PREVENTION OF PERINATAL TRANSMISSION OF HIV-1 Chokechai Rongkavilit Pediatric Infectious Diseases...

PREVENTION OF

PERINATAL TRANSMISSION OF HIV-1

Chokechai Rongkavilit

Pediatric Infectious Diseases

Children’s Hospital of Michigan

PACTU 5041

Objectives

To review the current global situation

To review clinical trials related to perinatal HIV transmission

To review strategies for prevention of perinatal HIV transmission

To review global response to prevent perinatal HIV transmission

Global Situation

Most HIV-infected children are in developing countries, mainly Africa.

More than 95% of HIV-infected children acquire HIV through vertical transmission from their mothers.

>7000 women of child bearing age acquire HIV each day worldwide.

2000 infants become infected every day worldwide.

UNAIDS Report 2004

Global summary of the HIV/AIDS epidemic

2001 2002 2003

Number of people living with HIV/AIDS

(in million)

Total

Adult

Children <15 y

40

37

2.7

42

38.6

3.2

40

37

2.5

People newly infected with HIV

(in million)

Total

Adult

Children <15 y

5

4.3

0.8

5

4.2

0.8

5

4.2

0.7

AIDS deaths

(in million)

Total

Adult

Children <15 y

3.0

2.4

0.6

3.1

2.5

0.6

3.0

2.5

0.5

UNAIDS

0 0 0 0 2 - E - 1 – 1 D e c e m b e r 2 0 0 3

C h i l d r e nC h i l d r e n ( < 1 5 y e a r s )( < 1 5 y e a r s ) e s t i m a t e d t o b e l i v i n g e s t i m a t e d t o b e l i v i n g w i t h H I V / A I D S a s o f e n d 2 0 0 3w i t h H I V / A I D S a s o f e n d 2 0 0 3

W e s t e r n E u r o p e5 0 0 0 – 7 0 0 0

N o r t h A f r i c a& M i d d l e E a s t

3 1 0 0 0 – 4 9 0 0 0S u b - S a h a r a n A f r i c a2 . 0 – 2 . 2 m i l l i o n

E a s t e r n E u r o p e &C e n t r a l A s i a9 0 0 0 – 1 5 0 0 0

E a s t A s i a & P a c i f i c6 0 0 0 – 1 2 0 0 0

S o u t h & S o u t h - E a s t A s i a

1 1 0 0 0 0 – 1 9 0 0 0 0

A u s t r a l i a & N e w Z e a l a n d

< 2 0 0

N o r t h A m e r i c a8 0 0 0 – 1 2 0 0 0

C a r i b b e a n1 9 0 0 0 – 3 1 0 0 0

L a t i n A m e r i c a3 7 0 0 0 – 5 0 0 0 0

T o t a l : 2 . 1 – 2 . 9 m i l l i o n

Perinatally Acquired AIDS Cases by Quarter-Yearof Diagnosis, 1985-2000, United States

Quarter-Year of Diagnosis

Number of Cases

0

50

100

150

200

250

300

19861985 1987 1988 1989 1990 19911992 19941993 1995 1996 1997 1998 1999 2000

Num

ber of

Cas

es

280-370 infants are born infected with HIV in US each year

Key Factors in Reducing Perinatal HIV Transmission in the US

Access to prenatal care

HIV counseling and testing

– Mandatory counseling during antenatal visits

– Voluntary testing

– Rapid testing in labor

Secure supply of antiretroviral drugs

– For treatment of mothers: maximize maternal health

– For perinatal prevention

Feasibility of elective c-section

Safe breast milk replacement

Care of mother/partner and child after delivery

A n te n a ta l H IV P re v a le n c e in W o m e n in D e v e lo p in g W o r ld

0 5 10 15 20 25 30 35 40

Botsw ana

South A frica

Namibia

Zambia

Ethiopia

Cote D'I viore

Mozambique

Kenya

T anzania

Uganda

Nigeria

Haiti

Guyana

R w anda

Percentage

HIV Prevalence trends among antenatal clinic attendees in South Africa: 1990-2002

0.7 1.7 2.24

7.6

10.4

14.2

17

22.8 22.424.5 24.8

26.5

0

5

10

15

20

25

30

%

1990 1992 1994 1996 1998 2000 2002

South Africa Department of Health Report 2004

Case Study

During a rotation in Thailand, you see a pregnant woman whom

you just discovered to have HIV. She is now 4 month pregnant.

What care would you provide to her at this point?

What else would you suggest to her and her husband?

Once she is in labour, what care would you provide to her?

Once the child is born, what care would you provide to the child?

She asks you about the likelihood of her unborn child being

infected and about breast feeding. What would you advise?

She lives with her in-laws and she is afraid that they might find out

about HIV. What would be your advice?

