March 12, 2014 - Maternal Fetal Transmission

Report
Preventing Mother to Child HIV-1
Transmission (PMTCT)
Karin Nielsen, MD, MPH
Clinical Professor
Pediatric Infectious Diseases
David Geffen UCLA School of Medicine
Epidemiology
Perinatal HIV-1 Infection
The majority of pediatric HIV infection occurs from
maternal-fetal transmission
Transmission rates vary by population and
geographic area 13% Europe
40% Africa
25%-30% USA overall
without treatment
Heterosexual transmission to women is now the most
common route
 As number of women HIV-infected increases perinatal
infection will also increase

Epidemiology Peds HIV
Global prevalence among pregnant
women:
– N America: 0.02 to 2%
– S America: 0.5 to 5%
– Sub-Saharan Africa: 20 to 45%
– India: 1%
ID: E1
UNAIDS/WHO global view of HIV infection 2002
40 million individuals living with HIV
Cumulative infection: 60 million
1300%
20%
20%
160%
100%
60%
40%
30%
20%
Increases in HIV infection 1996-2001
Courtesy of UNAIDS. Sourced from http://www.phrusa.org/campaigns/aids/maps.html
HIV prevalence among pregnant women
in South Africa, 1990 to 1999
HIV prevalence (%)
25
22.8
22.4
98
99
20
17
14.2
15
10.4
10
7.6
5
4
1.7
2.1
91
92
0.7
0
90
93
94
95
96
Source: Department of Health, South Africa
97
Estimated AIDS Prevalence among Women in the
United States and Perinatally Acquired AIDS Cases by
Quarter-Year , 1985 - 1999
300
Heterosexual contact
IDU
140
Pediatric cases
250
120
200
100
80
150
60
100
40
50
20
0
0
85
86
87
88
89
90
91
92
93
94
Quarter-Year
95
96
97
98
99
Number of Cases
Number of Cases (thousands)
160
Pediatric HIV-infection Facts
90% of HIV infections in women result from heterosexual
transmission of HIV.
In the absence of interventions, rates of infection in children
parallel rates of infection in women.
1 of 3 to 1 of 4 children born to HIV-infected women are
infected themselves in the absence of maternal treatment.
2000 HIV-1 infected children are born daily.
90% of infections in sub-Saharan Africa.
Overall MTCT rates are about 15%
– 30% women in Southern Africa.
– 4% in West Africa.
Worldwide < 10% of HIV-infected women benefit from any
intervention.
An additional 300,000 infants acquire HIV via breastfeeding
annually.
Children born to HIV-infected women have 3 x risk of death
regardless of HIV-infection status.
Pathogenesis
Factors Influencing Perinatal
Transmission of HIV
Viral
• Virus load (cell ass./cell
free)
• Phenotype (SI, tropism)
• Genotype
Immune
• Decreased CD4 count
• Humoral (NAb, ADCC/
gp120 V3 loop Ab, other)
• Cell mediated (CTL, CD8
supression)
• Mucosal immunity
Maternal
–
–
–
–
–
–
–
Clinical advanced disease
Primary HIV infection
Co-infection
Twins-first born
Obstetrical Events
Timing of Infection
Drug use
Fetal/Placental
– Prematurity
– Chorioamnionitis
– Infant host-immune
response
Perinatal HIV Infection
Timing of Infection
– In utero
– Intrapartum
– Post-partum (breastfeeding)
HIV infected infants:
– 30 - 50% have virus detectable at birth.
(Presumed in utero infection)
– 50 - 70% have no virus detectable at birth and
develop positive virologic results after one
week of age. (Presumed intrapartum
infection)
In Utero Transmission




Maternal virus load cell-associated, cell-free
Neutralizing antibody
CD4 count / cell-mediated immunity
Virus phenotype / tropism




Placental breaks
Maternal-fetal transfusion
HIV or other infection of placenta
Fetal loss
Intrapartum Transmission

Maternal virus load
- blood (cell-associated, cell-free)
- cervicovaginal secretions
 Duration of ruptured membranes
 Infant exposure to blood
- mucous membranes, swallowing
 Delivery mode-vaginal vs. c-section
 Trauma
 Maternal-fetal transfusion
 Placenta - abruption
- chorioamnionitis
- co-infections
Breastfeeding Transmission
Breakdown of skin
barrier
Intercurrent infections
(mastitis)
Maternal plasma/milk
viral load
Primary infection in
mother
Mixed feedings
Early introduction of
solids
Duration of
breastfeeding
Criteria for determing timing of HIV infection
in the infant
In utero infection:
– HIV positive peripheral blood lymphocyte
culture or positive DNA or RNA HIV PCR from
peripheral blood obtained from the infant
within the first 48 hours of life (in the absence
of breastfeeding).
Intrapartum infection:
– Negative virologic assays in the first 48 hours
of life followed by positive assays after 7 days
of life (with persistence of positivity thereafter)
in nonbreastfed infants.
Natural History of HIV in Children

Rapid progressors:
• Develop AIDS with rapid loss of CD4 cells within
first 2 years of life (20%)

Intermediate progressors:
• Develop AIDS by 7 – 8 years of age with gradual
loss of CD4 cells (60%)

