Lynne M. Mofenson, M.D.

Senior HIV Technical Advisor

Elizabeth Glaser Pediatric AIDS Foundation

Successes and Challenges Over the Last Decade in Research on Prevention

of Mother-to-Child HIV Transmission

What Have We Learned About Prevention of Mother-to-Child HIV Transmission in Last Decade?

What Have We Learned? The Good….

1.8% 0.6%0

10

20

30

40

% M

TC

T B

irth

Th

rou

gh

Ag

e 1

4 D

ays

AZT/sdNVP ART

Peripartum MTCT Significantly Lower with Maternal ART

0.8% 0.7%0

10

20

30

40

% M

TC

T T

hro

ug

h A

ge

24 M

on

ths

Infant NVPMaternal ART

PROMISE Trial Has Shown Maternal Treatment During Pregnancy

and Breastfeeding Can Reduce Transmission to Near 1%

Fowler MG et al. NEJM. 2016;375:1726-37

Antepartum

AZT/sdNVP

Antepartum

ART

Postnatal MTCT Very Low with Either Infant NVP or Maternal ART

Flynn PM et al. JAIDS. 2018;77:383-392

Postnatal

Infant NVP

Postnatal

Maternal ART

Antepartum Component

→ Women with CD4 >350

randomized to ART

vs AZT/sdNVP

Postpartum Component

→ BF women with CD4 >350

randomized to maternal ART

vs infant NVP

Overall

transmission with ART

1.3% at 24 months

in a breastfeeding population

Started 1st trimester Started 2nd trimester Started 3rd trimester

0.4% 0.9% 2.2%

ART Duration Affects Efficacy: Longer ART = More EffectiveMandelbrot L et al. CID 2015;61:1715-25

▪French Perinatal Cohort (8,075 women on ART) - evaluated association of

transmission with timing of treatment and delivery VL

Transmission:

For women starting ART

during pregnancy:

→Duration important for

optimal PMTCT; start 3rd

trimester = less effective

→Regardless of duration,

lowest rate transmission

with lowest delivery VL

Delivery RNA and Transmission According to Time ART Initiation

*threshold if assay LLD >50 c/mL

Timing ART:

Pre-Conception ART Had Greatest Efficacy for PMTCTMandelbrot L et al. CID 2015;61:1715-25

Delivery RNA and Transmission According to Time ART Initiation

→No infections in

2,651 women on

ART pre-conception

and with RNA <50

c/mL at delivery

→Even if on pre-

conception ART,

do see transmission

if higher VL at

delivery

Remarkable Increase in Women

Receiving ART During Pregnancy Globally

82%

44%

160,000

in 2018

450,000

in 2000

63% Decline in New Child HIV Infections Globally Since 2000

Number of new child infections, globally, 2000-2018

MTCT in High Resource Formula-Feeding Settings Are Currently 1% or Less

Peters H et al. Clin Infect Dis. 2017;64:527-8

UK National Study of HIV in Pregnancy and Childhood

MTCT in UK from 2000 to 2014

In 2012-2014 period in UK:

→ 60% of women were on ART at conception

→ 87% of women delivered with RNA <50 c/mL

→ Among those with delivery RNA <50 c/mL, MTCT was 0.14% (95% CI 0.02-0.52%)

7 infected infants born in UK

in 2012-2014 of 2,580 births to

women with HIV

0.27% (95% CI 0.11-0.56%)

Even in Low Resource Breastfeeding Settings

Significant Decline in Overall MTCT Rates are SeenThembisa South Africa Model Estimate: SPOTLIGHT https://www.spotlightnsp.co.za/2020/02/12/nuances-in-sas-hiv-epidemic-seven-graphs-that-tell-the-story/

4.1%

17.3%

→Largest decline was in peripartum infections

→Of new infections in 2019, 75% estimated

to occur postnatally through

breastfeeding

→ In 2019, estimated overall MTCT

was 4.1% (251,000 births to HIV+

mothers in South Africa = 10,196 new

child infections)