Risk Factors for Vertical Transmission

Maternal Factors

– advanced HIV disease: high HIV RNA, low CD4

– co-infection: sexually transmitted diseases

– drug abuse

– obstetric complications: prolonged rupture of amniotic

membrane

– Mode of delivery: vaginal versus c-section

– breast-feeding

Risk Factors for Vertical Transmission

Fetal / placental factor

– chorioamnionitis

– disruption of placenta: maternal-fetal blood exchange

– birth trauma

– Twin: 1st twin has higher risk

– prematurity

Obstetric Factors

RR P value

Cervicovaginal infection 1.3 (1.1-1.7) 0.018

Prolonged membrane rupture 1.4 (1.1-1.8) 0.009

Preterm labor < 37 wk 1.4 (1.1-1.9) 0.020

STD 1.5 (1.1-2.0) 0.003

bleeding at labor 1.9 (1.1-3.2) 0.020

invasive procedure 1.9 (1.3-2.7) 0.007

Mandelbrot, et al. Am J Ob Gyn 1996

N = 1632

Perinatal Transmission Rate

Baseline transmission (without intervention)

Europe/US 16%-20%

Asia 19%-24%

Africa 25%-40%

Breastfeeding increases risk by 5-20%

Timing of Transmission

In utero infection 30%

Intrapartum infection 70%

in utero intrapartum postnatal

Timing of Transmission

0

10

20

30

40

50

60

70

Proportion of infants infected

Delivery4 weeks8 weeks1st & 2nd trimester

Rouzioux C, et al. Am J Epidemiol 1995; 142: 1330

French cohort: Markov model

Evolution of Clinical Trials&

Advance in Prevention of Perinatal HIV Transmission

PACTG 076USA/France

Placebo controlled

Antepartum: ZDV 100 mg, 5 times daily

Intrapartum: intravenous ZDV

Neonatal: ZDV for 6 weeks

No breastfeeding

Connor EM, at al. N Engl J Med 1994;331:1173

ACTG 076

AP IP NN

Began at 14-34 weeksMedian duration 11 weeks

Placebo 22.6%

ZDV 7.6%

Transmissionreduction

66.4%

Sperling RS, et al. N Engl J Med 1996;335:1621

P < 0.001

CDC-Thailand Study

Placebo controlled

Antepartum: ZDV 300 mg twice daily

Intrapartum: oral ZDV 300 mg every 3 hours

Neonatal: none

No breastfeeding

Shaffer N, et al. Lancet 1999;353:773

CDC-Thailand Study

AP IP

Began at 36 weeksMedian duration 25 days

Placebo 18.9%

ZDV 9.4%


50.1%

Shaffer N, et al. Lancet 1999;353:773

P = 0.006

RETRO-CICote d’Ivoire

Placebo controlled


Intrapartum: ZDV 300 mg every 3 hours

Neonatal: none

Predominantly breastfeeding

Witkor SZ, et al. Lancet 1999;353:781

RETRO-CI

AP IP

Began at 36 weeksMedian duration 27 days

Placebo 21.7% 24.9%

ZDV 12.2% 15.7%


44% 37%

4 weeks 3 months

Witkor SZ, at al. Lancet 1999;353:781

P < 0.05

DITRAMECote d’Ivoire/Burkina Faso

Placebo controlled


Intrapartum: single dose of 600 mg at labor

Postpartum: ZDV 300 mg twice daily for 7 d

to mothers


Dabis F, et al. Lancet 1999;353:786

DITRAME

AP IP PP

Began at 36-38 weeksMedian duration 21 days

Placebo 21.8% 27.5%

ZDV 15.1% 18.0%


34% 38%

45 days 6 months

Dabis F, et al. Lancet 1999;353:786

P < 0.05

Short-Course ZDV Trials

18.9

24.927.5

9.4

15.718

0

5

10

15

20

25

30

Thailand Cote d’Ivoire Cote d’Ivoire/BurkinaFaso

% t

ran

sm

iss

ion

Placebo ZDV

50% 37% 38%

Began at 36 weeks

AP IP

Breastfeeding

IP AZV was given orallyNo neonatal ZDV component

New York State Study

Data from PCR testing service of NY State D

epartment of Health

Partial or full ACTG 076 protocol

Wade NA, et al. N Engl J Med 1998;339:1409

New York State Study

6.1%

10%

9.3%

18.4%

26.6% NONENONE

within 48 hrs

after 72 hrs

AP IP NN

Wade NA, et al. N Engl J Med 1998;339:1409

Transmission rate

Perinatal HIV Prevention TrialHarvard & Northern Thailand

Define optimal duration of prophylaxis

antepartum at 28 wk + neonatal for 6 wk (LL)

antepartum at 28 wk + neonatal for 3 d (LS)

antepartum at 35 wk + neonatal for 6 wk (SL)

antepartum at 35 wk + neonatal for 3 d (SS)

