Prof. Graham P. Taylor, UK

1. Mother to Child Transmission of
HIV: The Third Trimester
Graham P Taylor
Professor of Human Retrovirology

2. Concept
Is there an acquired immuno-deficiency
syndrome in children?
Amman AJ
Pediatrics. 1983 Sep;72(3):430-2
Photo by D Kunkel
http://classes.biology.ucsd.edu/bimm110.SP07/lec
tures_WEB/L09.05_Gametogenesis.htm
Maternal transmission of acquired immunodeficiency
syndrome
Cowan MJ et al
Pediatrics. 1984 Mar;73(3):382-6.
Recommendations for assisting in the prevention of perinatal transmission of human T-lymphotropic virus type
III/lymphadenopathy-associated virus and acquired immunodeficiency syndrome
MMWR 1985 Dec 6;34(48):721-6, 731-2.
Postnatal transmission of AIDS-associated
retrovirus from mother to infant
Ziegler et al
Lancet 1985 8434;896-8

3. The First Trimester
Safety concerns – particularly
Efavirenz
Role of mode of delivery
Role of single dose Nevirapine
Breast v Formula Feeding
Confusion over preterm birth

4. Breast v Formula
HIV-1 infection rates in a Vit A study in Durban
3/12
Never Breast Fed 156 18.8%
Excl. Breast-Fed 103 14.6%
Mixed Feeding 288 24.1%
Coutsoudis A, et al, Lancet, 1999; 354:471-476

5. Breast v Formula
HIV-1 infection rates in a Vit A study in Durban
3/12 15/12
Never Breast Fed 156 18.8% 20%
Breast-Fed 393 21.3%
Excl. Breast-Fed 103 14.6% 25%
Mixed Feeding 288 24.1% 35%
Coutsoudis A, et al, Lancet, 1999; 354:471-476
Coutsoudis A, et al, AIDS 2001;15:379-387

6. Breast v Formula
Randomised Clinical Study 425 women
Breast Formula
212 213
Compliance 96% 70%
Exclusive Breast 3/12 56%
6/12 3%
@ 24/12 HIV Positive 36.7% 20.5% p.001
Deaths 24.4% 20% p.3
HIV-Free Survival 58.0% 70% p.02
Nduati R, JAMA 2000, 283:1167-1174

7. Preterm birth and HAART
Regional Year Monotherapy HAART ORa
Ref
Switzerland 1996 -1998 19/112
(16.7%)
10/30 (33%) 2.0 1
Europe (ECS) 1986 -2000 93/555 (17%) 41/188 (22%) no PI
29/101 (29%) with PI
1.49 b
2.15b
2
Europe (ECS) 1986 -2004 118/704
(16.8%)
274/1075 (25.5%)
Started antenatally
Started pre-pregnancy
2.03
2.19
3
Germany/Austriac
1995 -2001 20/76 (26%) 29/75 (39%)
No PI
With PI
1.15
4.47
4
London UK 1995 -2006 3/52 (6%) 27/159 (16.9%) 5
UK National 1990 -2005 107/1061
(10.1%)
(incl dual)
476/3384 (14.1%) 1.5 6
USA (WITS) 1990 -1998 254/1590
(16%)
55/396 (14%)CART no PI
25/137 (18%) HAART with PI
0.95
1.45
7
USA (PSD) 1989 -2004 457/2601
(17%)
329/ 1781 (18%) no PI
132 782 (17%) with PI
d
8

8. Neural tube defect scare
Cynomolgus macaques
exposed to efavirenz
3/22 (13.7%)
Malformations
Efavirenz reclassified D
following 3 cases meningo-
myelocoele and one Dandy-
Walker Syndrome
retrospectively reported

9. The Second Trimester
Infant feeding
Antiretroviral
therapy
Mode of
Delivery

10. 21 years of TasP, PEP & PrEP
477 women (USA, France) CD4 >200x106
/L
Zidovudine 100mg x 5/day
2nd Trimester Zidovudine 1mg/kg/hr IVI during labour
Zidovudine 2mg/kg/6hr po neonate 6/52
HIV transmission - Placebo 25.5%
- Zidovudine 8.3%
67.5% relative reduction in transmission
,Connor EM et al NEJM 331: 1173-80 3.11.94