Peripartum infection

Postnatal infection

South Africa

What Have We Learned? The Bad…

While Coverage of Pregnant Women with ART Has Increased,

It Varies Significantly by Region

Source: UNAIDS 2019 estimates and Global AIDS Monitoring 2019

Coverage of HIV+ Pregnant Women with ART Globally By Region, 2019

92%86%

56%

76%

28%

59%

160,000

450,000 At current rate

of decline it

will take >22

years to

decrease new

infections to

our target of

20,000

Most of the decline in transmission

occurred between 2004 to 2012

(5.2% decline/year)430,000

230,000

Since 2015, slope of decline

has SLOWED to 3.9%/year

190,000

Slowing of Decline in New Child HIV Infections Since 2015

Number of new child infections, globally, 2000-2018

We have missed

2018 (and 2020 ) targets

40,000 20,000

Pregnancy and the Peripartum Period is a

Time of High Risk for HIV Acquisition for WomenThomson KA et al. J Infect Dis. 2018;218:16-25

→ Relative risk of

acquiring HIV per sex

act was significantly

increased in 2nd-3rd

trimester and early

postpartum periods

compared to non-

pregnant, non-

postpartum period.

Data on pregnancy and seroconversion in 2,751 HIV-uninfected women from 2 prevention studies

↑ HIV Transmission Risk Per Sex Act Translates into

High Rates of Incident Infection During Pregnancy/PPDrake AL et al. PLosMed 2014;11:e1001608

4.7 (3.3, 6.1)

2.9 (1.8, 4.0)

3.8 (2.0,4.6)

Pregnancy

Postpartum

Pregnancy and Postpartum

Overall

▪ Meta-analysis of data from 19 studies (all Africa)

→ Pregnancy &

postpartum constitute

periods of substantial risk

for HIV acquisition for

women (as defined by

WHO for use of PrEP)

Incident HIV during Pregnancy/BF

Is Associated with Increased Risk of MTCT, South AfricaDinh T et al. PLosOne 2015;10:e0125525

→ Global elimination of new pediatric HIV infection will not be possible

without eliminating incident infection in pregnant/PP women

→Although incident infection occurred in

only 6.7% of HIV+ women, incident HIV

accounted for 26% of all early MTCT.

▪ National survey of mother-infant pairs in South Africa: 28% (2,738/9,802) were

HIV-positive, of whom 6.7% (212/2,738) seroconverted during pregnancy.

Significant Proportion of Women on ART

Experience Viral Rebound Postpartum

▪ South Africa (Myer L. CID 2017): 523 women starting ART during pregnancy with initial viral

suppression to <50 copies/mL: 31% had >1 VL >1000 by 12 mo postpartum.

▪ National Study HIV Pregnancy and Childhood, UK (Huntington S. AIDS 2015):

→ In women conceiving

on ART, 10.7% rebound by 12 mo postpartum

→ In women starting

ART in pregnancy,

37.1% rebound by 12 mo postpartum

Primary Factors Related to New Child Infections Sub-Saharan Africa, 2018

PMTCT “Stacked Bar”

Incident infection

No ART

Stop ART

Late ART

Viremia on ART

PREGNANCY

Incident infection

No ART

Stop ART

Late ART

Viremia on ART

BREASTFEEDING

Primary Factors Related to New Child Infections Sub-Saharan Africa, 2018

PMTCT “Stacked Bar”

Incident infection

No ART

Stop ART

Late ART

Viremia on ART

PREGNANCY

Incident infection

No ART

Stop ART

Late ART

Viremia on ART

BREASTFEEDING

Globally, primary

missed opportunities are

No ART (mother not diagnosed or

started on ART) > Incident infection

> Stopped ART/poor retention

Democratic Republic of Congo, 2018 Malawi, 2018

Missed Opportunities, DRC:

No ART > Incident infection

Significant Country Differences in Missed Opportunities

→ Need to target

interventions to local

epidemiology

(e.g. invest in better

identification and treatment

of HIV+ women in DRC vs

PrEP programs to avoid

incident infection in

Malawi)

Missed Opportunities, Malawi:

Incident infection > Stopped ART

Number of new child infectionsNumber of new child infections

With Success of PMTCT, Increasing Numbers of Children Who Will Be Exposed to HIV and ART but Uninfected

▪ In 2018, an estimated 15

million children <15 years

been exposed to HIV and

uninfected (HEU)

▪ In countries with high HIV

prevalence among pregnant

women the proportion of

children that are HEU is high:

