HIV Infection In Pregnancy

1
HIV Infection In Pregnancy

• Andrew W. Helfgott, MD, MHA
• Medical College of Georgia
• 14th Annual HIV Conference
• Florida AETC
• April8-9, 2005

2
Legislation

• Since October 1996, Florida law has required
  health care workers who attend pregnant women to
  counsel them about the benefits of HIV testing.
  
• HIV testing must be offered at the initial
  prenatal care visit and again at 28-32 weeks.
  
• Women who appear at delivery with no record of an
  HIV test during pregnancy shall be counseled and
  offered HIV testing.
• If a woman declines HIV testing, a signed
  objection must be attempted.
•   Florida Statute - s.384.31 (this is a direct
  link)
•   Florida Administrative Code - Ch.64D-3.019
  (note the reference numbers before you click)

3
HIV IN FLORIDA

• Facts
• About 100,000 Floridians are infected with HIV,
  the virus that causes AIDS.
• Florida is ranked third in the country for total
  HIV/AIDS cases. It is ranked second for total
  pediatric cases.
• Of the pediatric cases, 94 were infected by
  perinatal transmission

4
Pediatric AIDS CasesReported by State
5
Pediatric AIDS CasesDiagnosed by County
6
Cumulative Pediatric (lt13 yr.) HIV/AIDS Cases By
Exposure Category, Reported through 2002
United States (N9,074)
Florida (N1,820)
Other Pediatric Risk includes sex with male or
receipt of blood products.
7
Perinatal HIV/AIDS Cases by Year of
Birth Florida, 1978-2002 (N1,755)
2002 data not complete due to reporting
lag. 75 perinatal AIDS and 6 perinatal HIV
cases were diagnosed after age 12. Note HIV
Infection Reporting Began 7/97.
8
Mothers Exposure Category by Year of Childs
Birth for Perinatally Acquired HIV/AIDSFlorida,
Born through 2002 (N1,755)
2002 data not complete due to reporting lag.
75 perinatal AIDS and 6 perinatal HIV cases were
diagnosed after age 12. Note HIV Infection
Reporting Began 7/97.
9
Time of Maternal HIV TestingAmong Perinatal AIDS
and HIV CasesBorn 1995-2002, Florida (N300)
10
Possible Missed Opportunities to Prevent
Perinatal Transmission of HIVof Births
1997-2002, Florida (N195)
11
AIDS Rates per 100,000 Population among Women
Reported by County of Residence, Florida, 2003
N1,456
Based on 2003 mid-year population, the rate for
women is 20.3 per 100,000 population. County
totals exclude Department of Corrections cases
(N23).
12
Cumulative Reported Pediatric AIDS CasesBy
County, Florida, Reported through 2002
N1,543
13
HIV/AIDS Cases Among Women of Childbearing Age
(Ages 15-44) By Race/Ethnicity and Year of
Report Florida, 1995-2002
HIV Infection Reporting Began 7/97.
14
Reported Adult AIDS Casesby Sex and Race
Ethnicity, Florida, 2003
Males N (3,374)
Females N (1,456)
Other includes Asian/Pacific Islander, or
American Indian/Alaska Native, Multiracial or
Other race.
15
Prenatal HIV Testing Among Women Delivering a
Live Birth, Florida, 1996-2001
95 C.I.
Comment Floridas percentage of childbearing
women tested prenatally for HIV is the highest
in the U.S., which has probably contributed to
the continued decline in pediatric AIDS cases.
Source Pregnancy Risk Assessment Monitoring
System (PRAMS).
16
Percent of Mothers of Perinatal HIV/AIDS Cases
Who Were Known to be HIV Positive Prior to
Birth By Year of Birth 1995-2002, Florida (184 of
300)
2002 data not complete due to reporting
lag. Note HIV Infection Reporting Began 7/97.
17
Percent of Perinatal HIV/AIDS Cases Born
1995-2002 Whose Mothers Knew They Were Infected
Prior to Birth And Received ZDV and/or Other
Antiretroviral Therapies By Year of Birth,
Florida (N184)
2002 data not complete due to reporting
lag. The same mother can be in multiple
categories
18
Reasons for no/inadequate prenatal care among
women enrolled in TOPWA, 1999-2002 Florida (N
9,948)
19
For Florida HIV/AIDS Surveillance Data Contact
[phone] Lorene Maddox, MPH Ext.
2613 Linda Friedlander, MS Ext. 2614
Tracina Bush Ext. 2612 Internet
http//www.doh.state.fl.us/disease_ctrl/aids/index
.html Intranet http//dohiws.doh.state.fl.us
For further information on Florida's perinatal
HIV prevention program please visit our website
at http// www9.myflorida.com/disease_ctrl/aids/P
erinatal/Perinatal.htm
20
Means of Perinatal Transmission of HIV

