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Preventing Mother to Child HIV-1 Transmission ( P MTCT ) 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

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Preventing Mother to Child HIV-1 Transmission (PMTCT) Karin Nielsen, MD, MPHClinical Professor Pediatric Infectious DiseasesDavid Geffen UCLA School of Medicine



Perinatal hiv 1 infection
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 mostcommon route

  • As number of women HIV-infected increases perinatal infection will also increase


Epidemiology peds hiv
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

1300%

20%

160%

20%

100%

60%

40%

30%

20%

Increases in HIV infection 1996-2001

UNAIDS/WHO global view of HIV infection 200240 million individuals living with HIVCumulative infection: 60 million

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 among pregnant womenin South Africa, 1990 to 1999

25

22.8

22.4

20

17

14.2

15

HIV prevalence (%)

10.4

10

7.6

5

4

2.1

1.7

0.7

0

90

91

92

93

94

95

96

97

98

99

Source: Department of Health, South Africa


Estimated AIDS Prevalence among Women in the United States and Perinatally Acquired AIDS Cases by Quarter-Year, 1985 - 1999

160

300

Heterosexual contact

Pediatric cases

IDU

140

250

120

200

100

Number of Cases

80

150

Number of Cases (thousands)

60

100

40

50

20

0

0

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

Quarter-Year


Pediatric hiv infection facts
Pediatric HIV-infection Facts and Perinatally Acquired AIDS Cases by Quarter-Year

  • 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

Pathogenesis and Perinatally Acquired AIDS Cases by Quarter-Year


Factors influencing perinatal transmission of hiv

Viral and Perinatally Acquired AIDS Cases by Quarter-Year

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

Factors Influencing Perinatal Transmission of HIV


Perinatal hiv infection
Perinatal HIV Infection and Perinatally Acquired AIDS Cases by Quarter-Year

  • 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 and Perinatally Acquired AIDS Cases by Quarter-Year

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 and Perinatally Acquired AIDS Cases by Quarter-Year

Maternal virus load

u

- blood (cell-associated, cell-free)

- cervicovaginal secretions

Duration of ruptured membranes

u

Infant exposure to blood

u

-mucous membranes, swallowing

Delivery mode-vaginal vs. c-section

u

Trauma

u

Maternal-fetal transfusion

u

Placenta - abruption

u

- chorioamnionitis

- co-infections


Breastfeeding transmission
Breastfeeding Transmission and Perinatally Acquired AIDS Cases by Quarter-Year

  • 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
Criteria for determing timing of HIV infection in the infant and Perinatally Acquired AIDS Cases by Quarter-Year

  • 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 and Perinatally Acquired AIDS Cases by Quarter-Year

  • 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
Pediatric Long Term Survivors in the U.S. 1997 and Perinatally Acquired AIDS Cases by Quarter-Year(Nielsen, et al Pediatrics)


Natural history of hiv 1 infection in children africa 2005
Natural history of HIV-1 infection in children, Africa 2005 and Perinatally Acquired AIDS Cases by Quarter-Year

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 and Perinatally Acquired AIDS Cases by Quarter-Year

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

50

60

70

Life expectancy at birth (years)

Source: U.S. Census Bureau, 2000


Early diagnosis of hiv infection
Early diagnosis of HIV infection and Perinatally Acquired AIDS Cases by Quarter-Year

  • 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
Maternal virus load and risk of perinatal transmission and Perinatally Acquired AIDS Cases by Quarter-Year

  • 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.


Delivery and and Perinatally Acquired AIDS Cases by Quarter-Year

Maternal Plasma HIV-1 RNA Levels at

Antiretroviral use during Pregnancy:

Impact on Perinatal Transmission

51.4

27.8

60

17.2

11.3

29.4

None

50

0

20.4

20

12.5

40

ZDV Mono (<4/94)

Rates per 100

0

19

14.7

7.2

30

6.1

ZDV Mono (>4/94)

0

20

4.5

Multi-ART

2.6

1.8

0

0

10

HAART

2.4

1.7

0

0

0

0

>100000

>3000-40000

Undetectable

(<400)