‒ 20-30% of all children in

Botswana, Eswatini,

Lesotho and South Africa

are HEU

Number of children HIV exposed and uninfected, globally, 2000-2018

Source: UNAIDS 2019 estimates

15,000,000

HIV and ART-Exposed Uninfected Children May Have Excess Morbidity and Mortality

▪ Evans C et al. Clin Infect Dis 2020 Jan 4 epub:

738 HIV-exposed uninfected (HEU)

and 3,989 HIV-unexposed children

(HUU) in SHINE study in Zimbabwe

18-month mortality was 40% higher

among HEU than HUU children

▪ Brennan AT et al. JAIDS 2019;82:1-8:

Meta-analysis of 12 studies (5,074

HEU and 12,881 HUU).

ACUTE DIARREHA

CHRONIC DIARREHA

PNEUMONIA

HEU had 20% increase in risk of acute diarrhea

and 30% increase in risk of pneumonia vs HUU

What Have We Learned? The Ugly…

Adverse Pregnancy Outcome Differs Between ART Regimens Zash R et al. JAMA Pediatr. 2017;171:e172222; Zash R et al. N Engl J Med. 2019;381:827-40

28.9%

9.9%

33.2%

10.7%

35.0%

11.3%

41.7%

17.9%

48.5%

19.5%

0%

10%

20%

30%

40%

50%

60%

Any adverse outcome Any severe outcome

Perc

en

t of pre

gn

an

cy o

utc

om

es

HIV uninfected DTG/TDF/FTC EFV/TDF/FTC NVP/TDF/FTC LPVr/TDF/FTC

(preterm [PTD], small for gestational age [SGA],

stillbirth [SB], neonatal death)

(very PTD, very SGA, SB, neonatal death)

DTG EFV NVP LPVr DTG EFV NVP LPVr

HIV+ Women on Different Preconception ART Regimens

Regardless of ART Regimen, Pregnancy Outcomes Are Worse in

Women with HIV on ART Compared to Women Without HIVZash R et al. JAMA Pediatr. 2017;171:e172222; Zash R et al. N Engl J Med. 2019;381:827-40

28.9%

9.9%

33.2%

10.7%

35.0%

11.3%

41.7%

17.9%

48.5%

19.5%

0%

10%

20%

30%

40%

50%

60%

Any adverse outcome Any severe outcome

Perc

en

t of pre

gn

an

cy o

utc

om

es

HIV uninfected HIV+ DTG/TDF/FTC HIV+ EFV/TDF/FTC HIV+ NVP/TDF/FTC HIV+ LPVr/TDF/FTC

(preterm [PTD], small for gestational age [SGA],

stillbirth [SB], neonatal death)

(very PTD, very SGA, SB, neonatal death)

DTG EFV NVP LPVr DTG EFV NVP LPVrHIV- HIV-

0

0.5

1

1.5

2

2.5

% w

ith

NT

D

0.94%

Tsepamo: Preconception Dolutegravir (DTG) and Neural Tube Defects (NTD)

0.12%0.05% 0.09%

Non-DTG preconception

May18 July Sept Nov Mar19

11300 14792

14 15

EFV pre-conception

May18 July Sept Nov Mar19

5787 7959

3 3

HIV-uninfected

May18 July Sept Nov Mar19

66057 89372

61 70

DTG preconception

May18 July Sept Nov Dec Mar19

N 426 1683

NTD 4 5

0.11%0.04% 0.08%

0.30%

Difference 0.20 (0.01, 0.59)Prevalence Difference

NTD by ARV/HIV Groups:DTG Preconception vs Others

Difference 0.26 (0.07, 0.66)

Difference 0.22 (0.05, 0.61)

Evolution of NTD Prevalence Over Time: May 2018-March 2019

Published/Presented Data on NTD with Preconception DTG

Study Food Folate Fortification #NTD/# PC Exposures

Tsepamo 2019 (NEJM 2019) No 5/1,683 (0.30%)

CDC-MOH Botswana 2019 (NEJM 2019) No 1/152 (0.66%)

Sibiude, France (CROI 2019) No 0/41

Chouchana, France (JAIDS 2019) No 0/49

Thorne, EPPICC 2018 No 0/64

Weissmann, Germany (Glasgow 2018) No 0/3

Kowalska, eastern Europe (Glasgow 2018) No 0/24

Bornhede, Sweden (Eur J ID 2018) No 0/14

Orrell, multicountry ARIA (Lancet HIV 2017) No 0/1

APR July 2019 International registry (most) 1/312 (0.32%)