11. Efficacy of PLCS + ZDVm
436 women randomly assigned to ECS or SVD
1993 – Mar 1998 - Analysis Nov 1998 - 370 infants
Assigned to n Pos %
ECS 170 3 1.8 }
SVD 200 20 10.5 }p<0.001
Allocated MOD No ZDV ZDVm
SVD 19.5% 4.3%
ECS 3.9% 0.8% (1/119)
% Reduction 80% 82%
European Mode of Delivery Study Lancet 1999;353:1035-39

12. Reduction in late transmission with post-partum
interventions: The BAN Study
RCT – Malawi – 24/52 BF (4/52 wean)
Mothers with CD4 > 250
Infants ZDV/3TC 1/52 + sdNVP
5% infected at birth - excluded
A. Maternal HAART Combivir/NVP or Kaletra
B. Infant prophylaxis Nevirapine
C. Nutritional supplements
n CD4 PP HIV Tx%/(incl) p
A. 851 428 2.9 (4.0)
B. 848 440 1.7 (2.6) B v C 0.0001
C. 668 442 5.7 (7.0) A v C 0.003
1.9% of infants receiving NVP had a hypersensitivity reaction
Chesale et al, NEJM 2010;362:2271-81

13. Safer Breastfeeding during HAART –
(Mother of the Baby Study)
RCT – Px to wean – max 6/12
Trizivir v Combivir/Kaletra
Combivir/Nevirapine – Observational
97% BF; 93% Exclusively BF; 71% BF ≥ 5/12
Viral load <400 <50 Transmission PTD
<37 <32
At delivery during BF in utero during BF
96% 81% 92% 83% 4 (1.4%) 2 15% 1%
93% 69% 93% 77% 1 (0.4%) 0 23% 3%
95% 77% 95% 84% 1 (0.6%) 0 10% 1%
MTCT Rate 1.1%
Shapiro et al, NEJM 2010;363:2282-94

14. The Third Trimester
Refining the
detail and
increasing the
robustness of
the process
Congenital Malformation data
from >16,000 prospective reports
of T1 exposure
Pre-term Birth –
a growing consensus
Dosing in the 3rd
Trimester
Managing late presentation
Elimination or Eradication

16. Individual drugs with sufficient numbers to identify
a > 1.5 fold increase in risk (Jan 2015)
Lamivudine 142/4527 3.1% 2.6 – 3.7
Zidovudine 133/4092 3.3% 2.7 – 3.9
Ritonavir 62/2628 2.4% 1.8 – 3.0
Tenofovir 58/2452 2.4% 1.8 – 3.0
Emtricitabine 46/1834 2.5% 1.8 – 3.3
Lopinavir 29/1242 2.3% 1.6 – 3.3
Nelfinavir 47/1214 3.9% 2.8 – 5.1
Nevirapine 32/1096 2.9% 2.0 – 4.1
Atazanavir 23/1037 2.2% 1.4 - 3.3

17. Abacavir 29/976 3.0% 2.0 - 4.2
Efavirenz 20/852 2.3% 1.4 - 3.6
Stavudine 21/810 2.6% 1.6 - 4.0
Didanosine 20/423 4.7% 2.9 - 7.2
Darunavir 9/314 2.9% 1.3 – 5.4
Indinavir 7/289 2.4% 1.0 – 4.9
Individual drugs with sufficient numbers to
identify a > 2.0 fold increase (Jan 15)

18. PTB and HAART in a Resource Poor setting
Mma Bana Study (HAART and Excl BF RCT)
PTD Rates <32 weeks
Combivir/Kaletra 61/270 (23%) 8 (3%)
Trizivir 42/283 (15%) 4 (1%)
Combivir/Nevirapine 16/156 (10%) 2 (1%)
Shapiro et al NEJM 2010;362:2282 - 94

19. Impact of PTB on babies of HIV treated mothers
Brussels – Single Centre 1985 – 2006
537 neonates: 82 born prior to 12/04/1994 (Pre-ART prophylaxis)
455 born post 12/04/1996 (ART era)
11.6% born pre-term
77 infants had 81 episodes of severe infection during 1st
year of life.
21 during neonatal period and 52 during remainder of 1st
year
Severe infection in infancy associated with
Birth during ART era 2.9 (1.1 – 8.1)
Severe neonatal infection was associated with
PTB aHR 21.3 (7.1 – 63.9)
Severe infection post neonatal period was associated with:
Older maternal age aHR 2.2 (1.2 – 4.1) p 0.02
Male Gender 1.7 (0.9 – 3.2) p 0.09
PTB 3.0 (1.5 – 5.9) p 0.001
Adler C Plos One 2015 DOI:10.1271 18th
August 2015