• Antepartum 5-15
• HIV in POCs From SABs
• Neonates w/ High Viral Loads
• Intrapartum 50-80
• Exposure to Cervico Vaginal Secretions During
  L D
• Postpartum 15-20
• Via Breastfeeding

21
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

22
Maternal Viral Load and Risk of Transmission WITS
Garcia, et al, NEJM 1999)
23
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

24
Risk Factors for Perinatal Transmission of HIV

• Maternal Immune Status
• HIV Viral Load
• Mode of Delivery
• Exposure to Blood/Secretions
• Duration of ROM
• Prematurity/LBW
• Presenting twin
• Breastfeeding

25
Prevention of Perinatal Transmission of HIV

• HIV Testing and Treatment in Prenatal Period
• Perinatal Transmission Rates For Women on CART
  as Low as 2
• 076 Protocol in Antepartum, Intrapartum and
  Neonatal Periods
• Cesarean Section for Viral Load gt 1000 copies/ml

26
Reducing HIV Transmission withSub optimal
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

(Wade, et al, NEJM 1998, )
27
Prevention of Perinatal Transmission of HIV

• HIV Testing and Treatment in Prenatal Period
• Perinatal Transmission Rates For Women on CART
  as Low as 2
• 076 Protocol in Antepartum, Intrapartum and
  Neonatal Periods
• Cesarean Section for Viral Load gt 1000 copies/ml

28
Elective Cesarean Section to Reduce Perinatal
Transmission

• Elective C/S Prior to labor _at_ 38 weeks ( in
  Conjunction w/ ACTG 076 Protocol 1-2
  Transmission
• C/S During Labor with Viral Load gt1000 copies in
  Conjunction w/ ACTG 076 protocol 4-7
  transmission

29
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

(Eur. Mode of Del. Collaboration,1999, Watts, et
al 2000).
30
Perinatal Transmission Rates Vary By Treatment
Approach

• 26 No ART
• 7.8 ACTG 076 Protocol
• Antepartum, Intrapartum, Neonatal ZDV
• 1.1 CART
• 2 CART and Cesarean Section

31
Treatment of HIV in Pregnancy

• Therapies of Known Benefit to Women Should NOT
  Be Withheld During Pregnancy UNLESS
• Adverse Effects Mother, Fetus, or Infant
• Adverse Effects Outweigh Benefit to the Woman
• Minkoff H, Augenbraun M. Antiretroviral therapy
  for pregnant women Am J Obstet Gynecol, 1997

32
TREATMENT IN PREGNANCY
33
Treatment of HIV in Pregnancy

• Pregnancy Should NOT Preclude the Use of Optimal
  Therapeutic Regimens.
• Recommendations Regarding the Choice of HAART for
  HIV() Pregnant Women Subject to Unique
  Considerations.
• Possible Changes Dosing Requirements
• Potential Effects HAART on Mother

34
Treatment of HIV in Pregnancy

• Considerations (contd)
• Potential Short/Long Term Effects HAART on
  Fetus/Neonate May be Unknown
• Potential for Teratogenicity
• Mutagenicity
• Carcinogenicity,
• Pharmacokinetics, Toxicity of Transplacentally
  Transferred Drugs.

35
Treatment of HIV in Pregnancy

• Clinical Data on HAART in Prenancy More Limited
  that in Non-Pregnant Women
• Sufficient Data on Some of the Available HAART
  Combinations to Allow Recommendations Related to
  Drug Choice.