Slow progressors:
• Minimal to no symptoms of HIV disease with a
normal to minimally decreased CD4 count at
age 8 years (20%)
Pediatric Long Term Survivors in the U.S. 1997
(Nielsen, et al Pediatrics)
Natural history of HIV-1 infection in
children, Africa 2005
Cumulative mortality in the absence of treatment (n >
3000):
60% Dead
by 5 years
of age!
18
Newell et al
Predicted loss in life expectancy
due to HIV/AIDS in children born in 2000
Predicted life expectancy
Loss in life expectancy due to HIV/AIDS
Botswana
Zimbabwe
South Africa
Kenya
Zambia
Côte d'Ivoire
Rwanda
Mozambique
Haiti
Cambodia
0
10
20
30
40
Life expectancy at birth (years)
Source: U.S. Census Bureau, 2000
50
60
70
Early diagnosis of HIV infection
All HIV- exposed babies are HIV EIA +
Early diagnosis is based on a + virologic
assay from the infant’s peripheral blood at
2 different timepoints:
– HIV DNA PCR (birth, 1 mo, 4 mo)
– HIV RNA PCR (same time periods)
– HIV PBL coculture (same time points)
Maternal virus load and risk of perinatal
transmission
HIV virus load is critical but is not the only risk
factor.
The higher the virus load the higher the risk of
transmission.
Women with a very high HIV virus burden have
a higher chance of in utero transmission of HIV.
– HIV RNA : > 50,000 copies/ ml; risk > 50%.
– In many studies (PACTG 185) there is no HIV
perinatal transmission in women with an
undetectable HIV virus load.
Maternal Plasma HIV-1 RNA Levels at Delivery and
Antiretroviral use during Pregnancy:
Impact on Perinatal Transmission
51.4
27.8
Rates per 100
60
17.2
11.3
29.4
50
40
19
30
20
0
7.2
4.5
0
12.5
0
14.7
6.1
2.6
1.8
0
>100000
0
2.4
>3000-40000
0
1.7
Undetectable
(<400)
Maternal Plasma HIV-1 RNA
ZDV Mono (<4/94)
ZDV Mono (>4/94)
0
Multi-ART
10
0
None
0
20.4
20
HAART
Cervical/Vaginal Secretions & HIV
30% of HIV+ pregnant women may have
detectable virus in secretions by PCR and/or
culture.
Infants may have HIV detected in gastric
aspirates - may be risk factor for intrapartum
transmission (Nielsen et al 96)
Levels of maternal plasma RNA may not
correlate with cervical/vaginal shedding
(Nielsen et al., ‘96)
Interruption of perinatal
HIV transmission
Intrauterine
vaccines
antiretroviral therapy
immune modulation
3
Gestation
Intrapartum
vaccines
antiretroviral therapy
immune modulation
C-section
vaginal washing
Post-partum
breast feeding
6 months
Labor and
Delivery
2 years
Role of neutralizing antibodies in
perinatal HIV transmission
Neutralizing antibodies against autologous
viruses are specific and important in prevention
of HIV vertical transmission.
Absence of neutralizing antibodies is more
common in women who transmit their infection in
utero; these women also tend to have a higher
HIV virus load.
The vast majority of virus isolates obtained from
newborns resist neutralization by maternal
antibodies suggesting that what occurs is
transmission of escape variants.
Virus phenotype and perinatal HIV
transmission
Most transmitted viruses have the R5 phenotype
(non-syncytia inducing, macrophage tropic, use
the R5 co-receptor for cell entry).
Even women who have viruses with X4
phenotype (syncytia inducing, T cell tropic, use
the X4 co-receptor for cell entry) tend to transmit
NSI viral populations to their infants.
The rare cases of vertical transmission of X4
tropic virus are associated with very rapid
disease progression in the infant.
Virus genotype and perinatal HIV
transmission
Through biologic and molecular
characterization of HIV isolates (nucleotide
sequencing of viral genes) studies have
demonstrated that:
– Usually only one virus clone is transmitted from the
mother to the newborn.
– The transmitted virus is generally homogeneous.
– This is similar to primary infection in adults where
only one clone is preferentially transmitted.
Potential Approaches for Prevention of
HIV-1 Transmission
Antiretrovirals
 during gestation
 intrapartum
 postpartum - infant
Local Approaches
 vaginal washing
 topical or oral
treatment of infant
 mode of delivery
Immune Based Therapy
Specific HIV immunoglobulin
HIVIG, monoclonals
(Combinations)
Other -immune modulators
HIV-1 Vaccine
– Maternal immunization
– infant
Combinations of above
MODE OF DELIVERY AND RISK OF
VERTICAL HIV-1 TRANSMISSION META-ANALYSIS
OF 15 PROSPECTIVE COHORTS
(THE INTERNATIONAL PERINATAL GROUP NEJM APRIL ‘99)
8,533 MOTHER/INFANT PAIRS
• MODE OF DELIVERY
N
%
TRANSMISSION
ELECTIVE C-SECTION
OTHER MODES
P<0.001
809
7,031
8.2%
16.7%
C-SECTION WITH/WITHOUT ZDV
VERTICAL HIV-1