Non-breastfeeding

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

Perinatal HIV Prevention Trial

transmission rate28 wk 6 wk

28 wk 3 d

35 wk 6 wk

35 wk 3 d

6.5 (4.1-8.9)*

4.7 (2.4-7.0)*

8.6 (5.6-11.6)*

10.5 (6.4-14.4)**

AP IP NN

N = 1437

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

*P = NS**early termination

Thai Red Cross ZDV Donation Program to Prevent

Vertical Transmission of HIV:

Effects of the Modified ACTG 076 Regimen

M. Khongphatthanayothin, C. Rongkavilit, S. Sirivichayakul, W.

Poolcharoen, C. Kunanusont, DB. Bien, U. Thisyakorn, P. Phanuphak

AIDS 2000;14:2921

Program Objective

To reduce vertical HIV transmission by procuring public d

onation of ZDV and offering the medication at no cost to H

IV-infected pregnant women.

Under the patronage of HRH Princess Soamsawali and in

collaboration with Ministry of Public Health, UNAIDS and

UNICEF.

Modified ZDV Regimen

Antepartum (start at 14-34 weeks’ gestation)

morning dose: 200 mg

evening dose: 300 mg

Intrapartum

300 mg orally every 3 hours till delivery

Infant

2 mg/kg four times daily for 6 weeks

Analysis

Analysis was limited to those with at least 1 HIV DNA

PCR done in infants at > 4 weeks of age.

HIV PCR was performed by dried blood spot techniqu

e.

Results

From June 1996 - August 1999, ZDV had been provided to 2,891 p

regnant woman-infant pairs from 81 hospitals in 40 provinces throu

ghout Thailand.

726 infants of 719 women had > 1 PCR done at > 1 month of age.

43 infants were HIV-infected.

Transmission rate was 6.0% (95% CI, 4.4 - 8.0%).

Results

AntepartumZDV

No. ofwomen

No. of infectedinfants

Transmission(95% CI)

At > 30 wk 122 4 3.3% (0.9-8.2)*

At < 30 wk 507 29 5.7% (3.9-8.1)*

* P = 0.21

Thisyakorn U, et al. AIDS 2000;14:2921

Efficacy of ACTG 076 Regimen

North Carolina 5.7%

WITS 7.7%

Ariel Project 8.6%

NC-Children’s AIDS 3.4%

Connecticut 4.2%

Thai Red Cross 6.0%

PACTG 185 4.1%

Study Transmission rate

HIV-NET 012Uganda and US NIH

Randomized: ZDV vs nevirapine (NVP)

ZDV: 600 mg at onset of labor

300 mg every 3 hrs till delivery

4 mg/kg BID for 1 wk to infants

NVP: 200 mg at onset of labor

one dose of 2 mg/kg to infants within 72 h

Predominantly breastfeeding (99%, median 9 mo)

Guay LA, et al. Lancet 1999; 354: 795

HIV-NET 012Uganda and US NIH

*P <0.01

Guay LA. Lancet 1999; 354: 795Jackson JB. Lancet 2003; 362: 859

Transmission Age 6-8 wk Age 14-16 wk Age 18 months

Zidovudine (N=313)

20.0% 22.1% 25.8%

Nevirapine (N=313)

11.8% 13.5% 15.7%

Transmission reduction

41%* 39%* 39%*

This simple, inexpensive nevirapine regimen significantly decreased MTCT in less-developed countries.

Cost-Effectiveness in Developing World

Regimen Cost pertreatment

Estimatedtransmission

Cost/caseprevented

Formula only 195 18.9% 1759

Formula+long AZT+neonatal AZT (076)

399 6.0% 1662

Formula+short AZT+C/S 368 3.0% 1362

Formula+short AZT 260 9.4% 1260

Formula+short AZT+neonatal AZT

272 6.4% 1154

Nevirapine+BF 4 13.1% 298

Teeraratkul A, et al. 5th Congress on AIDS in Asia and Pacific, 1999Marseille E, et al. Lancet 1999; 354: 803

in US dollars

French Perinatal Study

Prospective, non-randomized

Antepartum: ZDV (ACTG 076)

3TC started at 32 weeks

Intrapartum: ZDV IV + 3TC

Neonatal: ZDV + 3TC 2 mg/kg BID for 6 wks

Compare with ZDV monotherapy cohort

No breastfeeding

Blanche S, et al. 6th CROI 1999


AP IP NN

Transmission rate

ZDV + 3TC 2.6% (5/194)

ZDV 6.5% (53/810)