Maternal Plasma HIV-1 RNA


Cervical vaginal secretions hiv
Cervical/Vaginal Secretions & HIV and Perinatally Acquired AIDS Cases by Quarter-Year

  • 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 and Perinatally Acquired AIDS Cases by Quarter-YearHIV transmission

Intrauterine

Intrapartum

Post-partum

vaccines

antiretroviral therapy

immune modulation

vaccines

antiretroviral therapy

immune modulation

C-section

vaginal washing

breast feeding

3

6 months

Labor and

Delivery

Gestation

2 years


Role of neutralizing antibodies in perinatal hiv transmission
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
Virus phenotype and perinatal HIV transmission 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
Virus genotype and perinatal HIV transmission 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
Potential Approaches for Prevention of HIV-1 Transmission transmission

  • Specific HIV immunoglobulin

  • HIVIG, monoclonals (Combinations)

  • Other -immune modulators

  • HIV-1 Vaccine

    • Maternal immunization

    • infant

  • Combinations of above

Antiretrovirals

Immune Based Therapy

  • during gestation

  • intrapartum

  • postpartum - infant

Local Approaches

  • vaginal washing

  • topical or oral treatment of infant

  • mode of delivery


MODE OF DELIVERY AND RISK OF transmissionVERTICAL 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 809 8.2%

    OTHER MODES 7,031 16.7%

    P<0.001


C section with without zdv vertical hiv 1
C-SECTION WITH/WITHOUT ZDV transmissionVERTICAL HIV-1

MODE DEL/ ZDV% TRANSMISSION

OTHER MODES NO ZDV 19%

ELECTIVE C-SECTION NO ZDV 10.4%

OTHER MODES + ZDV 7.3%

ELECTIVE C-SECTION + ZDV 2%


DURATION OF RUPTURED MEMBRANES AND VERTICAL TRANSMISSION transmissionTHE 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% 2 HR DRM

    - 31% 24 HRS DRM

    P<0.01


Important considerations re elective c sections
IMPORTANT CONSIDERATIONS transmissionRE: 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/ transmissionAmericas & Europe


076 protocol
076 Protocol transmission

Infusion

Zidovudine or placebo

Oral

Oral

Zidovudine or placebo

Zidovudine or placebo

Mother

Infant Infection outcome

16 weeks

6 weeks

Gestation Labor Post delivery

ZDV: 8% Placebo: 25% (p < 0.0001)


Actg 185 trial hivig stiehm et al
ACTG 185 Trial HIVIG transmission(Stiehm et al)

Treatment Arms

HIVIG IVIG

Live births 206 196

Outcome 194 185

Infected Infants 7 8

Positive at Birth 0 5

Intrapartum 7 3

(-birth + 24 weeks)

Transmission Rate 5% 6%

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


Initial perinatal hiv clinical trials efficacy of regimens
Initial Perinatal HIV Clinical Trials transmissionEfficacy of Regimens

Breast-fed

Formula-fed

AZT AZT/ AZT AZT NVP AZT/ NVP AZT AZT/ AZT

3TC 3TC 3TC


Antenatal Antiretroviral Treatment and Perinatal Transmission in WITS, 1990-1999Blattner W. XIII AIDS Conf, July 2000, Durban S Africa (LBOr4)

Type ARV vs None

p value:

0.76

<0.01

<0.01

<0.01


Pactg 316
PACTG 316: Transmission in WITS, 1990-1999

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
Infant Infection Status PACTG 316 Transmission in WITS, 1990-1999

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 %) 8 (1.4 %) 17 (1.5%)

Intrauterine transmission: 5 (56 %) 5 (63 %) 10 (59 %)


Resistance to nvp
Resistance to NVP Transmission in WITS, 1990-1999

  • 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: Transmission in WITS, 1990-1999

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

Available antiretrovirals


Evaluation of new antiretrovirals for prevention of hiv perinatal transmission
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 perinatal transmissionAmericas:

Focus:

-- Pharmacokinetics, safety and efficacy of new antiretrovirals.

-- Primary infection during pregnancy

-- Late presenters and post exposure prophylaxis trials.

-- Pathogenesis models and trials


3 perinatal transmission% overall prevalence in women with no prenatal care through rapid HIV testing in labor

0.4%

1.4%

1

8. 2%


Background
Background perinatal transmission

  • 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.


