1. VERTICAL TRANSMISSION PREVENTION
Best Practices Amy Slogrove 19 July 2016
CTN PMTCT Symposium
AIDS 2016, Durban, South Africa
Good evening ladies and gentlemen, I am very pleased to be part of this symposium and to be able to share some thoughts on Best Practices in PMTCT.
This presentation is focused on what are currently considered to be the best practices for prevention of vertical transmission of HIV from mothers to their infants.

2. New HIV Infections in Children: 2001-2015
The evolution and expansion of practices and interventions to prevent paediatric HIV has dramatically changed over the last 2 decades, and we see a phenomenal decline from half a million new infections in 2001 to new infections in the year But additional children born each year with a life-long complex chronic disease is still substantial.
The number of women living with HIV and giving birth each year has been static at 1.5 million. And more than 50% of pregnant women in LMICs do not receive an HIV-test during pregnancy, which is the first step to preventing HIV infection in children. So there is still a lot of work to be done, and your time spent with us this on this beautiful Durban evening is warranted!
But: 1.5 million women living with HIV give birth each year – unchanged
>50% of pregnant women in LMICs do not receive an HIV-test

3. Hot off the press... Key updates related to PMTCT
Best practices for a public health approach in high prevalence settings
So to guide us in how to most efficiently and effectively prevent mother to child transmission are the new WHO consolidated guidelines, that following an in-depth review of the literature and available evidence, provide what can be considered as the best practices for a public health approach to PMTCT particularly in high prevalence settings.
There certainly may be other strategies better suited to low prevalence settings and alternative interventions for individual complicated situations.
But this document, with a number of key new or updated recommendations, essentially guides us in how to close this gap in PMTCT.

4. Overview Timing of HIV Testing Maternal Antiretroviral Therapy (ART)
Pregnant women & infants
Maternal Antiretroviral Therapy (ART)
Maternal Health & PMTCT
Infant Prophylaxis
Research Gaps / Responsibilities
Take Home Messages
We will focus on these key updates and consider briefly the evidence informing them, specifically related to the timing of HIV testing in mothers and infants, maternal ART and what it is expected to achieve for maternal health and for PMTCT and the reason for changes to recommendations for infant prophylaxis.
Finally consider research gaps and responsibilities and conclude with take home messages for PMTCT research.
There are a number of additional areas of importance that we will not have time to discuss today – including the body of implementation science work, feasibility, cost-effectiveness and community acceptability of these interventions and strategies.

5. Timing of HIV Testing: pregnant women
Time
HIV Viral Load
Highest Risk
Evidence
4% of breastfeeding women acquired HIV-infection during pregnancy or while breastfeeding (Kenya, Malawi, SA)
20% of postpartum transmission due to new HIV-infection in women while pregnant/breastfeeding (Zimbabwe)
Summary
Routine component of care
All HIV-negative pregnant women retested third trimester, labour, postpartum
Lactating mothers retested periodically
The WHO now strongly recommends that HIV testing should be a routine part of care not only in antenatal settings but also in childbirth, postpartum and paediatric care settings. And specifically that we should be retesting previously HIV-uninfected or unknown status pregnant women again during the third trimester, or peripartum when we can still provide effective PMTCT interventions. We must also be vigilant for new HIV-infection during breastfeeding, and although there is absolutely no doubt that breastfeeding is the optimal feeding strategy for infants and young children, there is a growing body of evidence that this is also a time when new HIV-infections occur during women, up to 4% of breastfeeding women in Southern and Eastern African countries becoming newly infected during pregnancy or while breastfeeding and these undiagnosed new infections account for about 20% of all postpartum transmission.
The stage of acute infection in the mother is the time of highest risk of transmission to the baby whether during pregnancy or breastfeeding. During acute infection in the mother, her viral load rises dramatically, and it is the viral load that determines vertical transmission risk.

6. Timing of HIV Testing: pregnant women
Time
HIV Viral Load
Highest Risk
In addition to the testing recommendation, the WHO has made a “good practice statement”, that even when HIV is only identified later in pregnancy or postpartum maternal ART should be initiated urgently, as the most effective way of preventing mother to child transmission is by reducing the maternal viral load.