36
Treatment of HIV in Pregnancy

• Data are Conflicting Regarding HAART in Pregnancy
  and association with Adverse Perinatal Morbidity
• Pre-Term Labor/Delivery
• IUGR

37
Treatment of HIV in Pregnancy

• RECOMMENDATIONS FOR MONITORING WOMEN
• Same Recommendations for Monitoring HIV-1()
  Gravidas as Non-Pregnant Include
• CD4 counts Q Trimester
• HIV-1 RNA levels Q Trimester
• Determine Need for
• HAART
• Alterartion inRX
• OI Prophylaxis
• (Public Health Service Task Force Recommendations
  - February 24, 2005 http//www.aidsinfo.nih.gov)

38
Treatment of HIV in Pregnancy

• Protease Inhibitors Use Associated W/
• New Onset Diabetes Mellitus
• Exacerbation Existing DM
• Diabetic Keto-Acidosis
• Pregnancy
• No Data
• Make Patients Aware of Risk. Monitor Glucose
  Levels
• (Dube MP, Sattler FR.. AIDS Clinical Care, 1998.
  10(6)41-4.)

39
Treatment of HIV in Pregnancy

• Mitochondrial Toxicity
• Induced by Nucleoside Analogs
• Include Myopathy, Neuropathy, Lactic Acidosis,
  Hepatic Steatosis
• Preponderence in Females
• Hepatic Steatosis
• Lactic Acidosis
• ?? Role in Development HELLP, Acute Fatty Liver
  Pregnancy
• (Boxwell et al ICAAC 1999)

40
Treatment of HIV in Pregnancy

• SCENARIO 1
• HIV-1() Gravida W/ No Prior HAART
• Standard Clinical, Immunologic, Virologic
  Evaluation.
• Consider 076 Protocol
• HAART for HIV RNA gt 1000 Copies
• May Consider Delaying RX Until 2nd Trimester
• (Public Health Service Task Force Recommendations
  - February 24, 2005 http//www.aidsinfo.nih.gov)

41
Treatment of HIV in Pregnancy

• SCENARIO 2 HIV-1() Gravida Already on HAART
• Continue HAART
• If HAART Stopped Reintroduce All Drugs
  Simultaneously
• Add ZDV if Not In Regimen
• Regardless of AP Regimen Add ZDV at Delivery and
  for Neonate
• (Public Health Service Task Force Recommendations
  - February 24, 2005 http//www.aidsinfo.nih.gov)

42
Treatment of HIV in Pregnancy

• SCENARIO 3 HIV() Gravida in Labor- NO PRIOR
  HAART
• Intraprtum ZDV Followed by 6 Weeks Neonatal ZDV
• ZDV and 3TC During Labor, Followed by one week
  ZDV-3TC for the Neonate
• Single Dose Nevirapine in Labor then Single Dose
  Neonatal Nevirapine at age 48 hours
• Two-dose Nevirapine Regimen in Combination W/ IV
  ZDV and 6 Weeks Neonatal ZDV
• Postpartum Maternal CD4, HIV RNA Viral Load
• (Public Health Service Task Force Recommendations
  - February 24, 2005 http//www.aidsinfo.nih.gov)

43
Treatment of HIV in Pregnancy

• SCENARIO 4 Infant Born to Untreated Mother
• Neonatal ZDV for 6 Weeks
• Start ZDV W/in 6-12 Hours of Birth
• Consider ZDV Plus Another Drug Unknown Clinical
  Efficacy
• Postpartum Maternal CD4, HIV RNA Viral Load
• (Public Health Service Task Force Recommendations
  - February 24, 2005 http//www.aidsinfo.nih.gov)

44
Treatment of HIV in Pregnancy

• Nevaripine in Pregnancy (CD4 gt 250cell/mm3)
• Increased Risk Rash/Hepatotocxicity, Severe, Life
  Threatening
• Use only if Benefit Clearly Outweighs Risk
• Monitor Clinically, LFTS q 2 Weeks 1st Month
  Every Month X 4 Then q 1-3 Months
• (Public Health Service Task Force Recommendations
  - February 24, 2005 http//www.aidsinfo.nih.gov)

