Transcript VERTICAL TRANSMISSION OF HIV - Children's Hospital of Michigan

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
Children (<15 years) estimated to be living
with HIV/AIDS as of end 2003
North America
8 000 – 12 000
Caribbean
19 000 – 31 000
Latin America
37 000 – 50 000
Western Europe
5 000 – 7 000
Eastern Europe &
Central Asia
9 000 – 15 000
North Africa
& Middle East
31 000 – 49 000
Sub-Saharan Africa
2.0 – 2.2 million
East Asia & Pacific
6 000 – 12 000
South
& South-East Asia
110 000 – 190 000
Australia
& New Zealand
< 200
Total: 2.1 – 2.9 million
00002-E-1 – 1 December 2003
Perinatally Acquired AIDS Cases by Quarter-Year
of Diagnosis, 1985-2000, United States
300
Number of Cases
250
200
150
100
s
a
fC
ro
e
b
m
u
N
50
0
1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000
Quarter-Year of Diagnosis
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
Antenatal HIV Prevalence in Women
in Developing World
Rwanda
Guyana
Haiti
Nigeria
Uganda
Tanzania
Kenya
Mozambique
Cote D'Iviore
Ethiopia
Zambia
Namibia
South Africa
Botswana
0
5
10
15
20
Percentage
25
30
35
40
HIV Prevalence trends among antenatal clinic
attendees in South Africa: 1990-2002
30
24.5 24.8
25
22.8 22.4
20
%
26.5
17
14.2
15
10.4
10
7.6
5
0.7
1.7 2.2
1990
1992
4
0
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
N = 1632
RR
P value
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
Cervicovaginal infection
Mandelbrot, et al. Am J Ob Gyn 1996
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
intrapartum
postnatal

In utero infection
30%

Intrapartum infection
70%
Timing of Transmission
French cohort: Markov model
Proportion of infants infected
70
60
50
40
30
20
10
0
1st & 2nd trimester
8 weeks
4 weeks
Delivery
Rouzioux C, et al. Am J Epidemiol 1995; 142: 1330
Evolution of Clinical Trials
&
Advance in Prevention of
Perinatal HIV Transmission
PACTG 076
USA/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 weeks
Median duration 11 weeks
Placebo
22.6%
ZDV
7.6%
Transmission
reduction
66.4%
P < 0.001
Sperling RS, et al. N Engl J Med 1996;335:1621
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 weeks
Median duration 25 days
Placebo
18.9%
ZDV
9.4%
Transmission
reduction
50.1%
P = 0.006
Shaffer N, et al. Lancet 1999;353:773
RETRO-CI
Cote d’Ivoire
 Placebo
controlled
 Antepartum:
ZDV 300 mg twice daily
 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 weeks
Median duration 27 days
4 weeks
3 months
Placebo
21.7%
24.9%
ZDV
12.2%
15.7%
Transmission
reduction
44%
37%
P < 0.05
Witkor SZ, at al. Lancet 1999;353:781
DITRAME
Cote d’Ivoire/Burkina Faso

Placebo controlled

Antepartum: ZDV 300 mg twice daily

Intrapartum: single dose of 600 mg at labor

Postpartum: ZDV 300 mg twice daily for 7 d
to mothers

Predominantly breastfeeding
Dabis F, et al. Lancet 1999;353:786
DITRAME
AP
IP
PP
Began at 36-38 weeks
Median duration 21 days
45 days
6 months
Placebo
21.8%
27.5%
ZDV
15.1%
18.0%
Transmission
reduction
34%
38%
P < 0.05
Dabis F, et al. Lancet 1999;353:786
Short-Course ZDV Trials
AP
IP
IP AZV was given orally
Began at 36 weeks No neonatal ZDV component
30
27.5
50%
% transmission
25
20
24.9
37%
38%
18.9
18
15.7
15
9.4
10
5
0
Thailand
Placebo
Cote d’Ivoire
Cote d’Ivoire/Burkina
Faso
ZDV
Breastfeeding
New York State Study

