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Dr Graham TaylorImperial College London

Friday 20 January 2012, Royal College of Obstetricians and Gynaecologist , London

HIV in PregnancyJoint RCOG/BHIVA Multidisciplinary Conference

Prevention of postPrevention of postPrevention of postPrevention of post----partum HIV partum HIV partum HIV partum HIV

mothermothermothermother----totototo----child transmission child transmission child transmission child transmission

Dr Graham P TaylorReader in Communicable Diseases

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Milestones in Prevention of HIV

mother-to-child transmission

1984 – Thomas et al report of paediatric AIDS – onset ~ 5 months JAMA. 1984 Aug 3;252(5):639-44

– Cowan et al report maternal transmission of acquired immune deficiency syndrome (Pediatrics. Mar;73(3):382-6)

1985 – Zeigler et al document postnatal transmission of AIDS-associated retrovirus from mother to infant. (Lancet. Apr 20;1(8434):896-8)

1992 – Dunn et al. systematic review HIV transmission risk through breast feeding 29% for post-natal maternal infection and 14% for pre-delivery infection (Lancet 1992; 340:585-8)

1994 –Connor et al, ACTG076 – 67% reduction in MTCT with zidovudine (NEJM 331:1173 – 1180)

1999 – The European Mode of Delivery Collaboration report 80% reduction in MTCT with pre-labour caesarian section (Lancet 353:1035-8)

Mother-to-child transmission of HIV-1

in a Breast-feeding population

0

5

10

15

20

25

30

35

40

-9 -7 -5 -3 -1 1 3 5 7 9 11 13 15 17Months

% HIV infected

Transmission

Accumulative

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The Dilemma

Approximately 200,000 infants become HIV infected each year through breast-feeding (WHO 2007)

The Dilemma

Infant Formula feeding reduces HIV transmission but is associated with

increased mortality from other causes

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A comprehensive decision analysis model

If relative risk of mortality from not-breast-feeding is ≤ 1.5 (compared with breast-feeding) and HIV prevalence >10% universal breast-feeding would carry a ≥ mortality than non-breast feeding

In developing countries RR is often ≥3 and even the child of a HIV infected mother has a better survival rate if breast-fed (Hu DJ et al, AIDS 1992;6:1505-13)

Formula-feeding can be safer than breast-feeding in a developing country setting

Randomised Clinical Study

Kenya 425 women Breast Formula212 213

Compliance 96 % 70%Exclusive Breast 3/12 56 %

6/12 3 %

@ 24/12 HIV Positive 36.7% 20.5% p .001Deaths 24.4% 20% p .3HIV-Free Survival 58.0% 70% p .02

Nduati et al JAMA 2000, 283:1167-1174

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Exclusive Breast-Feeding safer than mixed feeding

HIV-1 infection rates in a Vitamin A study in Durban 3/12 15/12

Never Breast Fed 156 18.8% 20%Excl. Breast-Fed 103 14.6% 25%Mixed Feeding 288 24.1% 35%

Coutsoudis et al AIDS 2001;15:379-387

Early weaning increases diarrhoea morbidity and

mortality among uninfected children born to HIV-

infected mothers in Zambia

Lusaka, randomised 4/12 breast-feeding v maternal choice618 HIV uninfected singletons 4 – 6 months diarrhoeal episodes 1.8 fold increase (95% CI 1.3 – 2.4)Diarrhoea-related hospitalisations or death RH 3.2 (2.1 – 5.1) Age 4 – 24 moFawzy et al JID 2011;203:1222-30

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Observational cohort – (DREAM)

341 infants exclusively breast fed 6/12

Maternal HAART ante-natal � 6/12 post-partum (continued if CD4 was <350)

Maternal Px = ZDV/3TC/NVP (nelf or lopinavir/rit)

Infant Px = ZDV 1 week + sd NVP

Expected cumulative Transmission rate 40%

Observed cumulative Transmission rate 2.8%

Overall HIV transmission � 93%

4 transmissions after 6/52 (~1.3%)

Breastfeeding during HAART - Mozambique

Marazzi et al, PIDJ, 2009; 28:483-7

Breastfeeding during HAART - Tanzania

Observational cohort

441 infants exclusive breast feeding 5 - 6/12 (abrupt wean)

Maternal HAART from 34/40 (Comb/NVP)

