Dr Graham P Taylor Reader in Communicable Diseases

Transcription

1 HIV in Pregnancy Joint RCOG/BHIVA Multidisciplinary Conference Dr Graham Taylor Imperial College London Friday 20 January 2012, Royal College of Obstetricians and Gynaecologist, London Prevention of post-partum partum HIV mother-to to-child transmission Dr Graham P Taylor Reader in Communicable Diseases 1

2 Milestones in Prevention of HIV mother-to-child transmission 1984 Thomas et al report of paediatric AIDS onset ~ 5 months JAMA Aug 3;252(5): 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 predelivery infection (Lancet 1992; 340:585-8) 1994 Connor et al, ACTG076 67% reduction in MTCT with zidovudine (NEJM 331: ) 1999 The European Mode of Delivery Collaboration report 80% reduction in MTCT with pre-labour caesarian section (Lancet 353:1035-8) % HIV infected Mother-to-child transmission of HIV-1 in a Breast-feeding population Months Transmission Accumulative

3 The Dilemma Approximately 200,000 infants become HIV infected each year through breastfeeding (WHO 2007) The Dilemma Infant Formula feeding reduces HIV transmission but is associated with increased mortality from other causes 3

4 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: ) Formula-feeding can be safer than breast-feeding in a developing country setting Randomised Clinical Study Kenya 425 women Breast Formula Compliance 96 % 70% Exclusive Breast 3/12 56 % 6/ /12 HIV Positive 36.7% 20.5% p.001 Deaths 24.4% 20% p.3 HIV-Free Survival 58.0% 70% p.02 Nduati et al JAMA 2000, 283:

5 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 % 20% Excl. Breast-Fed % 25% Mixed Feeding % 35% Coutsoudis et al AIDS 2001;15: Early weaning increases diarrhoea morbidity and mortality among uninfected children born to HIVinfected mothers in Zambia Lusaka, randomised 4/12 breast-feeding v maternal choice 618 HIV uninfected singletons 4 6 months diarrhoeal episodes 1.8 fold increase (95% CI ) Diarrhoea-related hospitalisations or death RH 3.2 ( ) Age 4 24 mo Fawzy et al JID 2011;203:

6 Breastfeeding during HAART - Mozambique 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%) 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 6

7 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 %; P = 0.24] Nine-month cumulative mortality - BF 3.3% (95% CI %) [P = 0.2] - FF 5.7% (95% CI %) 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 Nov 27;23(18):

8 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 % 393 2% PI % 401 2% NVP % % Shapiro et al, NEJM 2010;363: 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:

9 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 % 2.9 (4.0) B % 1.7 (2.6) B v C C % 5.7 (7.0) A v C % of infants receiving NVP had a hypersensitivity reaction Chesale et al, NEJM 2010;362: Breast-feeding related HIV Transmission during ARVs Study Intervention (PP) Transmission Rate Reference Vit A RCT n DREAM n 341 Mozambique Tanzania Uganda n 441 n 102 Maternal n 227 Choice 305 Mma Bana n 265 Botswana 265 RCT 170 BAN n 851 Malawi 848 RCT 668 Observational study 15 months FU Observational study HAART + 6/12 Excl BF Observational study HAART + 6/12 Excl BF Observational study HAART + 6/12 Excl BF Breast Fed Formula-Fed Trizivir CBV/Kaletra CBV/NVP CBV/NVP or Kaletra Infant NVP Nutritional supplements Exclusive BF 25% Never BF 20% Mixed feeding 35% Observed 2.8% Expected 40% 6/52 4.1% 6/12 5.1% No Transmissions 19% MR 0.5% 0 % 0.7% 0 % 0 % 3.0% 1.8% 6.4% Coutsoudis et al AIDS 2001;15: Marazzi et al, PIDJ, 2009; 28:483-7 Kilewo et al, JAIDS, 2009; 52: Homsy et al, JAIDS, 2010;53:28-35 Peltier et al, AIDS 2009;23: Shapiro et al, NEJM, 2010;362: Chesale et al, NEJM, 2010;362:

10 Breast or Infant Formula Milk HIV Mother-to-Child Transmission % T ra n s m is s io n s Max Min 0 None HAART + BF HAART + FF WHO revised (2009) recommendations 1. 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. 10

11 WHO revised (2009) recommendations 2. Mothers known to be HIV-infected (and whose infants are HIV uninfected or of unknown HIV status) should exclusively breastfeed their infants for the first 6 months of life, introducing appropriate complementary foods thereafter, and continue breastfeeding for the first 12 months of life. Breastfeeding should then only stop once a nutritionally adequate and safe diet without breast milk can be provided. WHO revised (2009) recommendations 3. Mothers known to be HIV-infected who decide to stop breastfeeding at any time should stop gradually within one month. Mothers or infants who have been receiving ARV prophylaxis should continue prophylaxis for one week after breastfeeding is fully stopped. Stopping breastfeeding abruptly is not advisable. 11

12 Very low risk of MTCT with interventions: UK & Ireland Data 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 Breast or Infant Formula Milk HIV Mother-to-Child Transmission 100 % T ra n s m is s io n s 10 1 Max Min 0.1 None HAART + BF HAART + FF 12

13 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 mothers Initiating HAART weeks gestation Treated til 6 months post-partum Zidovudine, lamivudine, nevirapine or nelfinavir Infant sd NVP 5.5 month exclusive breast feeding, Rapid wean Accumulative %transmission Birth weeks months months months 7.0 Accumulative HIV+ or death rate at 24 months 15.7% (95%CI )) Thomas TK et al PLoS Med Mar;8(3):e Epub 2011 Mar 29 13

14 HIV-1 drug resistance among breastfeeding infants born to HIV-infected mothers on HAART for PMTCT Kisumi Breast-feeding study (KiBS), Kenya 24 infants infected during breast-feeding in first 6 months of life. 15 mothers taking nevirapine, 9 taking nelfinavir (plus ZDV/3TC) % with mutations PCR 2 weeks - None PCR 6 weeks 30% (6/20) 14 weeks 63% (14/22) 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 6/12 10/14 mothers with detectable HIV had no mutations Zeh C et al, PLoS Med Mar;8(3):e Epub 2011 Mar 29 CD4 + T cells spontaneously producing HIV-I in breast milk from women with or without HAART 15 lactating women, including 5 on ZDV/3TC/Lopinavir/rit with no detectable HIV-1 RNA in plasma and breast milk Valea et al Retrovirology

15 Milestones in Prevention of HIV mother-to-child transmission 1984 Thomas et al report of paediatric AIDS onset ~ 5 months JAMA Aug 3;252(5): 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: ) 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 15