M184V mutation occurred in 40% of women a

fter delivery

2 infants exposed to ZDV+3TC developed mit

ochondrial myopathy


PETRA StudyTanzania/Uganda/South Africa

Various regimens of ZDV+3TC

Antepartum: ZDV 300 mg BID

3TC 150 mg BID

Intrapartum: ZDV 300 mg every 3 hrs

3TC 150 mg BID

Neonatal: ZDV 4 mg/kg BID

3TC 2 mg/kg BID


Petra study team. Lancet 2002;359:1178

PETRA Study

Arm A 5.7% 15%

Arm B 8.9% 18%

Arm C 14.2% 20%

Arm D 15.3% 22%

AP IP NN

At 36 weeks 1 week

Petra study team. Lancet 2002;359:1178

Transmission rate Wk 6 Mo 18

N=1797

SAINT StudySouth Africa

ZDV+3TC vs nevirapine (n=1319)

IPNN

ZDV + 3TC (PETRA B)

1 week

PP

NVP IPPP

NNsingle dose

Transmission at 8 wkIncluding (excluding) intrauterine infection

9.3% (3.6%)

12.3% (5.7%)

P = 0.1

Moodley D. J Infect Dis 2003;187:725

Breastfeeding 40%PP maternal drug to provide protection against early breast feeding transmission

ZDV+NVP Trial, MalawiIP NN

NVPNVP + ZDV or 7 days

HIV+ at birth(intrauterine)

HIV+ at 6-8 wk but neg at birth

(intrapartum/postpartum)

Overall HIV infection rate

by 6-8 wk

NVP 36/445 (8.1%) 23/353 (6.5%) 14.1%

NVP+ZDV 45/444 (10.1%) 25/363 (6.9%) 16.3%

It is not necessary to add ZDV in full NVP regimen. P=0.36

Taha TE. JAMA 2004;292:202

Perinatal HIV Prevention Trial, Thailand

ZDV

ZDV

ZDV

Mother Infant

28 wk GA 1 wk

NVP/NVP

NVP/PLC

PLC/PLC

No breastfeeding

Adding NVP in the short-course ZDV is beneficial.The result lead to modification of Thailand’s national guideline to implement ZDV+NVP as prophylactic regimen.

Transmission

1.9% (12/627)

2.8% (17/611)

6.3% (22/348)

Lallemant M. NEJM 2004;351:217

Combination of ZDV and single-dose NVP

International PACTG 316

• Multicenter study (USA, Europe, Brazil, Bahamas)• Assess benefit of adding single-dose NVP to standard ARV

Mother: standard ARV (ZDV at minimum) plus NVP (vs placebo) at

labour

Infant: standard ZDV plus NVP (vs placebo)

Mother (n=1270)

Median CD4, 434; Median HIV RNA, <400

22% on ZDV

28% on ZDV+3TC

49% on combination ARV therapy

Elective C-section 34% (0-81%)

Dorenbaum A. JAMA 2002;288:189

International PACTG 316

Transmission rate NVP = 1.4% (CI, 0.6-2.7) Placebo = 1.6% (CI, 0.8-2.9)

No benefit from additional NVP when women already received antenatal ARV (HAART), had good virologic response, had access to elective c-section and formula feeding.

NVAZ Trial, Malawi

Counseling and testing in antenatal clinics are often not

available in many developing countries.

Most women present only hours before delivery, unaware of

HIV status, and with little time to administer NVP before

delivery.

Protective concentrations of NVP in cord blood are achieved

only when intrapartum NVP is given >2 h before delivery.

Therefore, strategies of ARV prophylaxis in neonates only

were evaluated.

Taha TE. Lancet 2003;362:1171

NVAZ Trial, Malawi

20.9

12.1

15.3

7.7

0

5

10

15

20

25

% t

ran

sm

iss

ion

NVP (421) NVP+AZT(444)

Mother in advanced labour and did not receive intrapartum NVP

Infants randomized

– NVP single dose

– NVP single dose + AZT 4 mg/kg bid for 7 days

Figure shows net HIV status at 6-8 wk of age (green) and when in utero infection was excluded (red)

36% reduction in transmission

Taha TE. Lancet 2003;362:1171

Combination of AZT/NVP is more effective in infants when mothers

receive no ARV during pregnancy and delivery

International perinatal HIV studies

ACTG 076Thai/CDC

Retro-CIDITRAMEPETRA-APETRA-BPETRA-CHIVNET012SAINT

NVAZ

14 w

k

36 wk

labordeliv

ery

1 wk

6 wk

Transmission rate

AZT AZT+3TC NVP

FF

BF

7.6

9.5

15178

12191210

15

PHPT LL 6.54.7PHPT LS

28 w

k

PHPT 1.9

16MALAWI

WHO Guidelines 2004

Women with indications for starting ARV

ZDV (D4T) + 3TC + NVP

Infants: ZDV 1 wk or NVP or ZDV+NVP

Women without indications for starting ARV

1) ZDV at 28 wk + NVP at labor Infant: ZDV 1 wk or ZDV + NVP (PHPT,1.9-2.8%)

