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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%
Transmissionreduction
50.1%
Shaffer N, et al. Lancet 1999;353:773
P = 0.006
RETRO-CICote 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 weeksMedian duration 27 days
Placebo 21.7% 24.9%
ZDV 12.2% 15.7%
Transmissionreduction
44% 37%
4 weeks 3 months
Witkor SZ, at al. Lancet 1999;353:781
P < 0.05
DITRAMECote 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 weeksMedian duration 21 days
Placebo 21.8% 27.5%
ZDV 15.1% 18.0%
Transmissionreduction
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
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 a
fter delivery
2 infants exposed to ZDV+3TC developed mit
ochondrial myopathy
Blanche S, et al. 6th CROI 1999
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
Predominantly breastfeeding
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
Long-term Effects of ARV Exposure In Utero
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
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 microsco
py 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 d
iseases
– 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 6.6%
Emergent C-section 11.4%
Elective C-section 0.8%
Mandelbrot L, at al. JAMA 1998;280:55
P = 0.002
Impact of Modes of Delivery
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
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
% 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.
Impact of Modes of Delivery
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
Impact of Maternal Viral Load
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
Impact of Maternal Viral Load
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.
Impact of Maternal Viral Load
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
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 >1,0
00 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 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
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 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