Brazil case-control (IAS 2019) Yes 0/384

Advance, S Africa (IAS 2019) Yes 0/54

Money, Canada (BJOG 2019) Yes 0/69

Grayhack, US (AIDS 2018) Yes 0/28

Study Food Folate Fortification #NTD/# PC Exposures

Tsepamo 2019 (NEJM 2019) No 5/1,683 (0.30%)

CDC-MOH Botswana 2019 (NEJM 2019) No 1/152 (0.66%)

Sibiude, France (CROI 2019) No 0/41

Chouchana, France (JAIDS 2019) No 0/49

Thorne, EPPICC 2018 No 0/64

Weissmann, Germany (Glasgow 2018) No 0/3

Kowalska, eastern Europe (Glasgow 2018) No 0/24

Bornhede, Sweden (Eur J ID 2018) No 0/14

Orrell, multicountry ARIA (Lancet HIV 2017) No 0/1

APR July 2019 International registry (most) 1/312 (0.32%)

Brazil case-control (IAS 2019) Yes 0/384

Advance, S Africa (IAS 2019) Yes 0/54

Money, Canada (BJOG 2019) Yes 0/69

Grayhack, US (AIDS 2018) Yes 0/28

No folate food fortification, preconception DTG NTD prevalence

6 NTD / 2,031 = weighted estimate 0.36% (0.10-0.62)

NTD pooled prevalence, general population without food folate fortification: 0.09-0.1%

With folate food fortification, preconception DTG NTD prevalence

1 NTD / 847 = weighted estimate 0.12% (0.0-0.34)

NTD pooled prevalence general population with food folate fortification: 0.06%

Published/Presented Data on NTD with Preconception DTG

Study Food Folate Fortification #NTD/# PC Exposures

Tsepamo 2019 (NEJM 2019) No 5/1,683 (0.30%)

CDC-MOH Botswana 2019 (NEJM 2019) No 1/152 (0.66%)

Sibiude, France (CROI 2019) No 0/41

Chouchana, France (JAIDS 2019) No 0/49

Thorne, EPPICC 2018 No 0/64

Weissmann, Germany (Glasgow 2018) No 0/3

Kowalska, eastern Europe (Glasgow 2018) No 0/24

Bornhede, Sweden (Eur J ID 2018) No 0/14

Orrell, multicountry ARIA (Lancet HIV 2017) No 0/1

APR July 2019 International registry (most) 1/312 (0.32%)

Brazil case-control (IAS 2019) Yes 0/384

Advance, S Africa (IAS 2019) Yes 0/54

Money, Canada (BJOG 2019) Yes 0/69

Grayhack, US (AIDS 2018) Yes 0/28

No folate food fortification, preconception DTG NTD prevalence

6 NTD / 2,031 = weighted estimate 0.36% (0.10-0.62)

NTD pooled prevalence, general population without food folate fortification: 0.09-0.1%

With folate food fortification, preconception DTG NTD prevalence

1 NTD / 847 = weighted estimate 0.12% (0.0-0.34)

NTD pooled prevalence general population with food folate fortification: 0.06%

Published/Presented Data on NTD with Preconception DTGDefinitive conclusions cannot yet be drawn.

→ Surveillance is ongoing (Tsepamo Study, APR) and more

data will be available, as will data from other birth

surveillance programs in Malawi/Uganda as

DTG gets rolled out.

NTD risk, if real, appears to be significantly under 1%.

With risk/benefit analyses showing substantial DTG benefit in

women childbearing potential (Dugdale D. Ann Int Med 2019; Phillips A. Lancet HIV

2020), WHO now recommends DTG as preferred for all

individuals.

What Have We Learned?

▪Over the past decade we have learned a great deal about

how to prevent of mother to child HIV transmission, and our

substantial successes have led to the aspiration that we

could eliminate new pediatric HIV infection in the upcoming

decade.

▪However, we have also learned that we cannot be

complacent about our successes – progress has slowed

primarily due to implementation challenges – such as need

to improve identification of women with HIV and support

them to remain on treatment – as well as continued incident

infection in women.

Thank You For

Your Attention!