MODE DEL/ ZDV
TRANSMISSION
%
OTHER MODES NO ZDV
19%
ELECTIVE C-SECTION NO ZDV
10.4%
OTHER MODES + ZDV
ELECTIVE C-SECTION + ZDV
7.3%
2%
DURATION OF RUPTURED MEMBRANES AND
VERTICAL TRANSMISSION
THE INTERNATIONAL PERINATAL GROUP
META- ANALYSIS JAMA 1999
• 4721 VAGINAL DELIVERIES
• RISK OF VERTICAL TRANSMISSION
INCREASED LINEARLY FOR EACH ONE
HOUR INCREMENT
(ADJUSTED ODDS RATIO=1.02 (95%) CI 1.01,1.04)
• WOMEN WITH AIDS-- HIGHER RISK
- 8%
- 31%
2 HR DRM
24 HRS DRM
P<0.01
IMPORTANT CONSIDERATIONS
RE: ELECTIVE C-SECTIONS
• NO EFFECT ON IN UTERO INFECTION
• COMBINATION ANTIRETROVIRALS
• Virtually no transmissions when <500 HIV RNAcp/ml
• USE OF ANTIRETROVIRALS DURING LABOR
DELIVERY such as NVP
• MORBIDITY TO MOTHER: infectious complication
rates ranged from 11% to 26% for WITS and
PACTG 185 trials.
• Elective C-sections currently recommended in the
US for women with unknown virus loads or > 1000
cps/ ml HIV RNA.
Perinatal HIV Efficacy Trials/
Americas & Europe
076 Protocol
Infusion
Zidovudine or placebo
Oral
Oral
Zidovudine or placebo Zidovudine or placebo
Mother
16 weeks
Gestation
Infant
Infection outcome
6 weeks
Labor
Post delivery
ZDV: 8%
Placebo: 25% (p < 0.0001)
ACTG 185 Trial HIVIG (Stiehm et al)
Treatment Arms
HIVIG
IVIG
Live births
Outcome
Infected Infants
Positive at Birth
Intrapartum
206
194
7
0
7
196
185
8
5
3
(-birth + 24 weeks)
Transmission Rate
5%
Mean baseline HIV RNA - 49,000 RNA cp/ml
NO PERINATAL TRANSMISSION:
(N=84) UNDETECTABLE HIV RNA AT BASELINE(<500 HIV RNA)
(N=107)UNDETECTABLE HIV RNA AT DELIVERY p<.006
6%
Initial Perinatal HIV Clinical Trials
Efficacy of Regimens
100%
Breast-fed
Formula-fed
80%
% Efficacy
63%
60%
40%
37%
33%
28%
42%
42%
38% 40%
68%
50%
20%
0%
Iv Coast
(18 mo)
Petra
Arm A
(18 mo)
AZT
AZT/
3TC
CDC Iv
Coast
(3 mo)
Ditrame HIVNET
Iv Coast 012
(6 mo) (18 mo)
Petra
Arm A
(6 wk)
HIVNET
012
(6 wk)
AZT AZT NVP AZT/ NVP
3TC
CDC
Thai
Petra
Arm A
(6 wk)
PACTG
076
AZT AZT/
3TC
AZT
Antenatal Antiretroviral Treatment and
Perinatal Transmission in WITS, 1990-1999
Blattner W. XIII AIDS Conf, July 2000, Durban S Africa (LBOr4)
% Transmission
30
21%
20
19%
8%
10
4%
1%
0
None
(N=391)
Type ARV vs None
p value:
ZDV Mono ZDV Mono Multi- ART
(<4/94)
(>4/94)
(N=179)
(N=206)
(N=529)
0.76
<0.01
<0.01
HAART
(N=187)
<0.01
PACTG 316:
Controlled trial of Nevirapine given to HIV infected
pregnant women during labor and to newborn
Aim: To assess whether the addition of NVP as
a single dose to mother during labor and
one dose to infant would further reduce
perinatal transmission.
Large randomized trial-USA Europe Latin America
low transmission rates in both arms.
(NVP vs placebo 1.5%, vs. 1.4%)
No additional benefit shown if mother already
receiving ARVs.
Infant Infection Status PACTG 316
NVP
Placebo
Total
Mothers enrolled
754
752
1506
Mothers delivered
712
702
1414
Treatment dispensed
638
629
1267
infection status known
594
580
1174
No. (%) HIV infected
9 (1.5 %)
Intrauterine transmission: 5 (56 %)
8 (1.4 %)
5 (63 %)
17 (1.5%)
10 (59 %)
Resistance to NVP
PACTG 316:
New NVP resistance mutations detectable in 6
women following delivery (of 134 with detectable
virus loads).
1 in placebo arm (received EFV following
delivery)
5 of 64 (8%) in the NVP arm.
Mutations present: K103N and Y181C, V 106A.
Available antiretrovirals
NRTIS:
–
–
–
–
–
–
–
Zidovudine
Lamivudine
Didanosine
Zalcitabine
Stavudine
Abacavir
Tenofovir
NNRTIS:
–
–
–
–
Nevirapine
Efavirenz
Etravirine
Rilpivirine
Fusion inhibitors
– T-20
Protease inhibitors
–
–
–
–
–
–
–
–
–
–
Saquinavir hard gel
Saquinavir soft gel
Ritonavir
Nelfinavir
Indinavir
Amprenavir
Lopinavir/ ritonavir
Atazanavir
Tipranavir
Darunavir
Entry Inhibitors
– Maraviroc
Integrase inhibitors
– Raltegravir
– Elvitegravir/ cobicistat
Evaluation of new antiretrovirals for
prevention of HIV perinatal transmission
Animal studies:
– Teratogenicity
Risk- Benefit analysis
Antiretroviral activity
– AZT only reduces viral load by 0.5 log
– Activity against ZDV resistant strains.
Ability to cross the placenta
Oral use
Cost
PMTCT studies in the Americas:
Focus:
-- Pharmacokinetics, safety and efficacy of new antiretrovirals.
-- Primary infection during pregnancy
-- Late presenters and post exposure prophylaxis trials.
-- Pathogenesis models and trials
Distribuição espacial dos municípios com pelo
menos um caso de aids registrado. Brasil, 1994-2000.
3 % overall
prevalence in women
with no prenatal care
through rapid HIV
testing in labor
0.4%
1.4%
1
8. 2%
47
Background
 Women with undiagnosed HIV during pregnancy