2) ZDV+3TC at 36 wk till 1 wk PP Infant: ZDV+3TC 1 wk (PETRA A, 8%)

3) SD NVP to mother and infant (HIVNET012, 12%)

Women in labor with no prior ARV

1) SD NVP to mother and infant (HIVNET012, 12%)

2) ZDV+3TC till 1 wk PP Infant: ZDV+3TC 1 wk (SAINT,9.3%, PETRA B, 12%)

Infants born to women with no ARV

SD NVP + ZDV 1 wk (NVAZ, 15.3%)

US Guidelines 2004Women with no prior ARV

1) Combination ARV therapy including 3-part ZDV regimen if treatment is indicated or VL>1000

(delay Rx till 10-12 wk gestation)2) 3-part ZDV if ARV treatment is not needed (076, 7.6%)

Women currently on ARV therapy

Add or substitute ZDV after 1st trimester using 3-part ZDV regimen

Women in labor with no prior ARV

1) IP IV ZDV + neonatal ZDV for 6 wk (NY, 10%)

2) Oral ZDV+3TC to mother and ZDV+3TC 1 wk to infant (PETRA B, 12%)

3) SD NVP to mother and infant (HINET012, 12%)

4) IV ZDV +NVP to mother, ZDV 6 wk + SD NVP to infant

Infants born to women with no ARV

1) ZDV 6 wk (NY, 9.3%)

Consider elective C-section for those with VL >1000 near delivery (36 wk)

Long-term Effects of ARV Exposure In Utero

PACTG 219

Observational study to assess late effects of in utero

and neonatal exposure to antiretrovirals

Assessment of growth, cognitive/developmental funct

ion and quality of life until age 21 years

Culnane M, at al. JAMA 1999;281:151


234 uninfected children from ACTG 076122 in ZDV arm and 112 in placebo arm

As of Feb 1997, median age 4.2 y (3.2-5.6 y)

No deaths or malignancies

No difference in growth/developmentOne child in ZDV arm developed mild cardiomyopathy.

Culnane M, et al. JAMA 1999;281:151


Persistent mitochondrial dysfunction

NRTI and inhibition of DNA polymerase gamma

French National Epidemiology Network

8 children with mitochondrial dysfunction

4 exposed to ZDV/3TC, 4 to ZDV in utero

Clinical: none, seizure, cognitive impairment, myopathy

Lab: lactic acidosis, LFT, abnormal electron microsco

py and mitochondrial enzyme functions

2 died.

Blanche S, et al. Lancet 1999; 354: 1084


US cohorts

– >20,000 children born to HIV-infected mother

– 223 deaths reported

– None had evidences suggestive of mitochondrial d

iseases

– Ongoing assessments in other US cohorts

Perinatal Safety Review Working Group. JAIDS 2000;25:261


Incorporation of ZDV into DNA of infants exposed in utero

– DNA was extracted from cord blood PBMC in infants exposed to ZDV in utero.

– ZDV-DNA incorporation was found in 15 of 22 infants.

– Long-term consequences are unknown.

Olivero OA, et al. AIDS 1999; 13: 919

Impact of Modes of Delivery

French Perinatal Cohort

902 mothers received ZDV

Vaginal delivery 6.6%

Emergent C-section 11.4%

Elective C-section 0.8%

Mandelbrot L, at al. JAMA 1998;280:55

P = 0.002


California Cohort

Mode of deliveryNo. of

mothersTransmission

Bloodless C-section 53 5.7%

Vaginal or routineC-section

55 20.0%

P = 0.02

30-40% of the subjects received ZDV regimen.

Towers CV, et al. J Obstet Gynecol 1998;179:708


European Cohort

Mode of delivery % of infected infants

Vaginal delivery 10.2%

Elective C-section 2.4%

Emergency C-section 8.8%

European Mode of Delivery Collaboration. Lancet 1999;353:1035


European Cohort

% of infected infantsZDV useduring

pregnancy Vaginal delivery C-section

No 18.9% 6.8%

Yes 3.3% 2.1%

European Mode of Delivery Collaboration. Lancet 1999;353:1035

60-70% of mothers were on ZDV during pregnancy.


North American and European Cohort

withoutZDV

with ZDV

without electiveC-section

19.0% 7.3%

with elective C-section

10.4% 2.0%

International Perinatal HIV Group. N Engl J Med 1999;340:977

N = 8533

Impact of Maternal Viral Load

RT-PCR Assay

2.57.5 5.9

13.3

7.1

26.2

18.8

41.7

< 1730 1731-5660 5661-15,700 > 15,700

HIV-1 RNA (copies/ml) at entry

Tra

nsm

issi

on r

ate

(%)

ZDV

Placebo

ACTG 076

Sperling RS, et al. N Engl J Med 1996;335:1621


0

16.6

21.3

30.9

40.6

0

5

10

15

20

25

30

35

40

45

% t

ran

sm

iss

ion

<1000 1000-10000 10000-50000 50000-100000

>100000

Women Infants Transmission StudyN=552

Garcia PM. NEJM 1999;341:394

HIV RNA copies/ml


ACTG 076

ZDV treatment was associated with only a small reducti

on in HIV RNA (median 0.24 log).

