Successes and Challenges Over the Last Decade in Research...
Transcript of Successes and Challenges Over the Last Decade in Research...
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
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
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
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
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!