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

• 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 Transmission in the 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.

PACTG 076 AZT Regimen Targeted Multiple Potential Time Points of Transmission

Pregnancy Labor/Delivery Infant

AZT 100 mg

5 times daily

AZT IV 2 mg/kg

1 mg/kg/hr

2 mg/kg q 6 hr

x 6 weeks

TARGET:

In Utero

TARGET:

Intrapartum

TARGET: Postpartum

67% Reduction in the Risk of Transmission Placebo arm: 25.5%

AZT arm: 8.3%

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).

How Does AZT Lower Perinatal Transmission?

Effect of AZT on Viral Load in PACTG 076 Sperling RS et al. NEJM 1996;335:1621-9

Characteristic (AZT arm) PACTG 076

• Median Entry RNA 5,660

• Median Duration AZT 26 wks

• Median change entry-delivery 0.28 log

• Proportion of AZT efficacy explained by:

– RNA at delivery

– Change RNA entry-delivery

11%

17%

AZT Lowers Transmission Even in HIV-Infected Women with Very Low Viral Load

Ioannidis 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.

Importance of the Infant Pre- and Post-Exposure Prophylaxis Component of PACTG 076 Regimen

Wade N et al. N Engl J Med 1999;339:1409

6%10% 9%

18%

27%

0%

15%

30%

% T

ran

sm

iss

ion

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

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.

Infant Exposure to HIV in Vaginal Secretions:Potential Mechanisms of HIV-1 Transmission

Through Intestinal Mucosa of Infant

1 2 3

Lumen

Peyer’sPatch

Epithelium

LaminaPropria

M cell

Mono-nuclear

cells

PRENATAL INTRA POST

% Efficacy at 6 Wk

63%

42%

0%

INTRA

INTRA

POST

PLACEBO

PETRA Study of AZT/3TC Prophylaxis:Pre-Exposure Prophylaxis Alone is Ineffective

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

36 wks

1 wk mom& baby

Risk Factors for TransmissionIn Women/Infants in

Post- PACTG 076 Era:

Viral LoadType of Antiretroviral Therapy

Mode of Delivery

Delivery Plasma HIV RNA Level is Associated with Perinatal Transmission

1%6%

11%

21%

32%

0

10

20

30

40

% T

ran

smis

sio

n

<400 400-3000

3000-40000

40000-100000

>100000

Delivery Plasma HIV RNA

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

More Potent Antiretroviral Regimens Are Associated with Lower Perinatal Transmission

21%

8%4%

1%0

10

20

30

% T

ran

sm

iss

ion

None AZT Alone

Less PotentCombo

PotentCombo (PI)

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

0

20

40

60

PercentTransmission

>100

000

>400

00-1

0000

0

>300

0-40

000

>400

-300

0

Undetec

tabl

e (<

400)

HAARTMulti-ART

ZDV Mono (>4/94)ZDV Mono (<4/94)

None

Maternal Plasma HIV-1 RNA Copies/ml*

Antiretroviral Therapy

Maternal Delivery HIV RNA Levels and Antiretroviral Use are Independently Associated

With Perinatal TransmissionCooper E et al. JAIDS 2002;29:484-94

Elective Cesarean Delivery Reduces Transmission When PACTG 076 AZT Regimen is Given

The International Perinatal HIV Grp. N Engl J Med 1999;340:977-87

19%

10%7%

2%

0

12

24

% T

ran

smis

sio

n

Without AZT With AZT (all 3 parts)

Other Mode Delivery

Elective Cesarean

Addition of an intrapartum intervention further reduces perinatal transmission in face of AZT prophylaxis

Meta-analysis8,533 women

from 15 cohorts

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

• 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

17%

78%

42%25%

9%3% 4% 1%

0

50

100

% o

f W

om

en R

ecei

vin

g

Single Combo:Total

with PI AZT/3TC with NNRTI

OtherNRTIs

None Unknown

Type of Antiretroviral Therapy

Data from PACTG 367, N = 1,527

Increasing Rates of Cesarean Delivery Among HIV-Infected Women in U.S., 1994-2000