Infants ZDV/3TC 1/52

HIV+ HIV+/�6/52 4.1%

6/12 5.1% 8.6%

18/12 6.0% 13.6%

50% � Transmission rates compared with PETRA

Transmission associated with baseline viral load/duration of HAART

Kilewo et al, JAIDS, 2009; Aug 27th e-pub

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Breastfeeding during HAART - Uganda

Observational cohort

102 �exclusive breast feeding 3 - 6/12

Mothers all on HAART

92% BF for median 5/12

0/118 infants HIV +ve (HIV DNA PCR)

23 died (61% due to severe diarrhoea)

6 x � � if Breastfed < 6/12 (p 0.01)

Homsy et al, JAIDS, 2009; Sept 30th e-pub

Breast-feeding during HAART - Rwanda

Non-randomised study of breast-feeding + maternal HAART (BF) v formula feeding (FF)

Maternal choice after counselling

HAART from 28 weeks gestation for all

227 (43%) chose to breast-feed – with one post-natal transmission (0.5%)

305 (57%) chose to formula-feed – no post-natal transmissions

[95% CI 0.1-3.4%; P = 0.24]

Nine-month cumulative mortality - BF 3.3% (95% CI 1.6-6.9%)

[P = 0.2] - FF 5.7% (95% CI 3.6-9.2%)

HIV-free survival by 9 months - BF 95 % (95% CI 91-97%)

[P = 0.66] - FF 94 % (95% CI 91-96%)

Peltier et al, AIDS. 2009 Nov 27;23(18):2415-23

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Breastfeeding during HAART - Mma Bana Study

RCT – Px to wean – max 6/12 n

Botswana

CD4 > 200 Trizivir 285

CD4 > 200 Combivir/Kaletra 275

CD4 < 200 Combivir/Nevirapine – Observational 170

Infant Therapy sdNVP and ZDVm 4/52

Baseline

Median Viral load >100K CD4 Treatment limiting AE

Trizivir 13100 15% 393 2%

PI 9300 13% 401 2%

NVP 51700 37% 147 11%

Shapiro et al, NEJM 2010;363:2282-94

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 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

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Treat the mother or the infant? – 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 neuts� PP HIV Tx%/(incl�) p

A. 851 428 6.7% 2.9 (4.0)

B. 848 440 2.9% 1.7 (2.6) B v C 0.0001

C. 668 442 2.0% 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

Breast-feeding related HIV Transmission during ARVs

Study Intervention (PP) Transmission Rate Reference

Vit A RCT n 103156288

Observational study15 months FU

Exclusive BF 25%Never BF 20%Mixed feeding 35%

Coutsoudis et al AIDS 2001;15:379-

387

DREAM n 341Mozambique

Observational studyHAART + 6/12 Excl BF

Observed 2.8%Expected 40%

Marazzi et al, PIDJ, 2009; 28:483-7

n 441Tanzania

Observational studyHAART + 6/12 Excl BF

6/52 4.1%6/12 5.1%

Kilewo et al, JAIDS, 2009; 52: 406-16

n 102Uganda

Observational studyHAART + 6/12 Excl BF

No Transmissions19% MR

Homsy et al, JAIDS, 2010;53:28-35

Maternal n 227Choice 305

Breast FedFormula-Fed

0.5%0 %

Peltier et al, AIDS 2009;23:2415-2413

Mma Bana n 265Botswana 265RCT 170

TrizivirCBV/KaletraCBV/NVP

0.7%0 %0 %

Shapiro et al, NEJM, 2010;362:2282-2294

BAN n 851Malawi 848RCT 668

CBV/NVP or KaletraInfant NVPNutritional supplements

3.0% 1.8%6.4%

Chesale et al, NEJM, 2010;362:2271-2281

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HIV Mother-to-Child Transmission

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10

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30

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None HAART + BF HAART + FF

% T

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smis

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ns

Max

Min

Breast or Infant Formula Milk

The 2009 recommendations … provide two alternative options for women who are not on ART and breastfeed in resource-limited settings:

1) If a woman received AZT during pregnancy, daily nevirapine is recommended for her child from birth until the end of the breastfeeding period.

OR

2) If a woman received a three-drug regimen during pregnancy, a continued regimen of triple therapy is recommended through the end of the breastfeeding period.

WHO revised (2009) recommendations

1.