are at high risk of HIV-mother-to-child transmission.
 Observational data show HIV transmission of 9.3%
with infant ZDV started within 48 hours of birth
compared to 26.6% with no ZDV in infants born to
women without ARV in pregnancy. NEJM 1998:339
 Identification of HIV-exposed infants at delivery
allows starting infant ARV prophylaxis , formula
feeding or ARV prophylaxis during breastfeeding.
 Strategies such as HIV rapid testing during labor
identify women for their own medical care.
48
 Hypothesis:
Multidrug
antiretroviral
regimens given to
the HIV-exposed
neonate within 48
hours of birth, in
the absence of
maternal ARV
before labor, will
be more effective
in preventing
intrapartum MTCT
than ZDV alone.
NICHD/ HTPN 040
PACTG 1043
49
How common is HIV-infection
diagnosis at delivery?
%
Estimated coverage of women using IV ZDV
during labor per Brazilian region, 2002
60
50
40
30
20
10
0
Southeast
South
Source: Brazilian MOH 2002
Central-west
North
Northeast
50
Study Design and Objectives
 Study Design: Phase III, 3-arm, randomized
open-label.
 Primary objectives: To compare the efficacy at 3
months of age, safety and tolerance of 3 infant
ARV regimens for the prevention of vertical HIV
transmission to infants born to HIV-infected
women with no ARV during pregnancy.
 Secondary objectives: evaluate risk factors for
transmission, rates of ARV resistance and
disease progression between arms in infected
infants, and NVP, NFV, and 3TC pk.
51
Study Design: Phase III, 3-arm, randomized open-label.
Primary objectives: To compare the efficacy at 3 months of age, safety
and tolerance of 3 antiretroviral regimens for the prevention of vertical HIV1 transmission to infants born to HIV-infected women with no ART during
pregnancy.
No
ART
HIV+
mom
Within
48 hr
of life
Randomization
6 wks ZDV
6 wks ZDV+
3 doses NVP
Only
Formula
feeding
6 wks ZDV+
n= 1731
infants
2 wk NFV + 3TC
Study follow-up time: 6 months
52
Randomization at Study Sites n = 1745
4/2004 to 7/2010
 Brazil:
 Rio de Janeiro:
 Argentina:
• Hospital Dr. Diego Paroissien
Buenos Aires = 28
• Hospital dos Servidores do
Estado = 426
 U.S. sites:
• Hospital Geral de Nova Iguacu
• UMD, NJ = 5
= 418
• Miller Children’s Hosp, LB, CA = 1
 Belo Horizonte:
• San Juan City Hosp, PR = 2
• Univ Fed Minas Gerais= 43
• Gainesville, Univ FL = 2
• Jacksonville, Univ FL = 3
 Porto Alegre:
• Hospital Conceiçao = 102
 South Africa:
• Hospital Femina = 98
• Chris Hani Baragwanath Hosp
Johannesburg = 326
• Sta Casa da Misericordia = 83
• Tygerberg
 Sao Paulo:
Hospital
• Universidade Federal de Sao
Cape Town
Paulo, Sao Paulo = 11
= 153
• Universidade de Sao Paulo,
53
Ribeirao Preto = 43
HIV-Infection Status at 3 Mos
Kaplan-Meier
survival curves
used for estimates
of HIV transmission
Unassigned
n= 25 (1.5%)
Randomized
n= 1745
Enrolled
n= 1734
-50 infants
(2.9%):
Mother HIV-
Evaluable
n= 1684
Uninfected
n= 1424 (85%)
Unknown
n= 95 (5.6%)*
Infected
n= 140 (8.3%)
In utero
n= 93 (5.5%)
-11 infants
(0.6%):
no study drug
* 93/95 DNA neg before 3 mo
2 + at birth, no confirmation
Intrapartum
n= 47 (2.8%)
54
HIV-Infection Status by Study Arm
HIV
ZDV
ZDV +
NVP
ZDV + 3TC/
NFV
Overall
n
n
n
n
Infected in Utero
37
28
28
93
Infected Intrapartum
24
11
12
47
465
481
478
1424
Unknown
29
33
33
95
Unassigned
11
9
5
25
566
562
556
1684
Status
Uninfected
TOTAL
55
In Utero and Intrapartum HIV Transmission
% based on KM curves
Statistical comparisons between single and multiple ARV arms :
Hochberg’s modified Bonferroni approach
56
2 Pairwise
Comparisons:
HIV
ZDV vs. ZDV + NVP
ZDV vs. ZDV+3TC+NFV
ZDV
ZDV +
NVP
ZDV +
3TC/ NFV
Total
n= 566
n = 562
n = 556
n= 1684
n = 37
n = 28
n = 28
n = 93
6.8%
5.1%
5.2%
5.7%
5.0 - 9.3
n = 24
3.5 - 7.3
n = 11
3.6 - 7.4
n = 12
4.7 - 7.0
n = 47
4.9%
2.2%
2.5%
3.2%
95% CL
3.3-7.2
1.2 – 4.0
1.4 - 4.3
2.4 - 4.2
All infected
n = 61
n = 39
n = 40
n = 140
KM Rate All
95% CL
11.0%
8.7-14.0
7.1%
5.2-9.6
7.4%
5.5-9.9
8.5%
7.3-10.0
Status
Infected in utero
KM Rate (IU)
95% CL
Infected Intrapartum
KM Rate (IP)
p
0.2432
0.045
0.034
57
Timing of HIV Infection for Infants Testing Positive After
Birth by Study Treatment Arm (Intrapartum Only)
0.06
HIV Transmission Rate
0.05
0.04
0.03
0.02
0.01
ZDV
ZDV+3TC+NFV
ZDV+NVP
0.00
0
4
8
12
16
20
24
Study week
28
32
36
40
44
48
58
Risk Factors for Transmission
OR (95% CL)
p
Treatment arm
ZDV+3TC+NFV
0.48 (0.24 - 0.99)
0.0452
ZDV+NVP
0.41 (0.19 - 0.82)
0.0171
ZDV
1.0
2.09 (1.42 - 3.09)
0.0002
0.96 (0.86-1.07)
0.4276
Log10 Viral Load
