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Mother to Child Transmission of HIV: The Third Trimester
Graham P TaylorProfessor of Human Retrovirology
ConceptIs there an acquired immuno-deficiency syndrome in children? Amman AJ Pediatrics. 1983 Sep;72(3):430-2
Photo by D Kunkelhttp://classes.biology.ucsd.edu/bimm110.SP07/lectures_WEB/L09.05_Gametogenesis.htm
Maternal transmission of acquired immunodeficiency syndrome Cowan MJ et alPediatrics. 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 infantZiegler et al Lancet 1985 8434;896-8
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
Breast v FormulaHIV-1 infection rates in a Vit A study in Durban
3/12Never 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
Breast v FormulaHIV-1 infection rates in a Vit A study in Durban
3/12 15/12Never 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
Breast v FormulaRandomised Clinical Study 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.001
Deaths24.4% 20% p.3HIV-Free Survival 58.0% 70% p.02
Nduati R, JAMA 2000, 283:1167-1174
Preterm birth and HAART Regional Year Monotherapy HAART OR a 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 PI29/101 (29%) with PI
1.49 b
2.15b2
Europe (ECS) 1986 -2004 118/704 (16.8%)
274/1075 (25.5%)Started antenatallyStarted pre-pregnancy
2.03 2.19
3
Germany/Austria c 1995 -2001 20/76 (26%) 29/75 (39%)No PIWith 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 PI25/137 (18%) HAART with PI
0.951.45
7
USA (PSD) 1989 -2004 457/2601 (17%)
329/ 1781 (18%) no PI132 782 (17%) with PI
d 8
Neural tube defect scare
Cynomolgus macaques exposed to efavirenz3/22 (13.7%)Malformations
Efavirenz reclassified D following 3 cases meningo-myelocoele and one Dandy-Walker Syndrome retrospectively reported
The Second Trimester
Infant feedingAntiretroviral therapy
Mode of Delivery
21 years of TasP, PEP & PrEP477 women (USA, France) CD4 >200x106/LZidovudine 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
Efficacy of PLCS + ZDVm 436 women randomly assigned to ECS or SVD 1993 – Mar 1998 - Analysis Nov 1998 - 370 infantsAssigned to n Pos %ECS 170 3 1.8 }SVD 200 20 10.5 }p<0.001
Allocated MOD No ZDV ZDVmSVD 19.5% 4.3%ECS 3.9% 0.8% (1/119)
% Reduction 80% 82%
European Mode of Delivery Study Lancet 1999;353:1035-39
Reduction in late transmission with post-partum interventions: The BAN Study
RCT – Malawi – 24/52 BF (4/52 wean)Mothers with CD4 > 250Infants ZDV/3TC 1/52 + sdNVP 5% infected at birth - excludedA. Maternal HAART Combivir/NVP or KaletraB. Infant prophylaxis Nevirapine C. Nutritional supplements n CD4 PP HIV Tx%/(incl) pA. 851 428 2.9 (4.0)B. 848 440 1.7 (2.6) B v C 0.0001C. 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
Safer Breastfeeding during HAART – (Mother of the Baby Study)
RCT – Px to wean – max 6/12Trizivir v Combivir/KaletraCombivir/Nevirapine – Observational
97% BF; 93% Exclusively BF; 71% BF 5/12 Viral load <400 <50 Transmission PTD
<37 <32At delivery during BF in utero during BF96% 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
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
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
Abacavir 29/976 3.0% 2.0 - 4.2 Efavirenz 20/852 2.3% 1.4 - 3.6Stavudine 21/810 2.6% 1.6 - 4.0Didanosine 20/423 4.7% 2.9 - 7.2Darunavir 9/314 2.9% 1.3 – 5.4Indinavir 7/289 2.4% 1.0 – 4.9
Individual drugs with sufficient numbers to identify a > 2.0 fold increase (Jan 15)
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
Impact of PTB on babies of HIV treated mothers
Brussels – Single Centre 1985 – 2006537 neonates: 82 born prior to 12/04/1994 (Pre-ART prophylaxis)
455 born post 12/04/1996 (ART era)11.6% born pre-term77 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 withPTB 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 0.02Male Gender 1.7 (0.9 – 3.2) p 0.09PTB 3.0 (1.5 – 5.9) p 0.001
Adler C Plos One 2015 DOI:10.1271 18th August 2015
Antepartum Labor/ Postpartum Maternal Health (14 wks-term) Delivery (for duration of BF) (after BF cessation)
Infant NVP Prophylaxis
Triple ARVProphylaxis
Randomize
Late Presenters
Continue Triple ARV Regimen
Stop All ARVs
Mother
Randomize
Infant uninfected at birth
ZDVZDV +
sdNVP+TRV
Randomize
(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
Antepartum ComponentMaternal 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 safetydata on TDF in pregnancy, onlyHBV+ women randomized to Arm C
Only if HBV+ (4%)
96% randomizations
Antepartum ComponentMaternal 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
Maternal Baseline Characteristics:Young Pregnant African Women with High CD4 Count
Entry Characteristics (N=3,523) ValueAge (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%
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
Moderate Adverse Pregnancy Outcome
Severe Adverse Pregnancy Outcome
Birth weight Birth weightGest. Age Gest. Age
% w
ith E
vent
B vs CP=0.0
2
B vs CP=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 CP=0.004
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)
% w
ith E
vent
28/1432 17/1419 11/349 2/346 15/341
Any Grade 3+ AE Death Any Grade 3+ AE Death
Summary of 1077BF/FF Antepartum Component Infant Safety ResultsThere 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.
PROMISE ConclusionsResults 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.
Getting the dose right
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
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 dataTake with food
Rilpivirine(Eviplera FDC)
25mg od Insufficient dataTake with food
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 levelsNo evidence of failure
Lopinavir 400mg/100mg bd Reduced levelsNo dose adjustment
Atazanavir 300mg/100 daily Reduced levelsNo dose adjustment
Darunavir 600mg/100mg bd800mg/100mg od
Reduced levelsAvoid OD dosing w/o TDM
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
Don’t miss the boat
Time to Viral Load Decline to <50 c/mLDuring Pregnancy Following ART Initiation, S AfricaMyer 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
What to do with late starters?
Case Series- 11median 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
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
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)
PMTCT now approaching term
Cuba – has met the WHO goalsTransmission rates of <1% are being achievedPLCS is no longer necessaryHAART is recommended for all – pre-and post delivery
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?
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
My Thanks to
Lyn Mofenson who is always generous with the slides she meticulously prepares at conferencesMary Glenn Fowler who kindly shared the PROMISE slides