Data from PCR testing service of NY State
Department of Health

Partial or full ACTG 076 protocol
Wade NA, et al. N Engl J Med 1998;339:1409
New York State Study
Transmission rate
AP
IP
NN
6.1%
10%
within 48 hrs
9.3%
after 72 hrs
18.4%
NONE
26.6%
Wade NA, et al. N Engl J Med 1998;339:1409
Perinatal HIV Prevention Trial
Harvard & Northern Thailand

Define optimal duration of prophylaxis

antepartum at 28 wk + neonatal for 6 wk (LL)

antepartum at 28 wk + neonatal for 3 d

antepartum at 35 wk + neonatal for 6 wk (SL)

antepartum at 35 wk + neonatal for 3 d

Non-breastfeeding
(LS)
(SS)
Lallemant M, et al. N Engl J Med 2000;343:982
Perinatal HIV Prevention Trial
N = 1437
AP
IP
NN
28 wk
28 wk
6 wk
35 wk
6 wk
3d
6.5 (4.1-8.9)*
4.7 (2.4-7.0)*
3d
35 wk
transmission rate
8.6 (5.6-11.6)*
10.5 (6.4-14.4)**
*P = NS
**early termination
Lallemant M, et al. N Engl J Med 2000;343:982
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 donation of ZDV and offering the medication at
no cost to HIV-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
technique.
Results

From June 1996 - August 1999, ZDV had been
provided to 2,891 pregnant woman-infant pairs from
81 hospitals in 40 provinces throughout 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
Antepartum
ZDV
No. of
women
No. of infected
infants
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
Study
Transmission rate
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%
HIV-NET 012
Uganda 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 012
Uganda and US NIH
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.
*P <0.01
Guay LA. Lancet 1999; 354: 795
Jackson JB. Lancet 2003; 362: 859
Cost-Effectiveness in Developing World
Regimen
Cost per
treatment
Estimated
transmission
Cost/case
prevented
Formula only
195
18.9%
1759
Formula+long AZT
+neonatal AZT (076)
Formula+short AZT+C/S
399
6.0%
1662
368
3.0%
1362
Formula+short AZT
260
9.4%
1260
Formula+short AZT
+neonatal AZT
Nevirapine+BF
272
6.4%
1154
4
13.1%
298
in US dollars
Teeraratkul A, et al. 5th Congress on AIDS in Asia and Pacific, 1999
Marseille E, et al. Lancet 1999; 354: 803
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
French Perinatal Study
AP
IP
NN
Transmission rate
ZDV + 3TC
2.6% (5/194)
ZDV
6.5% (53/810)
Blanche S, et al. 6th CROI 1999
French Perinatal Study

M184V mutation occurred in 40% of women
after delivery

2 infants exposed to ZDV+3TC developed
mitochondrial myopathy
Blanche S, et al. 6th CROI 1999
PETRA Study
Tanzania/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

Predominantly breastfeeding
Petra study team. Lancet 2002;359:1178
PETRA Study
N=1797
AP
Arm A
IP
Transmission rate
Wk 6 Mo 18
NN
5.7%
15%
Arm B
8.9%
18%
Arm C
14.2%
20%
Arm D
15.3%
22%
At 36 weeks
1 week
Petra study team. Lancet 2002;359:1178
SAINT Study
South Africa

ZDV+3TC vs nevirapine (n=1319)
Transmission at 8 wk
Including (excluding) intrauterine infection
ZDV + 3TC
IP
(PETRA B)
NVP
IP
PP
NN
1 week
PP
NN
single dose
9.3% (3.6%)
12.3% (5.7%)
P = 0.1
Breastfeeding 40%
PP maternal drug to provide protection against early breast feeding transmission
Moodley D. J Infect Dis 2003;187:725
ZDV+NVP Trial, Malawi
IP NN
NVP
NVP + ZDV or 7 days
HIV+ at birth
(intrauterine)
(intrapartum/postpartum)
Overall HIV
infection rate
by 6-8 wk
HIV+ at 6-8 wk but
neg at birth
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
Combination of ZDV and single-dose NVP
Mother
Infant
Transmission
ZDV
NVP/NVP
1.9% (12/627)
ZDV
NVP/PLC
2.8% (17/611)
ZDV
PLC/PLC
6.3% (22/348)
28 wk GA
1 wk
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.
Lallemant M. NEJM 2004;351:217
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
% transmission
25