(continuous variable )
CD4 count
Not associated
Age
Race
Prenatal care
ZDV in labor
Maternal Syphilis
Region of birth
Mode of delivery
Gestational age
CD4 cell count
(100 cells/mm3)
Adjusted multivariate logistic regression analysis
59
ARV-Related Toxicities
(Lab SAEs grades >=2 )
Subjects with
abnormal results
ZDV
ZDV +
NVP
ZDV +
3TC/
NFV
Total
p
Anemia
153
131
147
431
0.307
Neutropenia
93
84
153
330
< 0.0001
Transaminitis (AST)
18
11
14
43
0.428
Thrombocytopenia
9
7
10
26
0.750
286
246
( < 75,000 )
Total
864
60
Summary/ Conclusions
 43 infant deaths occurred in the study. None were
related to study drug. 6 mo IMR were lower than 12
mo country-specific statistics. Majority of deaths were
due to respiratory infections.
 Infants at high risk of HIV-infection, i.e., born to
mothers who received no ARV during pregnancy
should receive a 2 or 3-drug ARV regimen within 48
hours of life to reduce the risk of HIV infection.
 Lower toxicity profile (< neutropenia) and ease of use
suggests a 2 drug regimen w/ NVP may be preferable.
 Resistance testing is ongoing and will provide further
61
insight as to choice of combination regimen.
Repercussion of 040
 HPTN 052
 HPTN 057
 ACTG 5175
 ACTG 5190
 ACTG 5221
 P1077-ongoing
 P1066- ongoing
 TBTC- ongoing
 NISDI collaboration- ongoing
 Frame project- ongoing
62
Antiviral Treatment as Prevention
 Extensive biological plausibility
• The concentration of HIV-1 in blood and genital
tract correlates with sexual transmission
• Antiretroviral agents that concentrate in the
genital tract reduce HIV-1 viral load
 Most observational reports indicate ART
reduces transmission of HIV-1 in couples
HPTN 052 Study Design
Stable, healthy, serodiscordant couples, sexually active
CD4 count: 350 to 550 cells/mm3
Randomization
Immediate ART
CD4 350-550
Delayed ART
CD4 <250
Primary Transmission Endpoint:
Virologically-linked transmission events
Primary Clinical Endpoint
WHO stage 4 clinical events, pulmonary tuberculosis, severe
bacterial infection and/or death
HPTN 052: HIV-1 Transmission
Total HIV-1 Transmission Events: 39
Immediate Arm
4
Delayed Arm
35
p < 0.0001
HPTN 052: HIV-1 Transmission
Total HIV-1 Transmission Events: 39
Linked
Transmissions: 29
Unlinked or TBD
Transmissions: 10
• 18/28 (64%) transmissions from infected
participants with CD4 >350 cells/mm3
Immediate
Arm: 1
Delayed
Arm: 28
• 23/28 (82%) transmissions in sub-Saharan
Africa
• 18/28 (64%) transmissions from female to
p < 0.001
male partners
Probability of Primary Clinical Event
(Death, WHO stage 4 clinical event, pulmonary TB or severe bacterial infection)
HR: 0.6 [ 0.4, 0.9 ], P=0.01
Delayed
Immediate
Number at risk
Delayed
Immediate
HPTN 052 Prevention Conclusion
Early ART that suppresses viral replication led
to 96% reduction of sexual transmission of
HIV-1 in serodiscordant couples
Primary infection during
pregnancy:
Patient
Population and
Outcomes
HIVexposed
Infants
known
outcomes
Maternal ARV use
pregnancy
(n=168)
142
(84.5%)
No Maternal ARV
use pregnancy
(n=88)
70
(80%)
TOTAL (n=256)
212
(83%)
HIV
+
1
8
9
HIV
TR
Miscarriages
Stillbirths
Neonatal
deaths
0.7 %
5
(3%)
6
(3.5%)
15
(8.9%)
11.4%
7
(8%)
4
(4.5%)
7
(8%)
4.2%
12
(4.7%)
10
(3.9%)
22
(8.6%)
Loss to
follow-up
HIV-1 MTCT and timing of maternal infection in PortoAlegre, Brazil
Nielsen- Saines, et al Dominique Dormont Int Conf Abs 1 2007
n
HIV-1 TR
(%)
95% CI (%)
1 /142
0.7
0.02 – 3.9
No Maternal ARV use
and unknown
seroconversion time
5 /61
8.2
2.7 – 18.1
No Maternal ARV use
and proven sero
conversion during
pregnancy
Total
3 /9
33.3
7.5 – 70.0
9 /212
4.2
1.9 – 7.9
Maternal ARV use
pregnancy
PMTCT Clinical Trials in Sub-Saharan Africa
PMTCT in Africa
Estimated 20-35% of pregnant
women meet WHO criteria for
starting ARV therapy.
Advanced disease, low CD4
are associated with increased
MTCT even in women
receiving short-course ARV
prophylaxis.
These women account for a
significant proportion of MTCT.
These women are also at
much higher risk for
development of NVP
resistance after SD NVP given
alone or with other ARVs.
Response to short-course ARV
prophylaxis varies by maternal
disease stage and CD4.
Single Dose Nevirapine for PMTCT
HIVNET 012, Intrapartum/Postpartum Nevirapine vs
ZDV: HIV Transmission
Owen M. XIII AIDS Conf, Julio 2000, Durban (LbOr01)
% Transmissão
30
24.1%
20.0%
20
10.4%
10
15.7%
11.8%
8.2%
P = 0.003
0
1-3 Days
6-8 Weeks
ZDV (N=308)
12 Months
NVP (N=311)
NVP Resistance in HIVNET 012
Jackson B. XIII AIDS Conf, July 2000, Durban S Africa
(LbOr013)

