hiv testing at birth: brief summary potential pros and...
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HIV Testing at Birth:
Brief Summary Potential
Pros and Cons
Lynne M. Mofenson, M.D.
Senior HIV Technical Advisory
Elizabeth Glaser Pediatric AIDS Foundation
Why Consider HIV Testing at Birth?
Goal of HIV testing is identification of an infected
infant in order to initiate antiretroviral therapy (ART)
early and therefore reduce morbidity and mortality.
Testing without early initiation of ART will not be
helpful.
How early do you need to start ART to reduce
mortality/morbidity?
Is there an incremental gain in reducing morbidity
and mortality with birth testing compared to current
standard 6 week PCR?
Lots of assumptions, but very little data!
Clinical
benefit
Laboratory
test
performance
Programmatic
issues
↓ Mortality
↓ Morbidity
↑ Neurodevelopment
↓ Viral reservoir
Turn-around time
Health resources
Acceptability
Retention
Cost
Sensitivity
Specificity
Prevalence of HIV
POTENTIAL PROS POTENTIAL CONS
Pros vs Cons of HIV Testing at Birth
Let’s examine some assumptions underlying these benefits/risks
Question:
What proportion of infected children will be
detected by adding an HIV test at birth?
HIV Testing and
Time of HIV Transmission
in Current ART Era
Timing of Infection and HIV Testing
>28 wks
Intra-
partum
35-40%
1-6 mos 6-24 mos0-1 mo
In utero
10-25%
<28 wks
Postpartum
35-40%
Early Late
Pregnancy Breastfeeding
Early Late
Without
ART
Labor-
Delivery
Timing of Infection and HIV Testing
Birth test detects only in utero
infection
>28 wks
Intra-
partum
35-40%
1-6 mos 6-24 mos0-1 mo
In utero
10-25%
<28 wks
Postpartum
35-40%
Early Late
Pregnancy Breastfeeding
Early Late
6 wk test detects
in utero + intrapartum/
early PP infection
Without ARV, IU infection accounts for only small proportion of
infections, although absolute rate relatively high.
In presence of ARVs, will there be change in proportion of
infections in utero vs intrapartum vs postnatal?
– May see ↑ in proportion of infection occurring in utero
depending on when maternal ART is started OR ↑postnatal
depending on duration breastfeeding and ARV adherence.
Without
ART
9 and 18 mo test
includes postnatal
infection
Labor-
Delivery
7% absolute
(19% proportion)
13% absolute
(35% proportion)
17% absolute
(46% proportion)
Nduati R. Kenya BF Study JAMA 2000;283:1167-74
OVERALL
37%
Timing of Transmission in Maternal ART StudiesVery Few Studies Provide Data on HIV Status at Birth
Overall 6 mo Birth 1d-6 wk 6 wk-6 mo
“Historical” 10-25% 35-40% 35-40%
Kesho Bora (N=394) 4.9% 1.8% 1.5% 1.6%
proportion of overall tx 37% 31% 33%
KiBS (N=487) 5.0% 2.5% (7 d) 1.7% 0.8%
proportion of overall tx 50% 34% 16%
Mma Bana (N=709) 1.1% 0.8% 0% 0.3%
proportion of overall tx 72% 0% 27%
Zambia B+ (N=219) 4.1% 18 mo 0.9% 0.5% 2.7% (all >6 mos)
proportion of overall tx 22% 12% 66%
Kesho Bora Lancet 2011; Thomas PLosMed 2011; Shapiro NEJM 2010: Ngoma JIAS 2015
There does appear to be a shift toward ↑ proportion in utero infection
with maternal ART but the extent varies btn studies and duration BF
Absolute rate of IU infection (<1-3%) relatively low with maternal ART
Question:
Does it make a clinical difference if
detect the infected child at birth
compared to 6 weeks?
Time of HIV Transmission
and Mortality Risk
Time of Transmission and Mortality
Overall mortality in HIV-infected infants in first
year of life is very high (35-50%1, 3).
However, mortality significantly varies by timing
of transmission.1Newell ML et al. Lancet 2004;364:1236-432Zijenah LS et al. AIDS 2004;18:273-803Mirinda E et al. PIDJ 2007;26:519-254Marston M et al. Int J Epi 2011;40:385-965Becquet R et al. PLosOne 2012;7:e28510
Without
ART
>28 wks
Intra-
partum
35-40%
1-6 mos 6-24 mos0-1 mo
In utero
10-25%
<28 wks
Postpartum
35-40%
Early Late
Pregnancy Breastfeeding
Early Late
Labor-
Delivery
Does Time of Infection Make a Difference?Higher Early Death with Perinatal (IU+IP) vs Postnatal HIV
Becquet R et al. PLosOne 2012;7:e28510
Meta-analysis of 12 studies including 12,112 infants of HIV+ mothers
(8,964 uninfected and 2,509 infected)
1,363 perinatal (med PCR 19 d)
581 postnatal
(HIV- >4 weeks, + later)
565 unknown time
12 mo death
Perinatal HIV+ 52%
Unknown time HIV+ 38%
Postnatal HIV+ 26%
Uninfected 4%
Cum
ula
tive p
robabili
ty o
f death
Limited Data – But Not a Clear Difference - Between
In Utero and Intrapartum Infection for Very Early Mortality
Included 89 IU, 104 IP/ePPinfants.