Mother in advanced labour and
did not receive intrapartum NVP

Infants randomized
20.9
20
– NVP single dose
15.3
15
10
– NVP single dose + AZT 4
mg/kg bid for 7 days
12.1
7.7

Figure shows net HIV status at 68 wk of age (green) and when in
utero infection was excluded (red)

36% reduction in transmission
5
0
NVP (421) NVP+AZT
(444)
Combination of AZT/NVP is more effective in infants when mothers
receive no ARV during pregnancy and delivery Taha TE. Lancet 2003;362:1171
International perinatal HIV studies
Transmission rate
7.6
FF
9.5
6.5
4.7
1.9
ACTG 076
Thai/CDC
PHPT LL
PHPT LS
PHPT
15
17
8
12
19
12
10
16
15
Retro-CI
DITRAME
PETRA-A
PETRA-B
PETRA-C
HIVNET012
SAINT
MALAWI
NVAZ
AZT
AZT+3TC
BF
NVP
WHO Guidelines 2004
Women with indications ZDV (D4T) + 3TC + NVP
for starting ARV
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 1) SD NVP to mother and infant (HIVNET012, 12%)
prior ARV
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 2004
Women 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
function and quality of life until age 21 years
Culnane M, at al. JAMA 1999;281:151
Long-term Effects of ARV Exposure In Utero
234 uninfected children from ACTG 076
122 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/development
One child in ZDV arm developed mild cardiomyopathy.
Culnane M, et al. JAMA 1999;281:151
Long-term Effects of ARV Exposure In Utero
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
microscopy and mitochondrial enzyme functions

2 died.
Blanche S, et al. Lancet 1999; 354: 1084
Long-term Effects of ARV Exposure In Utero

US cohorts
– >20,000 children born to HIV-infected mother
– 223 deaths reported
– None had evidences suggestive of mitochondrial
diseases
– Ongoing assessments in other US cohorts
Perinatal Safety Review Working Group. JAIDS 2000;25:261
Long-term Effects of ARV Exposure In Utero

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
Emergent C-section
Elective C-section
6.6%
11.4%
0.8%
P = 0.002
Mandelbrot L, at al. JAMA 1998;280:55
Impact of Modes of Delivery

California Cohort
Mode of delivery
No. of
Transmission
mothers
Bloodless C-section
53
5.7%
Vaginal or routine
C-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
Impact of Modes of Delivery

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
Impact of Modes of Delivery

European Cohort
ZDV use
during
pregnancy
Vaginal delivery
C-section
No
18.9%
6.8%
Yes
3.3%
2.1%
% of infected infants
60-70% of mothers were on ZDV during pregnancy.
European Mode of Delivery Collaboration. Lancet 1999;353:1035
Impact of Modes of Delivery

North American and European Cohort
without
ZDV
with ZDV
without elective
C-section
19.0%
7.3%
with elective Csection
10.4%
2.0%
N = 8533
International Perinatal HIV Group. N Engl J Med 1999;340:977
Impact of Maternal Viral Load
ACTG 076
RT-PCR Assay
Transmission rate (%)
41.7
26.2
18.8
13.3
7.1
7.5
ZDV
Placebo
5.9
2.5
< 1730
1731-5660
5661-15,700
> 15,700
HIV-1 RNA (copies/ml) at entry
Sperling RS, et al. N Engl J Med 1996;335:1621
Impact of Maternal Viral Load
Women Infants Transmission Study
N=552
40.6
45
% transmission
40
30.9
35
30
21.3
25
16.6
20
15
10
5
0
0
<1000
1000-10000 10000-50000
50000100000
>100000
HIV RNA copies/ml
Garcia PM. NEJM 1999;341:394
Impact of Maternal Viral Load
ACTG 076