31 NVP arm transmitters.

NVP resistance mutations were detected in
7/31 (23%) at 6 wks PP

no resistance in 5/6 women at delivery.

However, resistance no longer present in 4/4
women tested 13-18 mos PP.
Open-Label Evaluation of Single-Dose NVP
for MTCT and Resistance, S. Africa
Martinson et al. 11th Retrovirus Conf, Feb 2004 (abs 38)
% with NVP Resistance
100%
80%
60%
43%
44%
44%
40%
24%
20%
0%
4-6 wks
6-7 wks
7-10 wks
10-36 wks
Number Weeks Postpartum
Test for trend, p=0.006
Single-Dose NVP Prophylaxis is Associated with
NVP Resistance Acquisition in Mothers
% with detectable Resistance
100%
2
doses
SD NVP
AZT + SD NVP
>2 NRTI + SD NVP
SD NVP + 7 d AZT/3TC “tail”
75%
67% 69%
50%
38% 39% 40%
25%
10%
15%
18% 20%
25% 25%
0%
TOPS
Time: 6wk
Clade: C
US/France Thai Peri3
6 wk
B
4 wk
E,B
Thai
PHPT2
2 wk
E,B
Uganda
012
6 wk
A,D
Ireland
Ivory
Coast
S. Africda Zimbabwe S. Africa
7 wk 4 wk 7 wk
B,G,F CRF,A C
8 wk 4-6 wk
E,B
C
NVAZ
8 wk
C
Single-Dose NVP Prophylaxis is Associated with NVP Resistance
Acquisition in Infants Failing Prophylaxis
100%
SD NVP
AZT + SD NVP
SD NVP, no maternal SD NVP
% with Resistance
80%
87%
60%
40%
27%
20%
8%
0%
Clade:
Thai
E,B
13%
S Africa (NO
m om NVP)
C
33%
36%
42%
46%
53%
17% 20%
Cote
d'Ivorie
Thai
A
E,B
CRF01, 06
Malaw i
(NVAZ NO
m om NVP)
C
Thai
E,B
S Africa
(w ith m om
NVP)
C
S Africa
C
HIVNET 012
A,D
SAINT
C
Malaw i
(NVAZ w ith
m om NVP)
C
Single Dose Nevirapine for PMTCT
Significance:
– SD NVP to mother at delivery and to infant
postpartum WAS the standard of care in most
sub-Saharan countries.
– NVP’s long half-life, with sub-therapeutic drug
concentrations in the second week post-treatment
induces a high rate of resistance mutations.
– Nevirapine is part of almost all first line HAART
regimens in Africa.
– In the presence of NVP resistance, one could face
an epidemic of NVP resistant virus in Africa.
Role of NVP resistance
The “Tail-end” approach
Single dose NVP exposure to the mother
has been shown to induce resistance
levels from 21% to 100% depending on
the study and the assay used to determine
resistance.
Reason: NVP’s long half-life, with subtherapeutic drug concentrations in the
second week post-treatment.
NVP resistance
Several studies evaluated provision ARV
drug following single dose NVP to stop
development of resistance.
TOPS study in South Africa (Treatment
Options Preservation Study):
Resistance at 6 weeks post sd-NVP:
– sd-NVP: 60%
– sd-NVP + 4 days ZDV/3TC: 12%
– sd-NVP + 7 days ZDV/3TC: 10%
McIntyre, 2005
Impact of NVP resistance on subsequent
maternal treatment (Botswana) Lockman S, NEJM 1-07
218 women in Botswana received either sdNVP or
placebo at delivery (in an antenatal ZDV study).
6 months after starting HAART:
– 5% placebo arm had virologic failure
– 18.4% in sdNVP arm
In 60 women starting HAART within 6 mos postpartum
– 0 placebo arm with virologic failure
– 41.7% sdNVP arm with virologic failure (P < 0.001)
In 158 women starting HAART > 6 mos postpartum:
– 7.8% placebo arm with virologic failure
– 12% sdNVP arm with virologic failure (P=0.39)
Issues with NVP
HAART is a superior regimen for pMTCT than sdNVP
Development of Resistance following sdNVP
– To the mother
– To the infected infant
Mutations fade over time
Appears that impact on response to future clinical treatment
to mother not compromised.
Unknown about impact sdNVP resistance mutation has on
treatment of infant when nvp is used as part of HAART.
Appears to have no repercussion when used in subsequent
pregnancies.
Concerns for use of NVP in patients with higher CD4 cells
as part of HAART regimen.
No toxicity of NVP when used as single dose to the mother
or to the infant.
WHO Guidelines for PMTCT
WHO Guidelines for PMTCT
Option A:
WHO Guidelines for PMTCT
Option B:
Option B+:
Antiretrovirals for life for all women
initiating ART during pregnancy!
Breastfeeding and late postnatal
HIV transmission
What is known on HIV Transmission
through Breastfeeding?
HIV is present in breast milk.
Animal studies show HIV can be
transmitted to neonatal monkeys when
given orally.
Breastfeeding poses a substantial risk for
acquisition of HIV infection for the infant.
Prolonged breastfeeding (e.g., 24 months)