Transmission occurred at all HIV RNA values,

independent of maternal CD4 levels.

ZDV is protective at all levels of maternal HIV RNA.


median viral loadstudy

N (no.infected)

% belowdetection

transmitting nontransmittingassociation

Dickover et al. 97(20) 4% 94.054 4,596 P < .001

Cao et al. 209(19) 8% 15,000 6,000 P = .003

Thea et al. 105(51) 30% 16,000 6,600 P < .01

Mayaux et al. 236(45) 15% 10,567 3,574 P < .01

Shaffer et al. 280(68) <1% 61,500 14,400 P < .0001

Effect of C-section on MTCT in women on HAART

Transmission rate compared for elective c-section vs all other modes of delivery.

-HIV RNA <1000 vs >1000 copies/ml-1 drug vs multiple drugs

ECS Other modes

HIV RNA >1000

Single drug 1.8% 7.4%

Multiple drugs 2.3% 1.8%

HIV RNA <1000

Single drug 1.8% 4.3%

Multiple drugs 0.8% 0.5%

Elective c-section may not provide additional benefit in women on HAART with HIV RNA <1000.

Shapiro D. CROI 2004

HIV Transmission via Breast FeedingMajor Issue in Developing World

Approximately 1/3 to ½ of HIV infections in children occur via breast feeding.

Alternatives to breast feeding are often unaffordable and sometimes unsafe, due to lack of clean water.

Impact of BreastfeedingMalawi (1994-97)

0.7

0.6

0.3

0.2

0

0.2

0.4

0.6

0.8

1-5 mo 6-11 mo 12-17 mo 18-23 mo

Age Group While Breastfeeding

HIV

Inf

ecti

on R

ate

per

Per

son-

Mon

th (

%)

672 infants with negative HIV PCR at the first postnatal visit (median 1.7 mo)

Miotti PG, et al. JAMA 1999; 282: 744

Impact of Infant FeedingKenya (1992-98)

A randomized trial

197 in breastfeeding arm

204 in formula feeding arm

Of note: less compliant in the formula feeding arm (70% vs 96%)

Nduati R, et al. JAMA 2000; 283: 1167

Impact of Infant FeedingA randomized trial in Kenya, 1992-98

197 in breast feeding arm204 in formula feeding arm

Of note: less compliant in the formula feeding arm (70% vs 96%)

Cumulative infection rateInfant age

Breastfeeder Formulafeeder

Difference incumulative rate

P value

Birth 7.0 3.1 3.9 0.35

6 weeks 19.9 9.7 10.2 0.005

14 weeks 24.5 13.2 11.3 0.007

6 months 28.0 15.9 12.1 0.009

12 months 32.3 18.2 14.1 0.003

24 months 36.7 20.5 16.2 0.001

Nduati R, et al. JAMA 2000; 283: 1167

Impact of BreastfeedingSouth Africa (1995-98)

A study assessing feeding practice during the first 3 months of life

All women were counseled of transmission risk by breastfeeding, and

informed choice was made.

156 never breastfed

103 exclusively breastfed

288 received mixed feeding

Coutsoudis A, et al, Lancet 1999; 354: 471

Proportion of HIV Infection by 3 months (%)

6.4 6.8 5.2

14.8

8.7

14.2

18.8

14.6

24.1

Never breastfed Exclusivelybreastfed

Breastfed plusother food

1 day 1 month 3 months

Coutsoudis A, et al, Lancet 1999; 354: 471

Breast milk infectivityKenya

Measure of breast milk infectivity

Probability of breast milk transmission of HIV-1

Prenatal maternal plasma HIV RNA Maternal CD4 count

43120 < 43120 < 400 400

Per liter ingested .0010* .0003 .0010* .0004

Per day of exposure .0004* .0001 .0004* .0002

Randomized trial of breast feeding vs formula feeding

Infants with negative HIV PCR at 6 wk of age were followed.

Probability of breast milk transmission was 0.0003 per day of breast feeding.

Similar to probability of heterosexual transmission per unprotected sex act

Richardson BA. J Infect Dis 2003;187:736

Breast Milk Transmission

Median HIV RNA in colustrum/early milk is higher than that in

breast milk collected 14 days after delivery.

High maternal plasma HIV RNA and low maternal CD4 count

are associated with higher breast milk HIV RNA.

Breast feeding mothers who transmit virus have higher breast

milk HIV RNA.