Analysis restricted to those alive at 8 weeks.
IU vs IP/early PP: HR 1.91 (1.1-3.2), with differences not emerging until >90 days
Zijenah LS et al. AIDS 2004;18:273-80
Survival from 56 days to 6 months IU vs IP
In utero
Intrapartum/
early PP
In this meta-analysis of 9
trials including 3,468
children, not much
difference IU vs IP
infection in early mortality
?
Newell ML et al. Lancet 2004;364:1236-43
Is Very Early Mortality an Issue?
Emerging Peak in Early Infant Mortality, South AfricaBourne DE et al. AIDS 2009;23:101-6.
Evaluated overall mortality birth-5 years 1997-2002, S Africa
Saw emerging peak in mortality at 2-3 mos by 2002
Is Very Early Mortality an Issue?
Emerging Peak in Early Infant Mortality, South AfricaBourne DE et al. AIDS 2009;23:101-6.
Evaluated reported cause death as “likely” HIV related or not
2-3 mo peak was due to likely HIV-related mortality, whereas
non-HIV mortality did not change over time
Presumed HIV infection only, and
no data on time of transmission
HIV
/AID
S-r
ela
ted m
ort
alit
y
Early Infant Mortality in HIV-Infected Infants - ZimbabweMarinda E et al. PIDJ 2007;26:519-25
Similar to Bourne study, see rapid ↑ mortality with IU/IP infection starting
~60 days (2 months) to 120-180 days (3-6 months)
Similar to Zijenah Study, see potential difference IU-IP after ~90-120 days
ZVITAMBO trial (1997-2000), N=13,792: 2 Year Mortality
⁻ 2.9%
⁻ 9.2%
⁻ 33.2%
⁻ 65.0%
⁻ 67.5%
In utero infection (381)
Intrapartum infection (508)
Postnatal infection (258)
HIV-exposed uninfected (3,135)
HIV-unexposed (9,510)
Not clear differences HIV+ & HIV- in the neonatal 0-2 month period
Early Infant Mortality in HIV-Infected Infants - ZimbabweMarinda E et al. PIDJ 2007;26:519-25
Similar to Bourne study, see rapid ↑ mortality with IU/IP infection starting
~60 days (2 months) to 120-180 days (3-6 months); and similar to Zijenah
Study, see potential initial difference IU-IP after ~90-120 days
ZVITAMBO trial (1997-2000), N=13,792: 2 Year Mortality
⁻ 2.9%
⁻ 9.2%
⁻ 33.2%
⁻ 65.0%
⁻ 67.5%
In utero infection (381)
Intrapartum infection (508)
Postnatal infection (258)
HIV-exposed uninfected (3,135)
HIV-unexposed (9,510)
Not clear differences HIV and HIV- in the neonatal 0-2 month period
If there is not significant
effect of HIV on mortality
before age 2 mos, will
birth testing add any
benefit in terms of
mortality?
But What About Early Morbidity?
Violari A et al. NEJM 2008;359:2233-44:
– CHER: randomized at 6-12 wks to early vs deferred ART.
– Screening <6-12 weeks – children who did NOT enter
• CD4 <25%: 110/560 (19.6%)
• Symptoms: 16/560 (2.9%)
• Died: 7/560 (1.3%)
Innes S et al. JIAS 2014;17:18914
– Record review 403 kids starting early ART S Africa; started
median age 8.4 wks (7.2-9.7) (no data on time infection)
– Prior to starting ART (so age <8 wks):
• 51% had CD4 <25%
• 29% WHO stage 3 or 4
• 62% had advanced disease before starting ART
• Each month increase in age at ART associated with
1.69 increased odds of developing advanced disease
But What About Early Morbidity?
Violari A et al. NEJM 2008;359:2233-44:
– CHER: randomized at 6-12 wks to early vs deferred ART.
