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Prevention of Mother-to-Child HIV Transmission in the U.S. and Globally. Lynne M. Mofenson, M.D. Pediatric, Adolescent and Maternal AIDS Branch National Institute of Child Health and Human Development National Institutes of Health Department of Health and Human Services. Overview.

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prevention of mother to child hiv transmission in the u s and globally

Prevention of Mother-to-Child HIV Transmission in the U.S. and Globally

Lynne M. Mofenson, M.D.

Pediatric, Adolescent and Maternal AIDS Branch

National Institute of Child Health and Human Development

National Institutes of Health

Department of Health and Human Services

overview
Overview
  • Perinatal transmission in the U.S.:
    • PACTG 076 - mechanism efficacy
    • Risk factors for transmission in antiretroviral era
    • Transmission in the post-076 era
    • Challenges
  • Perinatal transmission global basis
    • Short-course antiretroviral prophylaxis trials results and relevance to U.S.
    • Challenges
perinatal hiv transmission u s
Perinatal HIV Transmission: U.S.
  • In U.S., ~6,000-7,000 HIV-infected women give birth annually.
  • Prior to 1994, ~25% of infants born to HIV+ mothers became infected.
  • Thus, 1,500-1,750 infants newly infected with HIV were born each year before 1994.
  • More than 16,000 HIV-infected children born in the U.S. since the beginning of the epidemic.
how did the pactg 076 azt regimen lower perinatal hiv transmission
How Did the PACTG 076 AZT Regimen Lower Perinatal HIV Transmission?
  • Effect on viral load: In PACTG 076, change in HIV RNA accounted for only 17% of observed AZT efficacy (Sperling et al. NEJM 1996;335:1621-9).
  • 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 administration to the infant after birth).
slide7
How Does AZT Lower Perinatal Transmission? Effect of AZT on Viral Load in PACTG 076Sperling RS et al. NEJM 1996;335:1621-9
slide8
AZT Lowers Transmission Even in HIV-Infected Women with Very Low Viral LoadIoannidis JPA et al. J Infect Dis 2001;183
  • Meta-analysis of 7 prospective cohorts/trials.
  • 44 cases transmission among 1,202 HIV+ women with delivery HIV RNA <1,000.
  • Transmission differed by receipt of AZT:
    • Mothers receiving AZT: 8/834, 1.0%
    • Mothers not receiving AZT: 36/368, 9.8%
  • Multivariate analysis (adjusting for maternal CD4 count, mode delivery and infant birth weight), AZT independently reduced transmission.
  • Data show importance of infant pre- and post-exposure prophylaxis in addition to lowering maternal viral load as mechanism prevention.
slide9
Importance of the Infant Pre- and Post-Exposure Prophylaxis Component of PACTG 076 RegimenWade N et al. N Engl J Med 1999;339:1409

AP+IP+PP IP+PP PP<24 hr PP>48 hr No AZT

Even When No Maternal AZT Received, Infant AZT

Started Within 24 Hours Reduces Transmission

slide10

Why Might Pre/Post-Exposure Prophylaxis Be Important?Amount of Cell-Free and Cell-Associated HIV in Cervicovaginal Canal is Associated with Transmission

  • Chuachoowong R et al. J Infect Dis 2000;181:99-106
    • Quantified CVL HIV RNA at 38 weeks gestation in 310 women in Thai short-course AZT trial.
    • Presence CVL RNA associated with 3.4-fold increase in transmission; effect independent of plasma RNA, and greatest when plasma RNA low.
    • AP AZT was associated with median 0.8 log decrease in HIV RNA in CVL.
  • Tuomala RE et al. J Infect Dis 2003;187:375-84
    • Assessed cell-associated HIV DNA in CVL in 78 women receiving antiretroviral therapy (65% AZT alone, 33% combination therapy).
    • Detection/titer of CVL DNA associated with transmission; 2.3-fold increase for each 1 log increase DNA.
slide11

1

2

3

Lumen

M cell

Epithelium

Mono-

nuclear

cells

Peyer’s

Patch

Lamina

Propria

Infant Exposure to HIV in Vaginal Secretions:

Potential Mechanisms of HIV-1 Transmission

Through Intestinal Mucosa of Infant

slide12

PETRA Study of AZT/3TC Prophylaxis:

Pre-Exposure Prophylaxis Alone is Ineffective

Petra Study Team. Lancet 2002;359:1178-86

% Efficacy

at 6 Wk

63%

42%

0%

1 wk mom

& baby

36

wks

PRENATAL

INTRA

POST

INTRA

POST

INTRA

PLACEBO

slide13

Risk Factors for Transmission

In Women/Infants in

Post- PACTG 076 Era:

