1. Raltegravir for the prevention of mother-to-child transmission of HIV MJ Trahan, V Lamarre, ME Metras, N Lapointe, F Kakkar Centre Hospitalier Universitaire Sainte Justine, Université de Montréal Centre Maternel et Infantile sur le Sida

2. No conflicts of interest to declare

3. Prevention of mother-child transmission (PMTCT): Canadian Context  Through the success of the national PMTCT programs, the overall risk of perinatal HIV transmission in the developed world has decreased to <1%  However, mother-to-child transmission has not been eliminated in Canada  Canadian Perinatal HIV surveillance database (1997-2014) ( Poster MOPEC445, Bitnun et al): 3200 pregnancies  0.1% > 4 weeks cART during pregnancy  3.1% detectable VL (40 - 1000 c/ml ) at time of delivery  4.3% ≤ 4 weeks of cART during pregnancy  15% without any maternal treatment  New strategies needed for the management of these high-risk situations Late presenting mothers Treatment failure during pregnancy Infants at “high-risk” of HIV infection

4. Use of RAL for PMTCT in high-risk situations  Raltegravir: FDA Pregnancy Category C, due to limited data to support its use  Under select circumstances, RAL has been used in late pregnancy in women with high viral loads to rapidly decrease viral load prior to delivery = case series on the use of RAL during pregnancy  Evidence of transplacental transfer of RAL (IMPAACT 1026S, 1097), however limited data on long term outcomes of infants exposed in utero to RAL  Toxicity concerns:  Animal studies: Supernumerary ribs in rabbits exposed to 3 fold human dose  Theoretical: Possible increase in unconjugated bilirubin, increasing risk of kernicterus (RAL and bilirubin are both albumin bound, and metabolized by UGTA1)

5. Objectives 1.To determine clinical outcomes among newborns exposed to RAL in utero (Maternal PMTCT) 2. To describe the use of RAL for the prophylaxis of newborns at high risk of HIV acquisition (Neonatal PMTCT)

6. Methods  Retrospective study from the Centre Maternel et Infantil sur le SIDA (CMIS) mother-child cohort, CHU Sainte-Justine, Montréal, Quebec  All infants born to women treated with RAL during pregnancy in the CMIS mother-child cohort between 2010 and 2015 (n=18)  Neonatal outcomes:  Clinical outcomes, biochemistry, growth to 6 months of age  Comparison group of infants exposed to combination ART with Atazanvir/Ritonavir or Lopinavir/Ritonavir in utero, matched by nearest date of birth

7. Use of RAL during pregnancy  RAL given to mothers at standard dosing of 400 mg BID during pregnancy in addition to cART (PI based) (n=18)  GA at beginning of maternal ARV treatment:  Pre-pregnancy (5)  During pregnancy (13): mean GA= 31.9 weeks (range 15-40 weeks)  Indications for RAL:  Drug Resistance (6)  High VL (>1000 copies/ml) in third trimester despite treatment (7)  Late initiation of therapy (7) (mean GA at start): 30.4 wks  Maternal characteristics at delivery:  CD4 count (mean): 370 cells/mm 3 (105-656)  Viral load  Undetectable (14)  Detectable (4) (40, 248, 910, 55 000 copies/ml)

8. Clinical outcomes among RAL exposed infants

9. Biochemistry

10. Congenital Anomalies

11. Growth parameters to 6 months of age

12. Newborns Exposed In Utero – RAL Levels PatientRAL level (mg/L)Age of first RAL level(days) 1< 0.01 (undetectable)13 20.93451 (16 hours of life) 3Not available- 4< 0.01 (undetectable)5 5 4 60.03811 (30 hours of life) 7Not available- 8< 0.01 (undetectable)14 9< 0.01 (undetectable)14 Therapeutic RAL dosage: 0.02 mg/L Clarke et al (MPACT P1097), JAIDS 2014

13. Summary – use of RAL in Pregnancy  No significant adverse events related in utero RAL exposure to 6 months of follow-up when compared to infants exposed to KAL or ATZ based maternal drug regimens alone  No HIV transmission among the “high-risk” group infants of RAL treated mothers, vs. 4.3 – 8.8% among similar cohort of high-risk HIV exposed infants of late presenting mothers (CPHSP 2014, Bitnun, CID 2014 ))

14. Neonatal Prophylaxis of Infants Born to Multidrug-Resistant Mothers  New challenge – Pregnancy among perinataly-infected women  Lifetime of ARV exposure + difficulties with adherence = multidrug- resistance  Challenge for post-natal prophylaxis since mothers are resistant to standard drugs approved for use in neonates (ZDV/3TC/NVP)  Formulation (granules for suspension) attractive option for prophylaxis of newborns at high risk of HIV infection  Clinical trial underway (IMPAACT P1110) for infants <4 weeks of age  RAL was used for neonatal prophylaxis as part of a triple-drug regimen in two newborns at high risk of HIV-infection in the CMIS cohort (Merck, Special Access, Health Canada Compassionate use)

15. Newborn 1 Indication for RAL: Detectable maternal VL in 3 rd trimester (480 copies/ml), history of non-adherence, and multidrug resistance (NNRTI, NRTI and PIs) Maternal Regimen: Dolutegravir, Etravirine, Darunavir/Ritonavir, TDF/FTC Infant Regimen: AZT 4mg/kg/ BID, 3TC 2mg/kg/BID, RAL 1.5mg/kg/BID for 6 weeks

16. Newborn 2 Indication for RAL: Maternal refusal of ART during pregnancy, VL 83 000 copies/ml at delivery, history of non-adherence during adolescence and multi-drug resistant (NRTI,NNRTI) Infant Regimen: AZT 4mg/kg/ BID, 3TC 2mg/kg/BID, Lopinavir/Ritonavir 300mg/m 2 BID, RAL 1.5mg/kg/BID for 6 weeks

17. Outcomes  Variability in drug levels between the two infants requiring TDM and dose adjustment  No adverse effects through 6 weeks of therapy (weekly haematology, biochemistry)  Both infants confirmed HIV uninfected (HIV viral load negative at birth, 2 weeks, 2 month, 4 months and HIV DNA PCR negative 4 weeks)  RAL well tolerated, minimal preparation challenges

18. Summary: RAL for PMTCT  Raltegravir in pregnancy may have a role to play in prevention of mother- child-transmission in high-risk situations  No cases of transmission among high-risk RAL exposed newborns  No significant adverse events from in utero exposure, to 6 months of follow-up  RAL granules for suspension in the newborn at doses of 1.3-6 mg/kg BID was well tolerated with no adverse events:  Further dosing recommendations: IMPAACT P1110, Poster MOPEB196  However – if this strategy is to be used, until further PK and toxicity data becomes available  Careful monitoring during pregnancy  Therapeutic drug monitoring during treatment of newborns  Long -term follow-up of exposed infants is necessary

19. Acknowledgements Merck Product Development Dr Hedy Teppler Dr Jeff Fortin Dr. Nancy Sheehan