7. Timing of HIV Testing: HIV-exposed infants
Birth
9 months
18 months
Waning of infant maternally-derived
antibody levels
Summary
4-6 weeks all HEI: virologic testing (DNA-PCR)
9 months all HEI: screen with serologic test, if reactive confirm with virologic test
Breastfeeding HEI: serologic 18 months or 3 months after breastfeeding cessation
Evidence
CHER trial – rapid HIV progression < 12 weeks of age
Rapid serologic 9 months – sensitivity 99.8% (95%CI %)
Discussion around value of birth
Moving on to testing of HIV-exposed infants...We are mostly all familiar with HIV-exposed infant testing and that HIV-infection should be excluded with a virologic HIV-PCR test at 4-6 weeks of age. The rationale behind this is to identify as early as possible infants infected antenatally or peripartum and to start ART as soon as possible due to the rapid disease progression and high mortality in these very young infants that was shown in the CHER trial. In addition HIV-infection should be screened for with a serologic antibody test at 9 months. This is important, because a rapid ELISA test is about one sixth the cost of a PCR test, and although we still need to confirm HIV-infection with a PCR test if the rapid ELISA antibody test is positive, if the test is negative we can confidently exclude HIV-infection. As we can see in the top right figure, infant maternally-derived antibodies start to wane from 6 months of age, and by 9 months 70% of infants have lost all maternal antibodies. Rapid tests in 9 month old infants have good sensitivity, with low risk of false-negative results, that has often been the anecdotal concern with using rapid tests in this age group.
Some infants linger longer with maternal antibodies persisting until about 15 months of age, and so to confirm a positive diagnosis of HIV in a child under 18 months of age we must use a virologic PCR test.
Very important to remember that as long as an infant is being breastfed they are exposed to HIV and so even in the presence of previously negative test results all breastfed infants should have HIV excluded again 3 months after all breastfeeding has ceased.

8. Timing of HIV Testing: Outside of PMTCT Programs
Inpatient
Outpatient
Developmental
Delay
Parent/Sibling
PMTCT programs
Summary:
More testing
Inpatient care (diarrhoea, pneumonia, sepsis)
Outpatient care (malnutrition, IMCI & TB clinics)
(Developmental delay)
Parents, siblings diagnosed with HIV
Evidence
22% of paediatric inpatients – undiagnosed HIV infection (Systematic review)
25% of malnutrition clinic attendants (Eastern & Southern Africa)
Highly acceptable to parents & caregivers
An important new recommendation is that in generalized epidemics we cannot only be thinking of HIV exposure and HIV infection in PMTCT program settings. Any child warranting inpatient treatment or any child attending malnutrition, IMCI or TB clinics, should have HIV infections excluded. In a systematic review of studies performing inpatient paediatric HIV testing, 22% of paediatric inpatients were newly diagnosed with HIV during the admission; and 25% of children attending malnutrition clinics in Eastern and Southern Africa were newly diagnosed with HIV in these clinics. Testing in these settings is highly acceptable to parents and caregivers, 92% of parents found inpatient and malnutrition clinic testing acceptable.
In addition a “good practice statement” by the WHO is that whenever an adult is diagnosed with HIV, we must consider whether there are children that need to have HIV-infection excluded.
So in high prevalence settings we need to be thinking of HIV testing beyond the traditional PMTCT settings.

9. Maternal ART Summary Simple! Better for maternal health
Better for PMTCT
Better for programs
Evidence
RCTs: TEMPRANO & START - adults
PROMISE: HIV transmission with triple ART (0.6%) vs. AZT+sdNVP (1.8%)
Malawi, South Africa – program feasibility
A major change from previous guidelines is that for HIV-infected pregnant women there is no longer a differentiation between those that need ART for their own health and those that only need prophylaxis for PMTCT. Now in line with the general adult guidelines, all pregnant and breastfeeding women should be initiated on ART. The evidence for this being the best strategy in adults generally comes from the TEMPRANO and START trials.
TEMPRANO observed a reduction in severe HIV morbidity (deaths, AIDS, severe non-AIDS diseases) when starting ART at CD4 counts > 500 compared to initiation at < 500
START observed less serious AIDS-defining illness or death when starting immediate vs. deferred (<350) ART (median CD4 in immediate group 651;deferred group 408)
How good is ART for preventing vertical HIV transmission? From the PROMISE study we know that ART is also better than monotherapy prophylaxis for PMTCT. And firstly in Malawi and now in South Africa there is evidence that universal maternal ART is a feasible strategy for PMTCT programs.

10. Maternal ART
Again I want to emphasize the “good practice” statement, that it doesn’t matter how late HIV is diagnosed in pregnancy or postpartum, maternal ART should be started urgently, as the best way to prevent mother-to-child transmission is to reduce viral load.