Strategies to lower viral load and improve CD4 count could

reduce breast milk transmission (ie, HIV therapy, multivitamin)

Mothers with advanced disease should avoid breast feeding.

Rousseau CM. J Infect Dis 2003;187:741

Studies to Prevent Postnatal Transmission (breast feeding)

ARV to women during breast feeding

– Optimal duration of treatment

– Combination therapy

ARV to infants during breast feeding

– Duration and frequency of infant treatment

– Combination therapy

Exclusive breast feeding

– Early weaning

Safer breast feeding: heated breast milk

SIMBA Study (Rwanda & Uganda)

Neonatal prophylaxis against breast milk transmission

Mothers received ZDV+ddI from 36 wk GA till 1 wk postpartum.

Infants were randomized to receive NVP vs 3TC for up to 7 months during breastfeeding

Transmission rate at 4 weeks = 6.9% and at 6 months = 7.8% in both arms

Risk of postnatal transmission between week 4 and month 6 was 1% (compared with 4.2% in historical data).

Vyankandondera J. IAS Conference, Paris 2003

Viral Resistance

ACTG 076

– 1 in 39 (2.6%) women developed mutation at codo

n 70 during study.

– None developed mutation at codon 215.

– 1 of 2 women with K70R mutation (1 with the muta

nt prior to entry) transmitted both wild type and res

istant strain to infant.

Eastman PS, et al. J Infect Dis 1998; 177:557

Viral Resistance

Women and Infants Transmission Study Group (USA)

Gene sequencing of reverse transcriptase region of 1

42 isolates from pregnant women

24% of isolates had ZDV resistance mutation

Using the multivariate analysis, those with ZDV resist

ance mutation had a 5-fold risk of perinatal transmissi

on (adjusted OR 5.2, 95% CI 1.4-18.9, P=0.01)

Welles SL, et al. AIDS 2000; 14: 263

Viral Resistance

HIVNET006

– Plasma were collected at 6 wk after nevirapine.

– 3 of 14 women developed K103N mutation (1/3 tra

nsmitters and 2/11 non-transmitters).

– 2 of these 3 had a K/N mixture, suggesting recent

selection of the resistant variant.

– 2 women had pre-dose samples, and none had K1

03N mutation.

Becker-Pergola G, et al. CROI 2000

Rates of NVP Resistance in Women after pMTCT Treatment

Study Drug % resistance Sampling Mutation frequency

HIVNET006 SD NVP 20 6 wk pp K103N (3/3)

HIVNET012 SD NVP 25 6-8 wk pp K103N (19/21)

Y181C (5/21)

PACTG316 ARV + SD NVP 15 6 wk pp K103N (9/14)

Y181C (3/14)

HIVNET023 SD NVP 28 8 wk pp K103N (8/10)

Y181C (2/10)

SAINT 2 doses NVP 67 4-6 wk pp K103N (62%)

Y181C (45%)

PHPT2 ZDV + SD NVP 20 12 d pp K103N (21%)

Y181C (2%)

NVP resistance became undetectable 6-12 months.

Rates of NVP Resistance in Infants after pMTCT Treatment

Study Drug % resistance Sampling Mutation frequency

HIVNET012 2 mg/kg SD NVP

46 6-8 wk pp Y181C (10/11)

K103N (2/11)

SAINT 6mg/kg SD NVP

53 4-6 wk pp Y181C (52%)

K103N (24%)

Intrapartum NVP and subsequent response to NVP-based therapy in mothers

000

333625

68

52

38

0

20

40

60

80

% HIV

RNA

<50 c

opies

/ml

Baseline 3 months 6 months

No IP NVPIP NVP, no NVP resistanceIP NVP, NVP resistance

269 Thai women with CD4 <250 who received AZT± NVP intrapartum

HIV genotyping at 10 days postpartum

32% of “NVP” group had NVP resistance (K103N)

Treated with D4T, 3TC, NVP Decreased virologic response to

treatment among women who received intrapartum NVP

No difference in clinical or immunologic outcomes

Jourdain G. NEJM 2004;351:229

Reduction of NVP resistance in mothers, South Africa

Aim to reduce NVP resistance in mothers receiving NVP for PMTCT Mothers and infants were randomized to:

– SD NVP

– SD NVP + combivir (AZT/3TC) for 4 days

– SD NVP + combivir (AZT/3TC) for 7 days

N=61 SD NVP Combivir 4 d Combivir 7 d

% maternal NVP resistance at 2 and/or 6 wk postpartum

53% 5% 13%

McIntyre J. XV International AIDS Conference, Bangkok 2004, LbOrB09

Combination Antiretroviral Therapy

WITS: Trends in transmission rate and maternal antiretroviral therapy: 1990-1999

Cooper ER. JAIDS 2002;29:484

Missed Opportunities for Perinatal HIV Prevention

CDC Pediatric Spectrum of Disease Project 4,755 HIV-exposed infants in 6 US sites in 1996-2000 92% had prenatal care, 92% of which had HIV testing before delivery The use of ZDV (± other drugs) increased from 78% to 87%

