Perinatal Transmission of HIV EvidenceBased Medicine Review

1
Perinatal Transmission of HIVEvidence-Based
Medicine Review

• By
• Fernando Garcia, MD
• Valley AIDS council
• AIDS Education Training Center

2
Objectives

• Review epidemiology of HIV in Pregnancy and
  Pediatric population
• Review guidelines of perinatal HIV transmission
  interventions
• Review modalities of treatment of HIV during
  pregnancy
• Review clinical scenarios/cases

3

• Perinatal HIV Transmission

• Without antiretroviral (ARV) drugs during
  pregnancy, mother-to-child transmission (MTCT)
  has ranged from 1625 in North America and
  Europe
• Today, risk of perinatal transmission can be with
• highly active antiretroviral therapy (HAART)
• elective cesarean section (C/S) as appropriate
• formula feeding

4
Estimated Children with HIV/AIDS Through 2005
Western Europe 5-7,000
Eastern Europe Central Asia 9-15,000
North America 9-14,000
East Asia Pacific 6,000 12,000
North Africa Middle East 31-49,000
Caribbean 19-33,000
South South-East Asia 110-190,000
sub-Saharan Africa 2.0-2.4 million
Latin America 37-55,000
Australia New Zealand
Total 2.4-3.1 million
5
Perinatally Acquired AIDS Cases, 1985-2005,
United States
6
Mortality in HIV-Infected Children
HIV Pediatric Prognostic Markers Collaborative
Study Group
7
Pediatric HIV Classification Clinical
Categories

• Category E Perinatally Exposed
• Category N Not Symptomatic
• Category A Mildly Symptomatic
• Category B Moderately Symptomatic
• Category C Severely Symptomatic

8
Prevention of Mother-to-Child Transmission
9
Case Study

• 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
• What are the recommendations for this mother and
  infant?
• What options for treatment we have?
• What follow-up care is needed for Angela and her
  baby?

10

• 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

11

• 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

12
Timing of Mother-to-Child Transmission

• Zimbabwe study
• Infant cohort
• ART not available
• Overall transmission rate 30.7

Infant mortality (6 months) 42 intrauterine
29 intrapartum
Zijenah LS, et al. 2nd IAS, Paris 2003, 58
13
Case Study

• Joan, G8P3, HIV for 3 years, admitted with
  ruptured membranes (4hrs). No prenatal care. Lost
  2 children to HIV. Urine for cocaine, GB strep
  (urine, cervix), other STDs negative. Unknown CD4
  and Viral load.
• What are the recommendations for this mother and
  infant?
• What alternative therapies can she choose to
  decrease perinatal transmission?
• What factors increase perinatal transmission?

14

• Factors Influencing Perinatal Transmission

• Maternal Factors
• HIV-1 RNA levels (viral load VL)
• 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

15
Factors affecting transmission

• Maternal factors
• HIV-1 RNA level (viral load) at delivery

100K
Highest rate of transmission observed in women
with VL100K and no ZDV therapy (63.3)
50K-100K
HIV-1 RNA copies/mL
10K-50K
1K-10K

0
10
20
30
40
50
Transmission rate ()
Garcia, NEJM, 1999
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Factors affecting transmission

• Neonatal factors
• Prematurity
• Birth weight
• Antiretroviral therapy
• Breastfeeding

17

• Do we need Viral load and CD4 count to provide
  treatment to the mother and infant?

18

• Maternal Viral Load (VL), ZDV Treatment and the
  Risk of Perinatal HIV Transmission

• Correlation between high maternal VL and
  transmission
• Transmission observed at every VL level,
  including undetectable levels
• No HIV RNA threshold below which there was no
  risk of transmission
• ZDV decreases transmission regardless of HIV RNA
  level
• Recommendation Initiate maternal ZDV regardless
  of plasma HIV RNA or CD4 counts

19
Results of ACTG 076(no Viral load where done)
30
This represents a 66 reduction in risk for
transmission (P in all subgroups
20
22.6
Transmission Rate ()
10
7.6
ZDV Group
Placebo
20
Reducing Intrapartum HIV TransmissionStudies of
Short Course ARV Therapy
21
Reducing HIV Transmission with Suboptimal
Regimens The New York Cohort
22
Case Study

• Twelve hours after birth, a baby HIV Elisa test
  comes back positive, mother refused HIV test in L
  D. She tested negative early in her pregnancy
  but the doctor wanted to repeat the test because
  she reported that her husband was back to using
  IV drugs.
• What are the recommendations for this mother and
  infant? Are they HIV positive?
• How will you present the 076 regimen to this
  woman and what are the options?
• What follow-up care is needed for the mother and
  her baby?