Viral Load

Type of Antiretroviral Therapy

Mode of Delivery

delivery plasma hiv rna level is associated with perinatal transmission
Delivery Plasma HIV RNA Level is Associated with Perinatal Transmission

Women & Infants Transmission Study, 1990-1999Cooper E et al. JAIDS 2002;29:484-94

slide15

More Potent Antiretroviral Regimens Are Associated with Lower Perinatal Transmission

Women & Infants Transmission Study, 1990-1999Cooper E et al. JAIDS 2002;29:484-94

slide17

Elective Cesarean Delivery Reduces Transmission When PACTG 076 AZT Regimen is GivenThe International Perinatal HIV Grp. N Engl J Med 1999;340:977-87

Meta-analysis

8,533 women

from 15 cohorts

Addition of an intrapartum intervention further reduces

perinatal transmission in face of AZT prophylaxis

activities in u s following the results of pactg 076
Activities in U.S. Following the Results of PACTG 076
  • Feb 1994: PACTG 076 results announced
  • Aug 1994: U.S. Public Health Service guidelines for use AZT to prevent transmission published.
  • July 1995: U.S. Public Health Service guidelines for prenatal HIV counseling and testing.
  • Periodic updates to guidelines when new information becomes available:
    • Latest update prophylaxis guidelines: Nov 2002
    • Latest update testing guidelines: Nov 2001
current usphs guidelines for prevention of mother to child transmission
Current USPHS Guidelines for Prevention of Mother-to-Child Transmission
  • Maternal plasma HIV RNA >1,000:
    • HAART
    • Elective C/S if >1,000 near delivery
  • Maternal plasma HIV RNA <1,000:
    • HAART or use of PACTG 076 AZT alone
  • No treatment prior to labor:
    • Intrapartum-postpartum AZT; AZT/3TC; nevirapine; or AZT/nevirapine
  • No treatment prior to or during labor:
    • Infant prophylaxis for 6 weeks with combination regimen or AZT alone
maternal antiretroviral use during pregnancy at pactg sites 1998 2000
Maternal Antiretroviral Use During Pregnancy at PACTG Sites,1998-2000

Data from PACTG 367, N = 1,527

slide21
Increasing Rates of Cesarean Delivery Among HIV-Infected Women in U.S., 1994-2000Pediatric Spectrum of Disease, CDC

N=6,467

slide23

81% decline

PACTG 076

500

USPHS AZT

Recommendations

400

300

No. of Cases

200

100

0

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

00

Half Year of Diagnosis

Incidence of Perinatally-Acquired AIDS United States, 1985-2000*

500

400

300

200

100

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00

* Reported through December 2000

progress on reducing mother to child hiv transmission in the u s
Progress on Reducing Mother-to-Child HIV Transmission in the U.S.
  • Mother to child transmission has been reduced to <2% in the U.S.
  • Number of infected infants born each year in U.S. has decreased from 2,000 before 1994 to under 300-400 currently.
  • Reduction transmission secondary to:
    • Enhanced prenatal HIV counseling and testing.
    • Recognition of the importance of viral load in transmission, and increase in use of HAART by pregnant women.
    • Increase in elective cesarean delivery.
challenges remain
Challenges Remain
  • Remaining significant barriers to elimination of perinatal HIV in U.S.:
    • Continued HIV transmission to women, especially adolescents, who have high rates of unintended pregnancy.
    • Lack of prenatal care, particularly in women who are illicit drug users (15% of HIV-infected women lack prenatal care).
    • Failure to identify HIV infection during pregnancy.
    • Antiretroviral drug resistance.
antiretroviral resistance in adults with new hiv infection u s canada
Antiretroviral Resistance in Adults with New HIV Infection, U.S./Canada
  • Frequency of antiretroviral resistance mutations among newly infected persons increasing:
    • Grant et al. JAMA 2002;288:181-8 (San Francisco)
      • From 1996-97 to 2000-01(N=225)
        • NRTI: 25% to 21%
        • NNRTI: 0% to 13%
        • PI: 3% to 8%
      • Resistance correlated with viral response
    • Little et al. NEJM 2002;347:385-94 (10 cities)
      • From 1995-98 to 1998-2000 (N=377)
        • Any: 8% to 23%
        • Multidrug: 4% to 10%
  • more pregnant women are now treatment-experienced.
slide27