ZDV treatment was associated with only a small
reduction 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.
Impact of Maternal Viral Load
study
N (no. % below
infected) detection
median viral load
association
transmitting
nontransmitting
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
Single drug
1.8%
7.4%
Multiple drugs
2.3%
1.8%
Single drug
1.8%
4.3%
Multiple drugs
0.8%
0.5%
HIV RNA >1000
HIV RNA <1000
Elective c-section may not
provide additional benefit
in women on HAART with
HIV RNA <1000.
Shapiro D. CROI 2004
HIV Transmission via Breast Feeding
Major 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 Breastfeeding
HIV Infection Rate per PersonMonth (%)
Malawi (1994-97)
0.8
0.7
0.6
0.6
0.4
0.3
0.2
0.2
0
1-5 mo
6-11 mo
12-17 mo
18-23 mo
Age Group While Breastfeeding
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 Feeding
Kenya (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 Feeding
A randomized trial in Kenya, 1992-98
197 in breast feeding arm
204 in formula feeding arm
Of note: less compliant in the formula feeding arm (70% vs 96%)
Infant age
Cumulative infection rate
Difference in
cumulative rate
P value
Breastfeeder
Formula
feeder
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 Breastfeeding
South 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
(%)
24.1
18.8
14.8
14.6
6.8
6.4
Never breastfed
1 day
14.2
8.7
5.2
Exclusively
breastfed
1 month
Breastfed plus
other food
3 months
Coutsoudis A, et al, Lancet 1999; 354: 471
Breast milk infectivity
Kenya
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 of HIV-1
Measure of breast
milk infectivity
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
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
codon 70 during study.
– None developed mutation at codon 215.
– 1 of 2 women with K70R mutation (1 with the
mutant prior to entry) transmitted both wild type
and resistant 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
142 isolates from pregnant women

24% of isolates had ZDV resistance mutation

Using the multivariate analysis, those with ZDV
resistance mutation had a 5-fold risk of perinatal
transmission (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
transmitters 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
K103N mutation.
Becker-Pergola G, et al. CROI 2000
Rates of NVP Resistance in Women after pMTCT Treatment
Study
Drug
% resistance
Sampling
HIVNET006 SD NVP
20
6 wk pp
HIVNET012 SD NVP
25
6-8 wk pp
K103N (19/21)
Y181C (5/21)
PACTG316
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%)
ARV + SD NVP
NVP resistance became undetectable 6-12 months.
Mutation
frequency
K103N (3/3)
Rates of NVP Resistance in Infants after pMTCT
Treatment
Study
Drug
% resistance
Sampling
HIVNET012 2 mg/kg
SD NVP
46
6-8 wk pp
Y181C (10/11)
K103N (2/11)
SAINT
53
4-6 wk pp
Y181C (52%)
K103N (24%)
6mg/kg
SD NVP
Mutation
frequency
Intrapartum NVP and subsequent response to
NVP-based therapy in mothers
% HIV RNA <50 copies/ml
80

68
60

52
33 36
40
38
25

20
0

00 0
Baseline 3 months 6 months
No IP NVP
IP NVP, no NVP resistance
IP 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
% maternal NVP
resistance at 2 and/or 6
wk postpartum
SD NVP
Combivir 4 d
Combivir 7 d
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)
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%
Peters V. Pediatrics 2003;111:1186
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.gov
Global HIV Prevention Working Group. UNAIDS 2003
Prevention Strategies

Prenatal
– Rapid scale-up of pMTCT programs to include counseling,
testing 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
Prevention Strategies

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 >1,000 copies/ml
– Antiretroviral drugs: variety of regimens based on local
capacity and scientific merit
MIRIAD Study Group. JAMA 2004;292:219
Prevention Strategies

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
 HIV
during early infancy
antibody
– Care of women, her child and her partner
Care of Infants Born to HIV-Infected Women
Infant’s age
Birth
Assess risk for other
infections
4 wk
6 wk 2 mo 3 mo 4 mo
X
ARV prophylaxis
CBC
X
HIV DNA PCR
(RNA PCR, HIV culture)
X
X
X
Prophylaxis for
Pneumocystis jiroveci
HIV antibody at 12-18 mo
Routine 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
Future Research Related to PMTCT
– 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
Future Research Related to PMTCT
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
transmission. 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