23
Management of HIV-Exposed Infants ALERT!!!!!!!

• Early testing
• NO breastfeeding
• AZT( other ART) 0-6 weeks
• TMP/SMX 6wks-4 months(?)
• Immunizations

24
Diagnosis of HIV Infection in Infants

• What test should we use?
• Anti-HIV IgG antibodies (ELISA)
• Viral culture
• P24 antigen testing
• HIV-DNA PCR
• 96 sensitivity, 99 specificity by 28 days of
  age)
• HIV-RNA PCR
• Slightly less sensitive, V.L.
• When should testing be done?
• 14 days optimal
• 1-2 months
• 4-6 months

25
Diagnostic Issues

• HIV Elisa and Western Blot positive in children
  18 m/o
• HIV is diagnosed by 2 positive HIV virologic
  tests performed on blood samples 2 separate
  dates.
• HIV is reasonably excluded with 2 or more
  negative virologic tests at age 1 month, one of
  which is performed at age 4 months.

26
Viral Load and Children

• Levels at birth rise from 100,000 to several
  million copies within the first 1-2 months of
  life
• Very slow decline over several years to reach
  set point
• Infants (100,000) may be at high risk for disease
  progression and death
• Predictive value of VL not good in young infants
• Much overlap with rapid and non-rapid progressors
• Evaluate CD4 counts and percentages as well

27
Case Study

• Rose, 41 y.o., first prenatal visit,
  approximately 19 weeks gestation, tested HIV 2
  months ago. CD4 725, HIV viral load sent to lab.
  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?

28
Preconception Care (continued)

• 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 OIs, 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

29
Comparison of ART Prophylaxis Trials
Red 67 51 24 30 50 37 --- 47
Pregnancy (weeks)
Labor
Perinatal (weeks)
0
1
36
6
14
ACTG 076
Notbreast fed
Bangkok
Retro-CI
DITRAME
PETRA-A
Breast fed
PETRA-B
PETRA-C
HIVNET 012
AZT AZT3TC NVP
Gray G. XIII IAC, Durban 2000. Session Lb5
30
Results of ACTG 076
30
This represents a 66 reduction in risk for
transmission (P in all subgroups
20
22.6
Transmission Rate ()
10
7.6
ZDV Group
Placebo
31
Reducing Intrapartum HIV TransmissionStudies of
Short Course ARV Therapy
32
Current Antiretroviral Medications

• PI
• Amprenavir APV
• Atazanavir ATV
• Fosamprenavir FPV
• Indinavir IDV
• Lopinavir LPV
• Nelfinavir NFV
• Ritonavir RTV
• Saquinavir SQV
• soft gel SGC
• hard gel HGC
• tablet INV
• Tipranavir TPV
• Fusion Inhibitor
• Enfuvirtide T-20

• NRTI
• Abacavir ABC
• Didanosine DDI
• Emtricitabine FTC
• Lamivudine 3TC
• Stavudine D4T
• Zidovudine ZDV
• Zalcitabine DDC
• Tenofovir TDF
• NNRTI
• Delavirdine DLV
• Efavirenz EFV
• Nevirapine NVP

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ARV Mechanisms Which Interrupt HIV Viral
Replication
34
Current Perinatal Prevention Recommendations(Mate
rnal Regimens)

• Oral ZDV 300mg BID
• (or 200mg TID)
• may defer ART in 1st trimester
• ZDV other ART for HIV-1 RNA 1000

PRENATAL

• Intravenous ZDV
• 2mg/kg bolus, then 1 mg/kg/hr
• NVP 200mg PO at onset of labor
• 3TC 150mg PO Q12 until delivery

INTRA- PARTUM
35
Current Perinatal Prevention Recommendations(Infa
nt Regimens)

• Oral ZDV 2mg/kg Q 6hrs
• x 6 weeks
• ZDV 4mg/kg Q12hrs
• 3TC 2mg/kg Q12hrs x 7 days
• NVP 2mg/kg x 1 dose _at_ 48-72hrs
• ZDV NVP

NEONATAL
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• Cesarean Section to Reduce Perinatal HIV
  Transmission