More HIV-Infected Pregnant Women are Antiretroviral-Experienced and Have ARV Resistance: Resistance in Women in PACTG 316*Cunningham C et al. J Infect Dis 2002:186:181-8

*23% on AZT alone; Combo no PI 36%; Combo PI 41%

impact of antiretroviral resistance on prevention of perinatal transmission
Impact of Antiretroviral Resistance on Prevention of Perinatal Transmission
  • Mofenson L et al. AIDS Conf 2002
    • PACTG 185 (86% AZT, 14% combo NRTI), case-control study of 24 transmitters, 72 controls
    • At delivery:
      • AZT resistance: 25% transmitters vs 11% controls (p=0.14)
      • Any NRTI resistance: 46% transmitters, 25% controls (p=0.15)
  • Welles S et al. AIDS 2000;14:253-71
    • WITS, case-control study of 142 pregnant women
      • Prevalence AZT resistance, 24%
      • Multivariate analysis, genotypic AZT resistance associated with 5.1-fold increased risk transmission
  • At present, most cases of antiretroviral failure with transmission despite antiretroviral prophylaxis are not due to drug resistance, but this may change as resistance becomes more frequent.
perinatal hiv transmission global12
Perinatal HIV Transmission: Global12
  • Globally, >2 million HIV-infected women give birth annually, most in resource-poor countries, where regimens used in US are too complex and expensive to use.
  • Transmission rates in breastfeeding women without antiretroviral prophylaxis are between 25-40%.
  • About 2,000 children become infected daily; in 2002, an estimated 800,000 infants were newly infected with HIV.
  • An estimated 3.2 million children were living with HIV in 2002.
slide31

Importance of Breastfeeding Postnatal Transmission:Timing of Mother-to-Child HIV Transmission with Breastfeeding and No Antiretroviral Prophylaxis

Early Postpartum

(0-6 months)

Late Postpartum

(6-24 months)

Early Antenatal

(<36 wks)

Labor and Delivery

Late Antenatal

(36 wks to labor)

0%

20%

40%

60%

80%

100%

Proportion of infections

international perinatal hiv trials
International Perinatal HIV Trials
  • Following PACTG 076:
    • Need to develop shorter, less expensive regimens more applicable to resource-limited settings.
    • Studies first focused on modifications of AZT-alone prophylactic regimens.
    • Studies also explored whether short-course combination regimens might have improved efficacy.
    • Studies asked if similar efficacy to combination could be achieved with alternative drugs that were less expensive and could be used in simple regimens.
completed trials focused on prevention ap ip transmission
Completed Trials: Focused on Prevention AP/IP Transmission

AP

IP

PP(baby, mother or both)

14

wks

28

wks

36

wks

3d to

1 wk

6

wks

076

NonBF

NonBF

Thai (Harvard)

NonBF

Thai (Harvard)

NonBF

Thai (Harvard), BMS

IvC (ANRS), PETRA, Thai (Harvard)

BF/NonBF

Thai (CDC), IvC (CDC)

NonBF/BF

PETRA, 012, SAINT

BF

PETRA

BF

PP: Minimal duration?

Is it needed?

AP: Minimum duration?

Is it needed?

IP: Work

alone?

short course azt studies
Short-Course AZT Studies
  • Short-course AZT prophylaxis is effective.
  • Longer (28 weeks) antepartum treatment is more effective than shorter (36 weeks) antepartum therapy, showing that a significant proportion of in utero infection occurs between 28 and 36 weeks.
  • Efficacy of prophylaxis is diminished by breastfeeding, but still persists at 24 months with short-course AZT.
slide35

Short-Course AZT Prophylaxis: Efficacy in

Formula-Fed vs Breast-Fed Infants

% Efficacy

at 6 Mos

50%

37%

% Efficacy

at 24 Mos

50%

26%

Placebo-controlled trials

Thailand Formula Feeding

PRENATAL

36 wks

INTRA

Shaffer et al. Lancet 1999;353:773-80

Ivory Coast BreastFeeding

PRENATAL

36 wk

INTRA

Wiktor et al. Lancet 1999;353:781-5

slide36
Short-Course AZT Prophylaxis, Formula-Fed Infants: Duration of AP/PP Therapy Lallemant M et al. N Engl J Med 2000;343:982-91

AP

IP

PP Infant

28 wk

36 wk

6 wk

3 d

Most Effective

(Tx 4% [vs SS])

Long-

Long

Long-

Short

Intermediate

(Tx 5%)

Intermediate

(Tx 9%)