Pediatric Spectrum of Disease, CDC

19% 19% 21% 20%26%

42% 44%

0

10

20

30

40

50

% C

esare

an

Deli

very

1994 1995 1996 1997 1998 1999 2000

N=6,467

Mother to Child HIV Transmission in the U.S. Over Time

1.5%2.0%3.3%

5.0%

7.6%

24.5%

0

10

20

30

40

1993: WITS

1994:PACTG

076

1997:PACTG

185

1999: WITS

2001:PACTG

247

2002:PACTG

316

% T

ran

sm

iss

ion

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

* Reported through December 2000

0

100

200

300

400

500

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

Half Year of Diagnosis

No

. o

f C

ases

PACTG 076

USPHS AZT Recommendations

81% decline500

400

300

200

100

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

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• 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

• 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.

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

44%

8% 8%2%

9%3%

%

%

%

%

% w

ith

Mu

tati

on

Resistance Mutation at Delivery

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

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 Transmission Global Picture

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.

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

0% 20% 40% 60% 80% 100%

Early Antenatal(<36 wks)

Late Antenatal(36 wks to

labor)

Labor and Delivery

Late Postpartum(6-24 months)

Early Postpartum(0-6 months)

Proportion of infections

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

3d to1 wk

36 wks

14wks

6 wks

IP

076

Thai (Harvard)

Thai (Harvard), BMS

IvC (ANRS), PETRA, Thai (Harvard)

Thai (CDC), IvC (CDC)

PETRA, 012, SAINT

PETRA

AP PP (baby, mother or both)

Thai (Harvard)

28wks

NonBF

NonBF

NonBF

NonBF

BF/NonBF

NonBF/BF

BF

BF

AP: Minimum duration? Is it needed?

PP: Minimal duration? Is it needed?

IP: Work alone?

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.

PRENATAL36 wks

INTRA

INTRA

Short-Course AZT Prophylaxis: Efficacy in Formula-Fed vs Breast-Fed Infants

PRENATAL36 wk

% Efficacy at 6 Mos

50%

37%

Thailand Formula Feeding

Ivory Coast Breast Feeding

% Efficacy at 24 Mos

50%

26%

Placebo-controlled trials

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

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

Short-Course AZT Prophylaxis, Formula-Fed Infants: Duration of AP/PP Therapy

Lallemant M et al. N Engl J Med 2000;343:982-91

Most Effective(Tx 4% [vs SS])

Least Effective (Tx 11%)

Intermediate(Tx 5%)

Intermediate(Tx 9%)

Long-Long

Long-Short

Short-Long

Short-Short

AP IP PP Infant

28 wk36 wk

3 d 6 wk

Long Better than Short Maternal Antepartum Therapy for Preventing In Utero Transmission

Lallemant M et al. N Engl J Med 2000;343:982-91

0

2

4

6

% T

rans

mis

sion

LL + LS SS + SL

AP: 28 wks AP: 36 wks

P<0.001

1.6%

5.1%

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.

AZT/3TC Better than AZT Alone:Open-Label AZT/3TC Perinatal Prophylaxis

Studies in Formula-Fed Populations

14wks

6 wks

IPAP PP (baby)32wksFrance

ANRS 075Mandelbrot

JAMA 2001

ThailandChaisilwattana CID 2002

Tx

1.6%

2.8%

vs AZT only1994-1996 hx control, 6.8%

vs AZT only 1994-1996hx control, 11.7%

AZT AZT plus 3TC

076 Backbone

Short AZT Backbone

34 wks

4 wks

PRENATAL INTRA POST

% Efficacy6 Wk 18 Mo

63% 32%

42% 18%

0% 0%

INTRA

INTRA

POST

PLACEBO

AZT/3TC Prophylaxis in Breast-Fed InfantsPetra Study Team. Lancet 2002;359:1178-86

36 wks

1 wk mom& baby

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.

INTRA POST

% Transmission 14-16 Wks 18 Mos

13.1% 15.7%

25.1% 25.8%

Efficacy 47% 41%

INTRA POST

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

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

Nevirapine

Ultra-ShortAZT

2 mg/kg x1200 mg x1

4 mg/kg bid x1 wk

300 mg q 3 hr

versus

Breastfed Infants

INTRA POST

% Transmission Birth Btn 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)

INTRA POST

Comparison of IP/PP Regimens: Single-Dose Nevirapine vs PETRA AZT/3TC - SAINT

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

Nevirapine(variant of

HIVNET 012)

AZT/3TC(PETRA)

Mom 200 mg x1Baby 2 mg/kg x1

200 mg x1

Mom & babyx1 wk

Q 3 hr

versus

Does the Addition of Single Dose NVP to Short-Course AZT Improve Efficacy?