• Pregnant women with VL 1000 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

37
Neonatal Effects of Maternal HIV Infection
38
HIV and Pregnancy Outcome
Prematurity - 2-fold increased risk of preterm
birth with CD4 association has been made with maternal
plasma HIV-RNA levels Low birth weight - Nearly
4-fold risk of a low birth weight neonate with
CD4 39
Prematurity and Antiretroviral Therapy

• An observational study in the US (PACTG 367)
  found NO association between combination therapy
  and preterm birth
• Elevated rates of
• preterm birth are
• seen among
• untreated women

The European Collaborative Study and the Swiss
Mother Child HIV Cohort Study (2000) found
2.6-fold increased odds of prematurity with or
without a PI
40
Long-term Consequences of HIV Infection in
Children
41
HIV and Childhood Development

• McMillan, Neurology, 2001
• Slow neurodevelopment and decreased head
  circumference persist through 24 months of age in
  HIV-infected infants
• Blanchett, Developmental Neuropsychology, 2002
• Normal cognitive development but subtle motor
  impairments in vertically infected children
• Children with HIV may have structural
  abnormalities in the brain that affect
  visual-motor and visual-spatial processing
• Bruck, Arquivos de Neuro-Psiquiatria, 2001
• HIV infected children score lower on
  developmental testing than HIV-exposed
  (non-infected) children

42
Cardiac Effects of HIV Exposure

• Long-term study of more than 500 children
• Hearts of infants born to HIV mothers were
  larger and had less contractility compared to
  infants born to healthy women
• Findings in infants regardless of infants
  infection status
• Effects diminished in non-infected children, but
  persisted in infected children
• Unclear what the long-term significance is, if
  any
• Initially thought to be related to maternal AZT
  use, but there were no differences between
  infants born to mothers using AZT versus those
  not on AZT

43
Cardiomegaly
44
HIV Morphologic and Metabolic Abnormalities

• Morphologic Features
• Lipoatrophy
• Central fat accumulation
• Fat deposition (buffalo hump, lipomas)
• Ectodermal dysplasia

• Metabolic Features
• Elevated blood lipids
• cholesterol
• triglycerides
• Insulin resistance, elevated blood glucose and
  diabetes mellitus, elevated C-peptide
• Osteopenia (?)
• Avascular necrosis (?)

Carr A. (State of the Art Lecture) 8th CROI,
Chicago, 2001. Issues in Metabolic Complications
45
Special Considerations
46
Case Study

• 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?

47
HIV-1 in Cervicovaginal Lavage
Cu-Uvin et al. IDSA Meeting 1998
48
HIV Resistance in Treatment Naïve Pregnant Women

• Retrospective review of HIV pregnant women in St
  Louis, MO, 20002001 n72
• Mean age 25 years
• ARV therapy naïve
• 75 African-American
• Mean CD4 448 cells/mm3
• Mean VL 3310 c/mL

Juethner SN, et al. XIV Int AIDS Conference,
Barcelona 2002, 5950
49
Teratogenicity of HAART
50
Teratogenicity of HAART
51
Mitochondrial Toxicity and Nucleoside Analogue
Drugs

• Nucleoside analogs known to induce mitochondrial
  dysfunction
• 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 and ddI combination should be avoided during
  pregnancy

52

• Heather wants to breastfeed the baby

53
Breastfeeding and HIV Transmission

• Rate 1017
• Risk per liter of milk
• Similar to heterosexual transmission per
  unprotected sexual act
• Factors related to transmission
• Breast milk viral load
• Maternal plasma viral load
• Low maternal CD4
• Breast lesions

• Breast milk viral load
• Colostrum
• ? Plasma viral load
• ? CD4
• ? Subclinical mastitis
• ? Genital tract virus

54
Breastfeeding and HIV Transmission
HIVNET 012 Study

• 42 risk reduction for HIV transmission with
  NVP compared to ZDV alone
• Risk of transmission from breastfeeding
  remained the same in both groups, but the overall
  transmission at 18 months was lower in the NVP
  group

55
Conclusions

• Minimize the risks of vertical transmission
• Early recognition of HIV infection in pregnancy
• Prevention of opportunistic infections
• Provide 3 drugs antiretroviral therapy
• Consider adding AZT to regimen
• No breastfeeding

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Perinatal Guidelines
http//AIDSinfo.nih.gov
57
Thank you!