Short-

Long

Short-

Short

Least Effective

(Tx 11%)

slide37
Long Better than Short Maternal Antepartum Therapy for Preventing In Utero Transmission Lallemant M et al. N Engl J Med 2000;343:982-91

5.1%

P<0.001

1.6%

AP: 28 wks

AP: 36 wks

short course combination regimens
Short-Course Combination Regimens
  • After short-course AZT found effective, researchers then asked if short-course combination regimens would be more effective than AZT alone.
  • AZT/3TC prophylaxis appears more effective than AZT alone.
  • 3-part AP/IP/PP drug prophylaxis is more effective than IP/PP alone.
  • IP-only not effective, showing importance of post-exposure prophylaxis component.
  • Efficacy diminished by breastfeeding and did not persist at 18 mos for the IP/PP AZT/3TC regimen.
slide39
AZT/3TC Better than AZT Alone:Open-Label AZT/3TC Perinatal Prophylaxis Studies in Formula-Fed Populations

AP

IP

PP (baby)

Tx

14

wks

32

wks

6

wks

France

ANRS 075

Mandelbrot

JAMA 2001

1.6%

076 Backbone

vs AZT only

1994-1996 hx control, 6.8%

34

wks

4

wks

Thailand

Chaisilwattana

CID 2002

2.8%

Short AZT Backbone

vs AZT only

1994-1996

hx control, 11.7%

AZT

AZT plus 3TC

slide40

AZT/3TC Prophylaxis in Breast-Fed Infants

Petra Study Team. Lancet 2002;359:1178-86

% Efficacy

6 Wk18 Mo

63% 32%

42% 18%

0% 0%

1 wk mom

& baby

36

wks

PRENATAL

INTRA

POST

INTRA

POST

INTRA

PLACEBO

alternative prophylaxis regimens
Alternative Prophylaxis Regimens
  • Research asked whether alternative drugs (like nevirapine) might provide efficacy similar to short combination regimens.
  • When only IP/PP prophylaxis is given, single-dose NVP is superior to IP/PP AZT alone, and similar to IP/PP AZT/3TC.
  • Efficacy diminished by breastfeeding, but while 2-part AZT/3TC was not effective at 18 months, NVP retained efficacy.
  • Addition of single-dose NVP to short-course AZT appears to improve efficacy.
  • However, adding NVP to standard regimens used in U.S. does not offer additional benefit.
slide42

Alternative Antiretrovirals: Single-Dose Nevirapine vs Ultra-Short AZT - HIVNET 012

Guay L et al. Lancet 1999;354:795-802

Breastfed Infants

% Transmission

14-16 Wks18 Mos

13.1% 15.7%

25.1% 25.8%

Efficacy

47% 41%

INTRA

POST

Nevirapine

2 mg/kg x1

200 mg x1

versus

Ultra-Short

AZT

INTRA

POST

300 mg

q 3 hr

4 mg/kg bid

x1 wk

slide43

Comparison of IP/PP Regimens: Single-Dose

Nevirapine vs PETRA AZT/3TC - SAINT

Moodley D et al. JID 2003;187:725-35

% Transmission

BirthBtn Birth-8 Wks

7.0% 5.7% (2.0-5.3)

Overall, 8 wks: 12.3%

5.9% 3.6% (3.7-7.8)

Overall, 8 wks: 9.3%

(Overall: p=0.11)

Nevirapine

(variant of

HIVNET 012)

INTRA

POST

Mom 200 mg x1

Baby 2 mg/kg x1

200 mg x1

versus

AZT/3TC

(PETRA)

INTRA

POST

Q 3 hr

Mom & baby

x1 wk

does the addition of single dose nvp to short course azt improve efficacy
Does the Addition of Single Dose NVP to Short-Course AZT Improve Efficacy?

Lallemant M et al. 2002 AIDS Conf, Barcelona Abs LBOr22

AZT

28 wk

oral

1 wk

DSMB stopped

AZT alone (arm 3)

@ interim analysis

due to significantly

higher transmission

Plus:

Arm 1 -

NVP

NVP

Arm 2 -

NVP

PL

Arm 3 -

PL

PL

Formula fed

F Dabis F et al. 2002 AIDS Conf, Barcelona Abs ThOrD1428

AZT

Transmission 7%

compared to 13%

historical control AZT

alone (95% breastfed)

36 wk

oral

1 wk

NVP

NVP

50% breastfed

slide45
Single-Dose NVP Does Not Improve Efficacy of Longer or More Complex ARV RegimensDorenbaum A et al. JAMA 2002;288:189-98