28 wk 1 wkoral

NVP NVP

PL PLPLNVP

oral 1 wk36 wk

NVP NVP

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

DSMB stoppedAZT alone (arm 3)@ interim analysisdue to significantlyhigher transmission

Arm 1 -Arm 2 - Arm 3 -

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

AZT

AZT

Plus:

Transmission 7% compared to 13%

historical control AZT alone (95% breastfed)

50% breastfed

Formula fed

Single-Dose NVP Does Not Improve Efficacy of Longer or More Complex ARV Regimens

Dorenbaum A et al. JAMA 2002;288:189-98

Women receivingARV during pregnancy

ContinueARV

AZT PerinatalProphylaxis

200 mgdose of NVP

vs

NVP Placebo

2 mg/kg dose of NVP@ 48-72 hr

vs

NVP Placebo

TransmissionRates

Pregnancy Labor Newborn

1.4%(95% CI, 1-3%)

1.6%(95% CI, 1-3%)

Randomize,stratified by:1) AP ARV (no, mono, combo)2) Entry CD4

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)

Gray G. 2002 AIDS Conf, Barcelona Abs LBOr13 *NB NVP

AZT 6 wk

7%

11%* Problem: 25% loss to follow-up between birth-6 wks

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

NB NVPNB NVP

NB NVP

NB NVP

AZT 1 wk

AZT 1 wkIP NVP

22%14%

14%18%

IP NVP

Stratify: Late vs Early Presenter

Is Combination Better than Standard 6 Wk AZT Post-Exposure Prophylaxis in Formula-Fed Infants?

AZT x 6 wks

AZT x 6 wks

AZT x 6 wks

NVP birth, 72, 168 hr

3TC/NFV x 2 wks

IV AZT*

IV AZT*

IV AZT*

Infant

Post-Exposure Infant Prophylaxis (PEPI)NICHD/HPTN 040 Trial (Brazil, U.S.)

*If mom diagnosed in time for IP prophylaxis

Current/Planned International Perinatal Trials

Infant or Maternal Antiretroviral Prophylaxis to Reduce Postnatal

Breast Milk HIV Transmission

Design of Ongoing/Planned Infant Prophylaxis Trials

36 wks

6 wks

IP

Botswana

Ethiopia/India

DITRAME+1

AP PP -- Infant

HPTN 046

34 wks

1 wk

6 mo

SIMBA/MITRA

Thai (Harvard)

Zambia (Harvard)/SA/HIVNET 024/Uganda

Malawi (CDC/NICHD)

Malawi (ongoing)

28 wks

AP: Optimal duration? Is it needed?

PP: Optimal duration? Will it work alone? What drug? Is combo better? Exclusive BF, type weaning?

14 wks

S. Africa/Brazil

Infant Prophylaxis Trials: A Variety of Regimens/Durations Under Study

Antepartum(28, 34, 36 wks)

Intrapartum

(oral)

Infant Postpartum(1, 6, 14 wks,6 mos)

None AZT alone AZT

AZT NVP x1 NVP

AZT/3TC AZT + NVP x1 3TC

AZT/ddI AZT/3TC + NVP x1 AZT + NVP

AZT/ddI + NVP x1 AZT/3TC/NFV

Exclusive BF + type weaning

Design of Maternal HAART Prophylaxis Trials

6 mos

IP

Kenya (CDC) open label

AP PP Mother 34-36 wks

Botswana (Harvard/EGPAF)open label

Malawi (CDC/UNC)

Multisite Africa(WHO)

PP maternal

regimen

AZT/3TC/NVP vs Baby NVP x 6 mos vs NVP x1 +- multivits

AZT/3TC/NVP vsAP/IP AZT/NVP x1 + Baby AZT x1 wk +

NVP x1

AZT/3TC/NVP

AZT/3TC/NVP

In randomized studies, CD4 <200 all get HAART, CD4 >200 or 200-500 are randomized

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.