20. Antepartum Labor/ Postpartum Maternal Health
(14 wks-term) Delivery (for duration of BF) (after BF cessation)
Infant NVP
Prophylaxis
Triple ARV
Prophylaxis
R
a
n
d
o
m
i
z
e
Late Presenters
Continue
Triple ARV
Regimen
Stop
All ARVs
Mother
R
a
n
d
o
m
i
z
e
Infant uninfected at birth
ZDV
ZDV +
sdNVP+
TRV
R
a
n
d
o
m
i
z
e
(Version 2.0)
Maternal
CD4 >350
Three PROMISE Randomizations:
Outcomes from Antepartum Component
ENROLLED 3,529 WOMEN
11/4/2014 - DSMB stopped Antepartum Component for efficacy

21. Antepartum Component
Maternal Randomisation (Version 2)
Pregnant Women
(Only HBV+ Women Randomized to Arm C)
Arm A
ZDV + sdNVP +
FTC-TDF tail
R
Arm B
3TC-ZDV + LPV-RTV
Arm C
FTC-TDF + LPV-RTV
Under Version 2.0, due to limited safety
data on TDF in pregnancy, only
HBV+ women randomized to Arm C
Only if HBV+ (4%)
96% randomizations

22. Antepartum Component
Maternal Randomization (Version 3)
Pregnant Women
(All Women Randomized 1:1:1 to 3 Arms)
Arm A
ZDV + sdNVP +
FTC-TDF tail
R
Arm B
3TC-ZDV + LPV-RTV
Arm C
FTC-TDF + LPV-RTV
28
Data Analysis Plan: Comparisons based on concurrent randomization
•Comparisons of Arms A and B include all women (all Versions, N=3,084)
•Comparisons of Arm C with Arm A or B restricted to Version 3 enrollees
(N=1,229)
Version 3.0 ALL women
randomized to A, B or C

23. Maternal Baseline Characteristics:
Young Pregnant African Women with High CD4 Count
Entry Characteristics (N=3,523) Value
Age (median) 26 years
Race – Black African 97%
Gestational age (median) 26 weeks
CD4 cell count (median) 530 cells/uL
WHO Clinical Stage 1 97%
Hepatitis B Surface Antigen + 4%
No ARV for prior PMTCT or no prior
pregnancy
94%

24. MTCT rates at age 14 days
1.8%
Difference in MTCT Risk:
-1.28% (95% CI -2.11%, -0.44%)
25 /
1,326
9/1,710

25. Moderate Adverse
Pregnancy Outcome
Severe Adverse
Pregnancy Outcome
Birth weight Birth weightGest. Age Gest.
Age
%withEvent
B vs C
P=0.0
2
B vs C
P=0.0
4
Version 3 (Arm A vs C, Arm B vs C): Moderate Adverse Pregnancy
Outcome Higher with FTC/TDF Triple ARV then ZDV,
Severe Outcomes Less in 3TC-ZDV than FTC-TDF Triple ARV
A vs C
P=0.004

26. Infant Deaths
Lower in 3TC-ZDV than FTC-TDF Triple Arm (V3)
All Versions
(Arm A v B)
Version 3 only
(Arm A v C, B v C)
%withEvent
28/1432 17/1419 11/349 2/346 15/341
Any Grade 3+ AE Death Any Grade 3+ AE Death

27. Summary of 1077BF/FF Antepartum
Component Infant Safety Results
There were no significant differences in infant
signs/symptoms and lab AEs by study arm for all infants and
for version 3.0 only infants.
There were 60 early infant deaths in all versions by 14 days;
including 28 deaths in version 3.0.
In Version 3.0 there was a significantly lower risk of infant
death for ZDV/3TC vs TDF/FTC:
• 0.6%(2/346) vs. 4.4% (15/341) p=0.001
• The difference was primarily seen in deaths among
infants <34 weeks gestation.

28. PROMISE Conclusions
Results support the 2013 WHO recommendations for use
of triple maternal ARV regimens in pregnancy to achieve
the lowest risk of transmission.
Antepartum triple ARV regimens were associated with
higher risk of moderate but not severe adverse maternal
and pregnancy outcomes including preterm birth and
low birth weight, which will require follow up in terms of
12 month infant mortality and HIV-free survival.
The difference in risk of early infant deaths in the FTC-
TDF triple ARV arm compared to the 3TC-ZDV triple
ARV arm was unanticipated and requires further
investigation.