PregnancyLaborNewborn

Transmission

Rates

Women receiving

ARV during

pregnancy

Continue

ARV

AZT Perinatal

Prophylaxis

1.4%

(95% CI, 1-3%)

1.6%

(95% CI, 1-3%)

200 mg

dose of NVP

vs

NVP Placebo

2 mg/kg

dose of NVP

@ 48-72 hr

vs

NVP Placebo

Randomize,

stratified by:

1) AP ARV

(no, mono,

combo)

2) Entry CD4

infant prophylaxis
Infant Prophylaxis
  • Many women may not present until in labor and only infant prophylaxis may be possible.
  • Epidemiologic data suggest infant AZT for 6 weeks after birth reduces transmission.
  • Infant prophylaxis must begin within 24-48 hours after birth to be effective when the mother has not received AP/IP drug.
  • Preliminary data suggest:
    • Single dose NVP given to the infant at birth may have efficacy similar to AZT.
    • Single dose NVP plus AZT may have better efficacy than NVP alone if mother hasn’t received single dose IP NVP.
preliminary data infant post exposure prophylaxis trials south africa malawi ongoing
Preliminary Data: Infant Post-Exposure Prophylaxis Trials (South Africa, Malawi; ongoing)

Gray G. 2002 AIDS Conf, Barcelona Abs LBOr13 *

7%

11%

NB NVP

AZT 6 wk

* Problem: 25% loss to follow-up between birth-6 wks

Taha T. 2002 AIDS Conf, Barcelona Abs ThOrD1427; ThPpD2146 *

22%

14%

NB NVP

Stratify: Late

vs

Early

Presenter

NB NVP

AZT 1 wk

14%

18%

IP NVP

NB NVP

IP NVP

NB NVP

AZT 1 wk

is combination better than standard 6 wk azt post exposure prophylaxis in formula fed infants
Is Combination Better than Standard 6 Wk AZT Post-Exposure Prophylaxis in Formula-Fed Infants?

Post-Exposure Infant Prophylaxis (PEPI)

NICHD/HPTN 040 Trial (Brazil, U.S.)

Infant

IV AZT*

AZT x 6 wks

NVP birth, 72, 168 hr

IV AZT*

AZT x 6 wks

3TC/NFV x 2 wks

IV AZT*

AZT x 6 wks

*If mom diagnosed in time for IP prophylaxis

slide49

Current/Planned International Perinatal TrialsInfant or Maternal Antiretroviral Prophylaxis to Reduce Postnatal Breast Milk HIV Transmission

design of ongoing planned infant prophylaxis trials
Design of Ongoing/Planned Infant Prophylaxis Trials

AP

IP

PP -- Infant

34

wks

36

wks

1

wk

6

wks

28

wks

6

mo

14

wks

Botswana

SIMBA/MITRA

HPTN 046

Ethiopia/India

Malawi (CDC/NICHD)

S. Africa/Brazil

Thai (Harvard)

DITRAME+1

Malawi (ongoing)

Zambia (Harvard)/SA/

HIVNET 024/Uganda

PP: Optimal duration?

Will it work alone?

What drug? Is combo better?

Exclusive BF, type weaning?

AP: Optimal duration?

Is it needed?

design of maternal haart prophylaxis trials
Design of Maternal HAART Prophylaxis Trials

PP maternal

regimen

AP

IP

PP Mother

6

mos

34-36

wks

Kenya (CDC)

open label

AZT/3TC/NVP

Botswana

(Harvard/EGPAF)

open label

AZT/3TC/NVP

AZT/3TC/NVP vs

Baby NVP x 6 mos vs NVP x1

+- multivits

Malawi (CDC/UNC)

AZT/3TC/NVP vs

AP/IP AZT/NVP x1 +

Baby AZT x1 wk +

NVP x1

Multisite Africa

(WHO)

In randomized studies, CD4 <200 all get HAART,

CD4 >200 or 200-500 are randomized

progress and challenges in reducing mother to child hiv transmission on a global basis
Progress and Challenges inReducing Mother-to-Child HIV Transmission on a Global Basis
  • Shorter, less expensive regimens than PACTG 076 have been found to be effective in reducing in utero and intrapartum transmission by 41-63%.
  • Although breastfeeding decreases the overall efficacy, most trials still show a significant decrement at 18-24 months.
  • New approaches, including infant or maternal prophylaxis are targeted at reducing postnatal transmission.
  • Implementation of known effective regimens is now key.