– Screening <6-12 weeks – children who did NOT enter
• CD4 <25%: 110/560 (19.6%)
• Symptoms: 16/560 (2.9%)
• Died: 7/560 (1.3%)
Innes S et al. JIAS 2014;17:18914
– Record review 403 kids starting early ART S Africa; started
median age 8.4 wks (7.2-9.7) (no data on time infection)
– Prior to starting ART (so age <8 wks):
• 51% had CD4 <25%
• 29% WHO stage 3 or 4
• 62% had advanced disease before starting ART
• Each month increase in age at ART associated with
1.69 increased odds of developing advanced disease
Does appear to be early
effect of HIV on CD4 and
symptoms before age 8
wks; could birth testing
and early ART make a
difference?
HIV Test Performance
HIV Test Performance
Important Factors Affecting Assay Accuracy
Time of acquisition of infection – birth test only detects
IU infection.
– Critical need for 2nd test at 6-10 weeks for those
testing negative to diagnose IP/early PP infection.
HIV prevalence in infants (depends on PMTCT).
– Low prevalence ↑ number false positive tests – must
have CONFIRMATORY test for those testing +.
Possibly maternal/neonatal ARV use (potential delay in
detection – but not enough data to determine now).
– Should 6 week test be delayed until 10-12 weeks
(after infant prophylaxis completed)?
At Low HIV Prevalence (e.g., PMTCT),
Rate of False Positive Single Test Increases
Performance of HIV assay with sensitivity of >95% and
specificity of 98% at various HIV prevalence levels
At Low HIV Prevalence (e.g., PMTCT),
Rate of False Positive Single Test Increases
False + results are common if only a single test
is performed when transmission rates are low
(regardless of time transmission).
If resources allow for only 2 viral tests, would a
single test at birth and 6 weeks with no
confirmation of + result be better than 1st test at
6 weeks with confirmation of + result?
Strategy
# False +/
100 ART initiations
6 wk only, with confirmatory test if + 0.6
Birth + 6 wk test, no confirmatory test 34.5
Modeling analyses by Andrea Ciranello for WHO
Programmatic Issues
EID Total TAT time: 61.7 days (CI = 55.3, 68.7)
Michelle Gill, EGPAF-2013 IAS Abs. MOAD0202
Programmatic Issues
How early can ART be started?
– Turn-around time from test to ART start
– Availability of treatment for neonates
• Formulation, dosing, safety
Assay sensitivity/specificity – need for confirmatory
test – what if start ART & confirmatory test negative?
How will birth testing affect return/retention?
– Will mothers return for 6 week test?
Health resources – who tests, extra visit for results,
lab burden?
Incremental cost vs benefit
Even if Tested in Timely Fashion, There are Significant
Delays from Testing to ART Start - S Africa ExampleLillan RR et al. PIDJ 2013;32:1080-5
PCR test 6.6 wks
PCR result visit 10.6 wks
1st visit for care 12.6 wks
ART started16.0 wksViral suppression 36.5 wks
Rapid increase in mortality in infants with in utero/intrapartum infection
beginning <60 days (2 months) through 120-180 days (3-6 months)
High Early Infant Mortality in Infants Infected
In Utero/IntrapartumMarinda E et al. PIDJ 2007;26:519-25
In utero infection
Intrapartum infection
Postnatal infection
HIV-exposed uninfected
HIV-unexposed
Suppress
VL
37 wk
Start
ART
16 wk
PCR
6.6 wk
With Birth PCR, How Quickly Need to Start ART to
Achieve Suppression Before Rapid Increase Mortality?
In utero infection
Intrapartum infection
Postnatal infection
HIV-exposed uninfected
HIV-unexposedPCR birth
Suppress
VL
12 wk
Start
ART
2-4 wk
Without POC test, will it be possible to do test, give results
and start ART by age 2 weeks?
(Maybe - Abs 4: med time to start in kids <12 mo/o was 8 d)
Source: Global AIDS Response Progress Reporting (WHO/UNICEF/UNAIDS); Proportion of HIV-exposed infants receiving virological testing by their second month of age.
EID coverage in 2014
0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1
Angola
Botswana
Burundi
Cameroon
Chad
Côte d'Ivoire
Democratic Republic of the Congo
Ethiopia
Ghana
Kenya
Lesotho
Malawi
Mozambique
Namibia
Nigeria
South Africa
Swaziland
Uganda
United Republic of Tanzania
Zambia
Zimbabwe
50%HIV-exposed
Infants received a virological test in 21
African GlobalPlan countries
What about optimizing
current recommendations?
Clinical
benefit
Laboratory
test
performance
Programmatic
issues
↓ Mortality
↓ Morbidity
↑ Neurodevelopment
↓ Viral reservoir
Turn-around time
Health resources
Acceptability
Retention
Cost
Sensitivity
Specificity
Prevalence of HIV
POTENTIAL PROS POTENTIAL CONS
Pros vs Cons of HIV Testing at Birth
ROUNDTABLE PANEL MEMBER THOUGHTS - DISCUSSION