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Mothers known to be HIV-infected(and whose infants are HIVuninfected or of unknown HIVstatus) should exclusively breastfeedtheir infants for the first 6 months oflife, introducing appropriatecomplementary foods thereafter, andcontinue breastfeeding for the first 12months of life.

Breastfeeding should then only stoponce a nutritionally adequate and safediet without breast milk can beprovided.

WHO revised (2009) recommendations

2.

Mothers known to be HIV-infectedwho decide to stop breastfeeding atany time should stop gradually withinone month. Mothers or infants whohave been receiving ARV prophylaxisshould continue prophylaxis for oneweek after breastfeeding is fullystopped.

Stopping breastfeeding abruptly is notadvisable.

WHO revised (2009) recommendations

3.

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Very low risk of MTCT with interventions: UK & Ireland

Data 2000 – 2006 n = 5136 infants

Managed according to BHIVA guidelines

Transmission

•1.1% overall

•0.8% if maternal ART >14 days

•0.1% if HAART and VL <50 (3/2202)

•0% if ZDVm + PLCS (0/467) 95% CI 0.8%

Townsend et al, AIDS 2008

HIV Mother-to-Child Transmission

0.1

1

10

100

None HAART + BF HAART + FF

% T

ran

smis

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ns

Max

Min

Breast or Infant Formula Milk

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BHIVA/CHIVA guidance on infant feeding in the UK 2010

Exclusive formula-feeding recommended for all babies of mothers infected with HIV regardless of viral load & ART.

All HIV positive mothers should be supported to formula feed their babies.

The risk of mother-to-child transmission from a woman who is on HAART and has a consistently undetectable HIV viral load is likely to be low but is not negligible.

Therefore, although formula feeding is still the best and safest option, if a woman is on effective HAART and has compelling reasons to breast feed, she should be supported to do so as safely, and for as short a period as possible.

Prolonged infant prophylaxis with nevirapine during the breastfeeding period, as opposed to maternal HAART is not recommended.

Kisumi Breastfeeding Study (KiBS)

487 mothersInitiating HAART 34 – 36 weeks gestationTreated til 6 months post-partumZidovudine, lamivudine, nevirapine or nelfinavirInfant sd NVP5.5 month exclusive breast feeding, Rapid weanAccumulative %transmissionBirth 2.56 weeks 4.26 months 5.012 months 5.724 months 7.0Accumulative HIV+ or death rate at24 months 15.7% (95%CI 12.7 – 19.4))

Thomas TK et al PLoS Med. 2011 Mar;8(3):e1001015. Epub 2011 Mar 29

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HIV-1 drug resistance among breastfeeding infants

born to HIV-infected mothers on HAART for PMTCT

Kisumi Breast-feeding study (KiBS), Kenya24 infants infected during breast-feeding in first 6 months of life.15 mothers taking nevirapine, 9 taking nelfinavir (plus ZDV/3TC)

% with mutationsPCR + @ 2 weeks - NonePCR + @ 6 weeks – 30% (6/20)PCR+ @ 14 weeks – 63% (14/22)PCR+ @ 6 months – 67% (16/24)

Mutations present in 9/9 nelfinavir-based and 7/15 nevirapine-based maternal therapies

10/24 mothers had no detectable HIV in plasma at 6/1210/14 mothers with detectable HIV had no mutations

Zeh C et al, PLoS Med. 2011 Mar;8(3):e1000430. Epub 2011 Mar 29

CD4+ T cells spontaneously producing HIV-I in breast

milk from women with or without HAART15 lactating women, including 5 on ZDV/3TC/Lopinavir/rit with no

detectable HIV-1 RNA in plasma and breast milk

Valea et al Retrovirology 2011

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Milestones in Prevention of HIV

mother-to-child transmission

1984 – Thomas et al report of paediatric AIDS – onset ~ 5 months JAMA. 1984 Aug 3;252(5):639-44

– Cowan et al report maternal transmission of acquired immune deficiency syndrome (Pediatrics. Mar;73(3):382-6)1985 – Zeigler et al document postnatal transmission of AIDS-associated retrovirus from mother to infant. (Lancet. Apr 20;1(8434):896-8)1994 – ACTG076 – 67% reduction in MTCT with zidovudine

(Connor et al, NEJM 331:1173 – 1180)1999 – The European Mode of Delivery Collaboration report 80% reduction in MTCT with pre-labour caesarian section (Lancet 353:1035-8)

2009 – Application of antiretroviral therapy during breast-feeding to PMTCT