45
Treatment of HIV in Pregnancy

• Nevaripine (NVP) in Pregnancy (contd)
• Rash Seen Check LFTs D/C NVP if Increased
• Hepatotoxicity Seen w/ Single Dose Use In Labor
• Women on NVP Regimen Can Be Continued If
  Responding and Tolerating
• (Public Health Service Task Force Recommendations
  - February 24, 2005 http//www.aidsinfo.nih.gov)

46
Treatment of HIV in Pregnancy

• Efavirenz in Pregnancy
• Avoid in 1st Trimester
• CNS Anomalies in Monkeys
• FDA Pregnancy Category Class D
• Women of Child Bearing Age Alternative ARV
  Regimens
• (Public Health Service Task Force Recommendations
  - February 24, 2005 http//www.aidsinfo.nih.gov)

47
Treatment of HIV in Pregnancy

• Indinavir in Pregnancy
• Unboosted Indinivir in Pregnancy Nor Recommended
• Optimal Dose for Combination of
  Indinavir/Ritonavir in Pregnancy Unknown Consider
  use if Unable to Use other Combinations.
• (Public Health Service Task Force Recommendations
  - February 24, 2005 http//www.aidsinfo.nih.gov)

48
Treatment of HIV in Pregnancy

• Antiretroviral Pregnancy Registry
• Abacavir
• No Increase in Birth Defects
• Prevalence of Birth Defects 3.5
• Overall Prevalence Birth Defects 3.1
• Lamivudine
• Prevalence Birth Defects 2.8
• (Public Health Service Task Force Recommendations
  - February 24, 2005 http//www.aidsinfo.nih.gov)

49
Treatment of HIV in Pregnancy

• Antiretroviral Pregnancy Registry
• Prevalence Birth Defects
• Stavudine 2.6
• Zidovudine 3.0
• Nevaripine 2.1
• Nelfinavir 4.0
• (http//www.apregistry.com/)

50
Introduction

• Standard of Care is Antiretrovirals for
  Prevention of Perinatal Transmission of HIV
• Widespread use Associated with Increased
  Antiretroviral Drug Resistance
• Resistance May Reduce Effectiveness of Perinatal
  Prophylaxis.

51
Introduction

• Increasing Incidence of Resistance in HIV
  Infected Individuals
• Potential for a Negative Impact on Treatment
  Course
• Monotherapy for Prevention of Perinatal
  Transmission of HIV MAY Increase Incidence of
  Resistant Virus

52
Introduction

• Impact of Resistance on Perinatal Transmission
  NOT Well Understood
• Perinatal and Sexual Transmission of Resistant
  Virus Well Documented.
• Does Perinatal Prophylaxis Induce Resistance?????
• Is Resistance Associated with Perinatal
  Prophylaxis Failure????

53
ZDV Resistance

• Factors Associated w/ ZDV Resistance at
  Delivery
• ZDV Use Prior to Pregnancy
• Higher Log HIV RNA
• Lower CD4 Percentage.
• Disease Stage

54
ZDV Resistance and Perinatal Transmission of HIV

• Detection of ZDV Resistance Mutations NOT
  Associated with Increased Risk Perinatal
  Transmission
• PACTG 076
• PACTG 185
• Swiss HIV Cohort
• Perinatal AIDS Collaborative

55
ZDV Resistance and Perinatal Transmission

• Women Infant Transmission (WITS)
• ZDV Resistance NOT Assoc w/ Transmission
• Adjust for ROM, Total Lymphocyte count
• Resistance Mutations Conferred Increased Risk
  Transmission FIVE FOLD.
• Bauer et al Eighth Retroviral Conf 2-2001

56
ZDV Resistance

• Point prevalence of any ZDV mutations 11-25
• Prevalence of HIGH Level ZDV Resistance 6-12
• Most Studies Rates of Resistance Determined in
  Patient Subsets
• Rate of resistance in Population Probably MUCH
  Lower

57
ZDV Resistance

• Data Supports Low Prevalence /Incidence ZDV
  mutations ZDV Naïve Parturients
• ZDV Experienced Gravidas, Level of Resistance
  Influenced by Duration of RX
• Inconclusive Data that ZDV Resistance Increases
  Likelihood Perinatal Transmission