Nichd htpn 040 pactg 1043

Hypothesis: perinatal transmission

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 040PACTG 1043


How common is hiv infection diagnosis at delivery
How common is HIV-infection diagnosis at delivery? perinatal transmission

Estimated coverage of women using IV ZDV during labor per Brazilian region, 2002

%

60

50

40

30

20

10

0

Central-west

North

Southeast

South

Northeast

Source: Brazilian MOH 2002


Study design and objectives
Study Design and Objectives perinatal transmission

  • 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.


Study Design perinatal transmission: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 HIV-1 transmission to infants born to HIV-infected women with no ART during pregnancy.

HIV+ mom

Within 48 hr of life

No ART

6 wks ZDV

Only Formula feeding

Randomization

6 wks ZDV+ 3 doses NVP

6 wks ZDV+

2 wk NFV + 3TC

n= 1731 infants

Study follow-up time: 6 months


Randomization at study sites n 1745 4 2004 to 7 2010

Brazil: perinatal transmission

Rio de Janeiro:

Hospital dos Servidores do Estado = 426

Hospital Geral de Nova Iguacu = 418

Belo Horizonte:

Univ Fed Minas Gerais= 43

Porto Alegre:

Hospital Conceiçao = 102

Hospital Femina = 98

Sta Casa da Misericordia = 83

Sao Paulo:

Universidade Federal de Sao Paulo, Sao Paulo = 11

Universidade de Sao Paulo, Ribeirao Preto = 43

Argentina:

Hospital Dr. Diego Paroissien Buenos Aires = 28

U.S. sites:

UMD, NJ = 5

Miller Children’s Hosp, LB, CA = 1

San Juan City Hosp, PR = 2

Gainesville, Univ FL = 2

Jacksonville, Univ FL = 3

South Africa:

Chris Hani Baragwanath Hosp Johannesburg = 326

Tygerberg

Hospital

Cape Town

= 153

Randomization at Study Sites n = 17454/2004 to 7/2010


Hiv infection status at 3 mos
HIV-Infection Status at 3 Mos perinatal transmission

Randomized

n= 1745

Kaplan-Meier survival curves used for estimates of HIV transmission

-11 infants (0.6%):

no study drug

Enrolled

n= 1734

-50 infants (2.9%):

Mother HIV-

Unassigned

n= 25 (1.5%)

Evaluable

n= 1684

Uninfected

n= 1424 (85%)

Unknown

n= 95 (5.6%)*

Infected

n= 140 (8.3%)

* 93/95 DNA neg before 3 mo 2 + at birth, no confirmation

In utero

n= 93 (5.5%)

Intrapartum

n= 47 (2.8%)


Hiv infection status by study arm
HIV-Infection Status by Study Arm perinatal transmission


In Utero and Intrapartum HIV Transmission perinatal transmission

% based on KM curves

Statistical comparisons between single and multiple ARV arms : Hochberg’s modified Bonferroni approach


2 Pairwise perinatal transmission ZDV vs. ZDV + NVP Comparisons: ZDV vs. ZDV+3TC+NFV


Timing of HIV Infection for Infants Testing Positive After Birth by Study Treatment Arm (Intrapartum Only)

HIV Transmission Rate

Study week


Risk factors for transmission
Risk Factors for Transmission Birth by Study Treatment Arm (Intrapartum Only)

Not associated Age

Race

Prenatal care

ZDV in labor

Maternal Syphilis

Region of birth

Mode of delivery

Gestational age

CD4 cell count

Adjusted multivariate logistic regression analysis


Arv related toxicities lab saes grades 2
ARV-Related Toxicities Birth by Study Treatment Arm (Intrapartum Only)(Lab SAEs grades >=2 )


Summary conclusions
Summary/ Conclusions Birth by Study Treatment Arm (Intrapartum Only)

  • 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 insight as to choice of combination regimen.