can double the overall risk of mother-tochild transmission.
Breastfeeding and pMTCT
The major and last obstacle in PMTCT.
Alternatives to breast milk not always
achievable, yet possible in many settings (filters,
pre-made formula)
Breast milk virus load responds to viral
suppression with HAART.
Use of maternal HAART during lactation
reduces transmission.
Other option is potential use of ARV prophylaxis
by the infant for the first six months of lactation.
Timing of Postnatal Transmission
Early Postnatal Transmission (4-8 wks)
– Difficult if not impossible to differentiate
between infection acquired intrapartum
versus that acquired during the first few
weeks of life by breast feeding.
– Data suggest that first 6-8 weeks of
breastfeeding appears to be high risk
period.
Late Postnatal Transmission
– Continued risk for duration of breastfeeding.
Estimates of Monthly Breastfeeding MTCT Risk
Estimated % Monthly Risk
SAINT
Nairobi
Malawi
W.Africa
BHITS
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
2d-6-8 wk
Early BF
Transmission
1,2-5 mo
6-11 mo
12-18 mo
Late BF Transmission
18-24 mo
Overall Late (After Age 1 Month) Postnatal
Transmission Rates in Different Studies
# / 100 child yrs
12
10
9.3
9.2
8
6.2
6.9
6
3.2
4
2
0
Cote
D'Ivoire
Tanzania
Malawi
Leroy
Meta
Analysis
BHITS
Clinical Risk Factors for Postnatal
Transmission (After Age 3 Mos): Nairobi (N=410)
Embree et al: AIDS 2000: 14:2535
Not Infected
Postnatal Infection
% with Risk Factor
80
60
40
20
0
Nipple
Lesion
Mastitis
BF >15 mos Infant thrush
<6 mo/o
Maternal seroconversion during lactation 6-fold increased risk
SAINT: Comparison of
Mother-to-Child Transmission in
Breast- and Bottle-Fed Infants
Percent HIV-Infected
10
7.71%
8
6.57%
6
4.49%
3.78%
4
2.01%
2
0.53%
0
Intrauterine
Birth to 4 Weeks
4 to 8 Weeks
(baseline)
Breast
Bottle
Moodley D: 13th International AIDS Conference, Durban, 2000. Abstract LbOr2.
Greatest Protection in Breastfed Infants is
from Diarrheal Mortality in First 6 Months of Life
WHO Collaborative Study Team, Lancet 2000
Pooled Odds Ratio for Mortality if Not Breastfeeding
6.1
8
Odds ratio
(4.1-9.0)
6
2.4
4
(1.6-3.5)
1.9
(1.2-3.1)
2.5
(1.4-4.6)
2
0
o
m
6
DD
s
o
m
6
RD
s
6-1
o
m
1
DD
s
6-1
o
m
1
RD
s
DD-diarrheal mortality
RD- respiratory mortality
Infectious Morbidity and
Mortality of HIV-exposed
uninfected, formula-fed infants
enrolled in the NICHD/ HPTN
040 Study.
Phase III Randomized Trial of the Safety and
Efficacy of Three Neonatal Antiretroviral
Regimens for the Prevention of Intrapartum
HIV-1 Transmission
100
Proportion of subjects with at least 1 SAE
25
20
%
15
10.4
10
3.7
5
3.4
3
1.7
1
0.9
0
All Infectious
SAEs
Resp
Systemic/
CNS
Overall %
GI
Brazil %
GI gr 2
Congenital
Other
South Africa %
101
Weight-for-Age and Height-for-Age Z-scores
by study visit n= 1000 Infants
-0.05
-0.09
-0.15
M
e
a
n
Z
s
c
o
r
e
Brazil WAZ
-0.25
-0.34
-0.35
-0.45
-0.55
-0.40
Brazil HAZ
-0.49 South Africa HAZ
-0.54
-0.56
-0.65
-0.67
-0.75
-1.05
-0.67
-0.79
-0.85
-0.95
-0.53
-0.85
-0.86
-0.95
-0.95
South Africa WAZ
-1.15
-1.06
-1.13
-1.25
Birth
Month 1
Month 3
Study Visit
Month 6
102
Comparison data BF African infants
Differents surveys WAZ distribution 1-24 months children
0
1mo
3mo
6mo
9mo
12mo
16mo
18mo
24mo
-0,5
-1
-1,5
-2
-2,5
Dream
Dream moz
Dream mal
Tanz. Villamor
Malawi rur Espo
Zambia
103
Method of Infant Feeding and HIV Transmission in
Breastfeeding Children
Coutsoudis A. XIII AIDS Conf, July 2000, Durban S Africa (LbOr6)
% Transmission
40
36%
26%
30
19%19%
20
25%
19%
8% 7% 7%
10
0
Infant Age:
1 Day
Never Breastfed
(N=157)
Exclusive Breastfed (N=118)
Mixed Feeding
(N=276)
6 Mos
15 Mos
At 6 months:
Exclusive vs Mixed: 0.6 (0.3-1.0)
Exclusive vs Never: 1.2 (0.6-2.2)
% with Growth Faltering
Growth Faltering Post Weaning at 6 Months
in KiBS Study (N=63) Compared to VT Study
Without Early Weaning (N=440), Kisumu,
Kenya
35
30
25
20
KiBS
VT
15
10
5
0
1 mo
3 mo
6mo
9mo
12mo
Age (Months)
(Mary Glenn Fowler MD)
HPTN 046
Study Design
Phase III, randomized, double-blind, placebo-controlled study
in breastfeeding infants born to HIV-1 infected mothers
6 months
6 weeks
NVP x 6 wks
Breastfeeding
Randomize
Birth
18 months
Extended NVP x 6 mos
Follow-up
Placebo x 6 mos
Follow-up
HPTN 046