Intervention Transmission risk

Prenatal ZDV+ARV + intrapartum & neonatal ZDV 3%

Prenatal ZDV+ intrapartum & neonatal ZDV 6%

Intrapartum & neonatal ZDV 8%

Neonatal ZDV (given within 24 h) 14%

None 20%

Peters V. Pediatrics 2003;111:1186

Missed Opportunities for Perinatal HIV Prevention

20% of the cohort had at least 1 missed opportunity for perinatal

HIV prevention (prenatal care, prenatal HIV testing, prenatal

ARV)

Peters V. Pediatrics 2003;111:1186

Infected infants (328)

Uninfected infants (3258)

No prenatal care 18% 8%

Prenatal care but no prenatal HIV testing

29% 4%

Prenatal care, prenatal HIV test, but no prenatal ARV

9% 4%

Any missed opportunity 56% 16%

Missed Opportunities and Barriers for Perinatal HIV Prevention

US Africa

Receive prenatal care 92% 26%-95%

Delivery in health care facilities

99% 5%-68%

Receive services & prophylaxis for PMTCT

90-92% 3-8%

Elective C-section in HIV+ women

44% ?

Prevalence of breast feeding

27%

No social pressure to breastfeeding

95%

Socioeconomic pressure to

breastfeeding

www.usaids.govGlobal HIV Prevention Working Group. UNAIDS 2003

Prevention Strategies

Prenatal

– Rapid scale-up of pMTCT programs to include counseling, testi

ng and full options of intervention

– “Opt-out strategy” HIV testing (universal testing with rights to

refusal)

>95% of pregnant women agree to testing

– Access to antiretroviral drugs: HAART for pregnant women

meeting treatment criteria or per country’s guidelines


Intrapartum

– Rapid HIV testing if maternal HIV status is unknown

(sensitivity 100%, specificity 99.9%, turnaround time 66 min)

– Proper obstetric care

– Elective cesarean delivery, especially those with plasma HIV >1,0

00 copies/ml

– Antiretroviral drugs: variety of regimens based on local capacity

and scientific merit

MIRIAD Study Group. JAMA 2004;292:219


Postpartum

– Avoid breast feeding or wean early

– Prompt antiretroviral drugs to infants after birth

– Promotion of maternal and child health

– Infant’s follow-up

PCR during early infancy

HIV antibody

– Care of women, her child and her partner

Care of Infants Born to HIV-Infected Women

Infant’s age

Birth 4 wk 6 wk 2 mo 3 mo 4 mo

Assess risk for other infections

X

ARV prophylaxis

CBC X X X

HIV DNA PCR

(RNA PCR, HIV culture)X

Prophylaxis for Pneumocystis jiroveci

HIV antibody at 12-18 moRoutine well-child vaccination should be followed. AAP. Pediatrics 2004;114:497

Barriers to Prevention of Perinatal HIV Transmission

Lack of infrastructure to promote maternal and child health

Limited HIV counseling and testing services

Stigmatization and discrimination: community, health personnel

Domestic violence following disclosure to the partner

Cost of antiretroviral drugs and infant formula

Lack of social support for those choosing alternatives to

breastfeeding (stigma and culture)

Minimal interest among policy makers and country leaders

Limited support from developed countries

Future Research Related to PMTCT

Intervention & treatment strategies

– Vaginal microbicide

– new antiretroviral drugs: tenofovir

– preventive HIV vaccines

– Safe infant feeding

– Long-term safety of combination ARV therapy in

pregnant women and infants


– Control of NVP resistance: addition of ARV to NVP

– Treatment of mothers (and infected infants) after

NVP prophylaxis

– Pediatric and neonatal data on antiretroviral drugs

– Family-centered care in resource-limited setting


Social science

– Counseling and testing tools applicable to even the most

resource-poor countries

– Risk-behavior modification or interventions with increasing access

to counseling, testing and care in developing countries

– Risk-behavior modification in youth in developing countries

– Family planning in HIV-affected couples

– How the society can best assist orphans into adulthood

Conclusion

Known risk factors for perinatal HIV transmission

There are many interventions to reduce perinatal HIV tran

smission. No “One size fits all”, but Access for All

Every effort must be made to prevent one child from HIV.

It is never too late to initiate prophylaxis.

Perhaps the best strategy of all to prevent vertical transmission is to

protect women from becoming infected.

Public education

Pre-marital HIV counseling and testing

Faithfulness of her partner

Empower girls and women to be able to take care of herself and take

control of her life

By compassion we make others' misery our own,

And so, by relieving them, we relieve ourselves also.

--Thomas Browne

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