Repercussion of 040
Repercussion of 040 Birth by Study Treatment Arm (Intrapartum Only)

  • HPTN 052

  • HPTN 057

  • ACTG 5175

  • ACTG 5190

  • ACTG 5221

  • P1077-ongoing

  • P1066- ongoing

  • TBTC- ongoing

  • NISDI collaboration- ongoing

  • Frame project- ongoing


Antiviral treatment as prevention
Antiviral Treatment as Prevention Birth by Study Treatment Arm (Intrapartum Only)

  • 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 Birth by Study Treatment Arm (Intrapartum Only)

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 Birth by Study Treatment Arm (Intrapartum Only)052: HIV-1 Transmission

Total HIV-1 Transmission Events: 39

Immediate Arm

4

Delayed Arm

35

p < 0.0001


HPTN Birth by Study Treatment Arm (Intrapartum Only)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

  • 23/28 (82%) transmissions in sub-Saharan Africa

  • 18/28 (64%) transmissions from female to male partners

Immediate Arm: 1

Delayed Arm: 28

p < 0.001


Probability of Primary Clinical Event Birth by Study Treatment Arm (Intrapartum Only)

(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 Birth by Study Treatment Arm (Intrapartum Only)

Early ART that suppresses viral replication led to 96% reduction of sexual transmission of HIV-1 in serodiscordant couples


Primary infection during pregnancy
Primary infection during pregnancy: Birth by Study Treatment Arm (Intrapartum Only)


Hiv 1 mtct and timing of maternal infection in portoalegre brazil
HIV-1 MTCT and timing of maternal infection in PortoAlegre, Brazil

Nielsen- Saines, et al Dominique Dormont Int Conf Abs 1 2007


PMTCT Clinical Trials in BrazilSub-Saharan Africa


Pmtct in africa
PMTCT in Africa Brazil

  • 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.



HIVNET 012, Intrapartum/Postpartum Nevirapine vs ZDV: HIV TransmissionOwen M. XIII AIDS Conf, Julio 2000, Durban (LbOr01)

P = 0.003


Nvp resistance in hivnet 012 jackson b xiii aids conf july 2000 durban s africa lbor013
NVP Resistance in HIVNET 012 TransmissionJackson 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. AfricaMartinson et al. 11th Retrovirus Conf, Feb 2004 (abs 38)

Test for trend, p=0.006


Single-Dose NVP Prophylaxis is Associated with NVP Resistance Acquisition in Mothers

2

doses

SD NVP

AZT + SD NVP

>2 NRTI + SD NVP

SD NVP + 7 d AZT/3TC “tail”

Time: 6wk 6 wk 4 wk 2 wk 6 wk 7 wk 4 wk 7 wk 8 wk 4-6 wk 8 wk

Clade: C B E,B E,B A,D B,G,F CRF,A C E,B C C


Single-Dose NVP Prophylaxis is Associated with NVP Resistance Acquisition in Infants Failing Prophylaxis

SD NVP

AZT + SD NVP

SD NVP, no maternal SD NVP

Clade: E,B C A E,B C E,B C C A,D C C

CRF01, 06


Single dose nevirapine for pmtct
Single Dose Nevirapine for PMTCT Resistance Acquisition in Infants Failing Prophylaxis

  • 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
Role of NVP resistance Resistance Acquisition in Infants Failing Prophylaxis

  • 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 sub-therapeutic drug concentrations in the second week post-treatment.


Nvp resistance
NVP resistance Resistance Acquisition in Infants Failing Prophylaxis

  • 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
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
Issues with NVP (Botswana)

  • 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 pmtct1
WHO Guidelines for PMTCT (Botswana)

Option A:


Who guidelines for pmtct2
WHO Guidelines for PMTCT (Botswana)

Option B:

Option B+:

Antiretrovirals for life for all women initiating ART during pregnancy!



What is known on hiv transmission through breastfeeding
What is known on HIV Transmission through Breastfeeding? (Botswana)

  • 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-to-child transmission.