Randomized Infants
1,522 breastfed, uninfected infants born to 1,505
HIV-infected mothers randomized at age 6
weeks

N=759 extended nevirapine

N=763 placebo

Study drug regimen (NVP or placebo) continued
through age 6 months or cessation of
breastfeeding, whichever was earliest

Infants followed though 18 months of age
HPTN 046
HIV Infection in Infants of Mothers
Not on ART by CD4 count and
Study Arm
Postnatal Transmission (%, 95% CI) After Age 6 Weeks in Infants
Age 6 mos
Age 9 mos
Age 12 mos
CD4 <350
CD4
>350
CD4 <350
CD4
>350
CD4 <350
CD4
>350
Extende
d NVP
4.8%
(0.2-9.4)
0.7%
(0-1.5)
7.5%
(1.713.3)
0.9%
(0-1.9)
8.9%
(2.515.2)
1.5%
(0.3-2.7)
Placebo
8.1%
(1.314.8)
2.8%
(1.34.4)
8.1%
(1.314.8)
3.3%
(1.7-4.9)
10.0%
(2.417.6)
3.3%
(1.7-4.9)
P Value
0.438
0.014
0.901
0.014
0.831
0.079
WHO Guidelines: CD4 <350: ART-Eligible for Own Health)
CD4 >350: ART-Ineligible (ARV for prophylaxis only)
OVERALL STUDY Sequential Randomized 2x2 Factorial Trial
Promise Study- P1077 (IMPAACT)
CD4 >350
AP 28-term
IP
PP for Duration BF
Weaning
Infant uninfected
at birth
R
a
n
d
o
m
i
z
e
HAART
AZT
HAART
AZT +
SD NVP+
SD TRV
AZT +
Late presenters SD NVP+
SD TRV
R
a
n
d
o
m
i
z
e
HAART
Mother
Infant
Infant NVP
(if uninfected
and <12
mos old at
time of
weaning)
R
a
n
d
o
m
i
z
e
Continue
HAART
Stop
All ARVs
R
a
n
d
o
m
i
z
e
0
CTX
to 18 months
No CTX
Future research on PMTCT
Further studies on
pathogenesis.
Development of effective
strategies.
Safety of replacement
feedings for infants.
Safety of breastfeeding
for mothers
Evaluate PK of ARVs in
breastmilk and role for
potential passage to
infant (protection or
induction of resistance?)
HIV TRANSMISSION RATES
Mother/Infant Pairs
Los Angeles Study
70
Total Number of Babies/year
% Infected
60
60
50
50
40
40
30
30
20
20
10
10
ZDV
076
0
0
1988 1989
1990
1991 1992
1993
1994
* All mother/infant pairs prospectively enrolled prior to delivery
1995
% of Babies Infected
Number of Babies with Outcomes
70

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