58
3TC Resistance

• Factors Associated with 3TC Resistance Mutation (
  M184V) After Delivery
• Lower CD4 Count
• Higher HIV RNA Levels
• Longer Duration Therapy

59
3TC Resistance

• Rapid Development Of 3TC Resistance In Pregnancy
• Prevalence of 3TC Resistance High, 45 Perinatal
  Transmission Rate 1.5
• Short Course 3tc/ZDV Regimens Result in Perinatal
  Transmission Rates 2
• Mono and Dual Generally NOT Indicated. Triple
  Therapy is Recommended.

60
3TC Resistance

• Insufficient data to Determine if 3TC Mutations
  Assoc w/ Increased Risk of perinatal transmission
• Implications Of Resistance on Future Treatment
  Unclear.

61
Nevirapine Resistance

• Rapid Emergence High Level Resistance to NVP
• Associated with
• High Viral Load
• Prolonged Drug exposure
• Decreased Oral Clearance.

62
Nevirapine Resistance

• Questions Remain
• 1) Transmission of NVP Resistant HIV
• 2) Long Term Clinical Implications

63
Other Resistance Implications

• Infants Infected despite Prophylaxis
• Documented Perinatal Transmission of Resistant
  Disease.
• Data Supports Low Prevalence Resistance in HIV
  Infected Infants
• Data Suggests Transmission of Resistant Virus/
  Induction of Resistance is Rare

64
Other Resistance Implications

• Possible Role of Resistance in Perinatal
  Transmission
• Possible Impact of Resistance on Perinatal
  Prophylaxis
• Possible Impact on Future Therapy
• ALL UNCLEAR.

65
Recommendations

• International AIDS Society USA Panel
• All Pregnant Women w/ Detectable Virus Have
  Resistance Testing Even if Anti-Retroviral Naïve
• JAMA 2000

66
EuroGuidelines Recommendations

• 1) Mothers with detectable viraemia on existing
  antiretroviral therapy and presenting early for
  antenatal care should be screened for resistant
  viruses
• 2) Therapy naïve mothers presenting early for
  antenatal care should be screened for resistant
  viruses
• 3) Mothers presenting late for care and delivery
  should have a rapid screen for resistant virus
  to guide prophylaxis in late pregnancy and in the
  newborn baby.
• AIDS 2001 15309-320

67
Recommendations

• PHS Recommendations
• Recommendations for Resistance testing in
  HIV-Infected Pregnant Women are the Same for
  Non-Pregnant Patients
• Acute HIV infection
• Virologic Failure or Sub-Optimal Viral
  Suppression After Initiation of Antiretroviral RX
  
• High Likelihood Exposure to Resistant Virus
  (Community Prevalence/ Source Characteristics).
• www.hivatis.org

68
Other Pregnancy Considerations

• Woman w/ Repeat Pregnancy Having Taken ART in
  Previous Pregnancy ONLY
• Women w/ Repeat Pregnancies Non Compliant
• Pt to be Tested
• Adherent
• Actually on MEDS

69
Clinical Scenario

• AZT Experienced Gravida
• Presents in 2nd Trimester Off ART for
  Months/Years(Since Birth of Previous Child)
• Obtain RT?
• Start ART and if no Response RT?

70
Other Thoughts

• Consider Resistance Testing When Pt enters
  Prenatal Care.
• Crucial to Lower Viral Load Reduce Probability of
  Transmission.
• Not on Proper Regimen due to Resistance Crucial
  Time.
• By the Time Resistance Found Maybe Too Late to
  Prevent Transmission.

71
Other Thoughts

• Worried about Costs
• Small Number Pregnant Women to Be Tested.
• How Many Cases Pediatric AIDS to Justify
  Resistance Testing.
• Perinatal Prophylaxis Actually Prevents Disease.

72
Antiretroviral Resistance Testing in Pregnancy

• Until Further Data is Accumulated, Consider
  Offering Antiretroviral Resistance Testing to
  all HIV-1 Infected Gravidas who
• Are Adherent to Therapeutic Regimens
• Have Viral Load gt 1000 copies

73
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