Breastfeeding and pmtct
Breastfeeding and pMTCT (Botswana)

  • 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
Timing of Postnatal Transmission (Botswana)

  • 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
Estimates of Monthly Breastfeeding MTCT Risk (Botswana)

Early BF Transmission

Late BF Transmission



Clinical Risk Factors for Postnatal Rates in Different StudiesTransmission (After Age 3 Mos): Nairobi (N=410)Embree et al: AIDS 2000: 14:2535

Maternal seroconversion during lactation 6-fold increased risk


Saint comparison of mother to child transmission in breast and bottle fed infants
SAINT: Comparison of Rates in Different StudiesMother-to-Child Transmission in Breast- and Bottle-Fed Infants

10

7.71%

8

6.57%

6

Percent HIV-Infected

4.49%

3.78%

4

2.01%

2

0.53%

0

Birth to 4 Weeks

4 to 8 Weeks

Intrauterine(baseline)

Breast

Bottle

Moodley D: 13th International AIDS Conference, Durban, 2000. Abstract LbOr2.


Greatest Protection in Breastfed Infants is Rates in Different Studiesfrom Diarrheal Mortality in First 6 Months of Life WHO Collaborative Study Team, Lancet 2000

Pooled Odds Ratio for Mortality if Not Breastfeeding

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


Proportion of subjects with at least 1 sae
Proportion of subjects with at least 1 SAE uninfected, formula-fed infants enrolled in the NICHD/ HPTN 040 Study.

%


Weight-for-Age and Height-for-Age Z-scores uninfected, formula-fed infants enrolled in the NICHD/ HPTN 040 Study.

by study visit n= 1000 Infants


Comparison data bf african infants
Comparison data BF African infants uninfected, formula-fed infants enrolled in the NICHD/ HPTN 040 Study.


Method of Infant Feeding and HIV Transmission in Breastfeeding ChildrenCoutsoudis A. XIII AIDS Conf, July 2000, Durban S Africa (LbOr6)

Infant Age:

At 6 months:

Exclusive vs Mixed: 0.6 (0.3-1.0)

Exclusive vs Never: 1.2 (0.6-2.2)


Growth Faltering Post Weaning at 6 Months in KiBS Study (N=63) Compared to VT Study Without Early Weaning (N=440), Kisumu, Kenya

(Mary Glenn Fowler MD)


Study design
Study Design (N=63) Compared to VT Study Without Early Weaning (N=440), Kisumu, Kenya

HPTN 046

Birth

6 months

18 months

6 weeks

Phase III, randomized, double-blind, placebo-controlled study

in breastfeeding infants born to HIV-1 infected mothers

Follow-up

Extended NVP x 6 mos

NVP x 6 wks

Randomize

Placebo x 6 mos

Follow-up

Breastfeeding


Randomized infants

1,522 breastfed, uninfected infants born to 1,505 HIV-infected mothersrandomized 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

Randomized Infants

HPTN 046


Hiv infection in infants of mothers not on art by cd4 count and study arm
HIV Infection in Infants of Mothers HIV-infected mothersNot on ART by CD4 count and Study Arm

HPTN 046

WHO Guidelines: CD4 <350: ART-Eligible for Own Health)

CD4 >350: ART-Ineligible (ARV for prophylaxis only)


HAART HIV-infected mothers

HAART

AZT

AZT +

SD NVP+

SD TRV

OVERALL STUDY Sequential Randomized 2x2 Factorial Trial

Promise Study- P1077 (IMPAACT)

CD4 >350

AP 28-termIPPP for Duration BFWeaning

R

a

n

d

o

m

i

z

e

Infant uninfected

at birth

Continue

HAART

Mother

R

a

n

d

o

m

i

z

e

HAART

R

a

n

d

o

m

i

z

e

Stop

All ARVs

R

a

n

d

o

m

i

z

e

0

Infant

(if uninfected and <12

mos old at

time of weaning)

CTX

to 18 months

Infant NVP

No CTX

AZT +

SD NVP+

SD TRV

Late presenters


Future research on pmtct

Further studies on pathogenesis. HIV-infected mothers

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?)

Future research on PMTCT


Hiv transmission rates mother infant pairs los angeles study
HIV TRANSMISSION RATES HIV-infected mothersMother/Infant PairsLos Angeles Study

70

70

Total Number of Babies/year

% Infected

60

60

50

50

40

40

% of Babies Infected

30

30

Number of Babies with Outcomes

20

20

10

10

ZDV

076

0

0

1993

1994

1995

1988

1989

1990

1991

1992

* All mother/infant pairs prospectively enrolled prior to delivery


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