11. Infant Prophylaxis Evidence Summary
High risk infants – born to women with:
< 4 weeks ART prior to delivery
Viral load > 1000 copies/ml within 4 weeks prior to delivery
Incident HIV infection during pregnancy or while breastfeeding
HIV only identified postpartum
Infant dual prophylaxis (AZT+NVP)
Breastfed – 12 weeks
Formula – 6 weeks
Not high risk
Mothers on ART > 4 weeks
VL < 1000 during last 4 weeks of pregnancy
Infant NVP prophylaxis
Breastfed – 6 weeks
Formula – 4 to 6 weeks
Evidence
HPTN040 – no ARVs during pregnancy; 2/3 drug infant prophylaxis better than 1
HPTN046 – breastfed infants, mothers on ART; no difference in PN transmission with 6 weeks vs. 6 months of infant NVP
The infant prophylaxis strategy has also changed, and infants are now divided into those that are considered as “high risk” for HIV infection and those that are not high risk.
High risk infants include those born to women with Essentially all women that are likely to have an unsuppressed viral load. These infants should then receive dual prophylaxis with AZT and NVP, that should be given to all infants for at least 6 weeks and continued to 12 weeks in breastfed infants. This strategy is informed by the HPTN040 trial that showed that dual or triple infant prophylaxis was better than single drug prophylaxis when mothers had received no ARVs during pregnancy.
Infants not at high risk require only NVP mono prophylaxis, and only for a maximum of 6 weeks even when breastfeeding. The evidence that it is safe to limit the duration of prophylaxis to 6 weeks even when breastfeeding comes from HPTN046 that showed no difference in postnatal transmission with 6 weeks or 6 months of infant NVP, but this is provided that mothers are on ART and with a suppressed viral load.

12. Infant Prophylaxis – just a bridge
Importantly, infant prophylaxis is really only a bridge to allow time for maternal viral suppression. The risk of transmission is all related to the duration of maternal ART and whether the mother is virologicaly suppressed or not.
Maternal viral load & duration of maternal ART
are key determinants of transmission risk

13. Research Gaps / Responsibilities
Maternal & Infant HIV Testing
Better understanding of mothers responses to negative HIV results – testing fatigue?
Does birth testing add value for PMTCT programs, infants & families?
Universal maternal ART
TDF/3TC/EFV as effective for PMTCT as the LPV/r based PROMISE regimens?
Effect of ART on pregnancy outcomes & short/ long-term HIV-exposed infant outcomes?
Infant prophylaxis
Is NVP+AZT the right dual therapy combination for high risk infants?
What is appropriate prophylaxis for infants of mothers on failing regimens / with drug resistance ?
Breastfeeding
Family & community acceptability of interventions, services, delivery strategies
Although these guidelines are fairly well based on evidence, there have been some extrapolations and a number of gaps in our understanding remain. And whenever we provide an intervention there is almost always a risk-benefit ratio to be weighed up. So as researchers in this field we have a responsibility to fill these gaps to ensure that the risk-benefit ratio of our recommendations remains on the positive side.
The guidelines now include a lot of testing of both mothers and infants, and we don’t really understand how mothers will respond to all this testing and whether testing fatigue may ensue. The question of the value of birth testing is currently being hotly debated and there is still a large gap in our understanding of how whether this will actually translate to improved infant survival.
The recommended first-line regiment for universal ART is TDF/3TC/EFV and is this as efficient for PMTCT as the LPV/r based regimen used in the PROMISE study? And there is still a lot of work to be done to better understand how ART impacts both positively and potentially negatively on birth outcomes as well as short and long-term outcomes of HIV and ARV exposed infants.
The recommended dual therapy combination for high risk infants of NVP + AZT has not been directly evaluated.
We have a long way to go in identifying strategies to support all mothers in sustained breastfeeding. And we continuously need to evaluate the acceptability to families and communities of the recommended interventions, services and delivery strategies.

14. Take Home Messages Test, test & test again Universal maternal ART
Pregnant women, HIV-exposed infants & outside of PMTCT programs
Universal maternal ART
Best for maternal health & also most effective for PMTCT
Infant prophylaxis
Only a bridge & high risk infants need a stronger bridge
Research responsibilities
Many
Invest in research competencies
To end, the 5 take home messages for best practices in PMTCT:
Test, test and test again, pregnant women, HIV-exposed infants & outside of PMTCT programs
Universal maternal ART is the best strategy for maternal health and also currently the most effective intervention for PMTCT
Remember that infant prophylaxis is only a bridge and that high risk infants need a stronger bridge with dual instead of only mono-prophylaxis
As far as research responsibilities go, there are many and so my last take home message is that investing in research competencies through small workshops like this and through formal training are critical to conducting research that will see us meet these responsibilities

15. Acknowledgments
CTN International Postdoctoral Fellowship Award Joel Singer & Jacquie Sas Stellenbosch University University of British Columbia University of Cape Town
I would like to acknowledge the CTN family, but particularly Joel Singer and Jacquie Sas who have been pivotal in my progression to this point. And the institutions that have supported this journey.