• 2 lost to follow up

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Rapid Testing MIRIAD

• 10 received intrapartum AZT
• 8 received AZT NVP
• 9 received no intrapartum ARV
• All infants received AZT
• 17 infants also received NVP

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Rapid Testing MIRIAD

• Infection Status of Infants
• 3 infected
• 2 PCR positive day 1
• 1 PCR positive week 6

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Early intervention is the key to prevention
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