29. Getting the dose right

30. Nucleoside/tide RT Inhibitors
Compound Standard Adult Dose PK in pregnancy
Abacavir 600mg od/300mg bd No adjustment
Emtricitabine 200mg od No adjustment
Lamivudine 300mg od/150mg bd No adjustment
Tenofovir df 245mg od No adjustment
Zidovudine 250/300mg bd No adjustment
Tenofovir af 10mg daily No data

31. Non-Nucleoside RT Inhibitors
Compound Standard Adult Dose PK in pregnancy
Nevirapine 200mg bd/400mg od No adjustment
Efavirenz
(Atripla FDC)
600mg od No adjustment
Etravirine 200mg bd Insufficient data
Take with food
Rilpivirine
(Eviplera FDC)
25mg od Insufficient data
Take with food

32. Protease Inhibitors
Compound Standard Adult Dose Pharmacokinetics
Nelfinavir Not available Reduced levels
Saquinavir 1000mg/100mg bd Adequate levels
Fosamprenavir 700mg/100mg bd Adequate levels
Atazanavir with
TDF
300mg/100mg od 50% reduced levels
No evidence of failure
Lopinavir 400mg/100mg bd Reduced levels
No dose adjustment
Atazanavir 300mg/100 daily Reduced levels
No dose adjustment
Darunavir 600mg/100mg bd
800mg/100mg od
Reduced levels
Avoid OD dosing w/o TDM

33. Integrase Strand Transfer Inhibitors
Compound Standard Adult Dose PK in pregnancy
Raltegravir 400mg bd No adjustment
Dolutegravir
(Triumeq FDC)
50mg od Insufficient data
Elvitegravir
(Stribald FDC)
150mg od
(+ cobicistat)
Insufficient data

34. Don’t miss the boat

35. Time to Viral Load Decline to <50 c/mL
During Pregnancy Following ART Initiation, S Africa
Myer L et al. CROI 2015. Seattle, WA. Abs. 864
 Median time to RNA <50 was 14 weeks but varied by pre-ART RNA.
 By delivery, 73% were <50 c/mL.
 Critical determinants – gestational age at ART start, pre-ART viral load.
Time to RNA <50 c/m by pre-ART VL

36. What to do with late starters?
Case Series- 11median GA35.7 weeks median HIV VL 73959
1.93 Log median decrease in VL by delivery
8 days therapy 50% achieved VL<1000 HIV RNA copies /ml
Boucorian et al Can J ID Med Micr0 2015;26: 145-150
Case Series 14 median GA36 weeks median HIV VL 35,364
2.6 log median decrease in VL by delivery (17 [7- 32] days) 7/14 VL<50;
11/14 VL<1000 HIV RNA copies/ml
(Calculated group T/2 minimum of 1.8 days)
Nobrega I et al AIDS Res Hum Retrovirol 2013; 29:1451-4
Rapid viral suppression with Raltegravir

37. Initiating combination antiretroviral
therapy in pregnancy: impact on HIV RNA decay
Viral decay (T/2)
Days
Time to undetectable
(days)
NNRTI-based 2.3 41
PI-based 2.6 42
INSTI-based 1.5 27
Unpublished data from the London HIV Perinatal Research Group

38. Eradication of PMTCT
No transmission if conceived on ART, received ART
throughout pregnancy and delivered with VL<50.
Mandelbrot et al CID 2015 July (e-pub)

39. PMTCT now approaching term
Cuba – has met the WHO goals
Transmission rates of <1% are being achieved
PLCS is no longer necessary
HAART is recommended for all – pre-and post delivery

40. What is left to do?
Does the baby need ART?
If so how long for?
Can ART/HAART during breast-feeding guarantee an
uninfected child?
What is happening after age 6/12?
Can PTB be avoided?
Is there a pregnancy friendly regimen?
What do we know about the new drugs?

41. What about the new/less used drugs?
(APR safety data Jan 2015)
 Raltegravir 3/154
 Elvitegravir 0/18
 Dolutegravir 0/3
 Cobisistat 0/18
 Rilpivirine 0/110
 Etravirine 1/54
 TAF - not reported separately
 Saquinavir 7/184 2 reports in 2014
 Fos-amprenavir 2/108 4 reports in 2014
 Enfuvirtide 0/20 no new exposures since 2013
 Maraviroc 0/18
 Tipranavir 0/4 no new exposures since 2013

42. My Thanks to
Lyn Mofenson who is always generous with the
slides she meticulously prepares at
conferences
Mary Glenn Fowler who kindly shared the
PROMISE slides