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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
No conflicts of interest to declare
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

Late
Infants at
presenting
“high-risk”
mothers
of HIV
Treatment
infection
failure
during
pregnancy
New strategies needed for the management of these high-risk
situations
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)
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)
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
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/mm3 (105-656)
 Viral load
 Undetectable (14)
 Detectable (4) (40, 248, 910, 55 000 copies/ml)
Clinical outcomes among RAL
exposed infants
RAL (18)
KAL (18)
ATZ (18)
p
Gestational
age
38.6 ±1.82
38.4± 1.62
39.1± 1.34
0.37
APGARS
0,5,10
8,9,9
8,9,9
8,9,9
0.75
Birthweight (g)
3140± 553
30240± 415
3233± 525
0.50
Length (cm)
49.5± 2.2
49.2± 2.5
49.9± 1.9
0.80
Head
33.9± 1.5
Circumference
33.7± 1.4
34.3± 1.7
0.48
Neonatal
complications
Meconium
Aspiration (1)
Jaundice (1)
Transient
tachypnea(1)
Transient
tachypnea(2)
Preterm/IUGR (2)
IUGR/
Hypoglycemia
(1)
Clinically
significant
requiring
NICU
intervention
Hypoglycemia
(3)
Respiratory
distress
syndrome(1)
Clavicular
fracture (1)
Biochemistry
RAL
KAL
ATZ
p
50.1/7.5
51.3/6.7
74.6/7.4
0.03
Bilirubin total 22.4
(2 wks)
31.8
63.6
0.06
Bilirubin total 10.6
(1 month)
13.7
17.6
0.33
AST
(2wks)
30.6
33
32.4
0.80
ALT
(2wks)
15.8
17.5
15.3
0.41
Hg
(1 month)
107.7
101.5
112.5
0.21
Neutrophil
(1 month)
1423
1322
1862
0.10
Bilirubin
total/direct
(birth) umol/l
Congenital Anomalies
ON ARV at
conception
Congenital
anomaly
RAL
KAL
ATZ
7/18
5/18
12/18
0/7
0/5
4/12
Nystagmus and
torticollis
Supranumerary
finger
Hemangioma
(entire leg)*
Patent Ductus
Arteriosus
Oculocutanous
albinism*
Neonatal
Ventricular
Tachycardia
Panhypopituitarism*
Hypospadias*
Bilateral
sensineural
deafness
Growth parameters to 6 months of
age
Weight
Length
9
Head circumference
70
50
8
Head Circumference (cm)
7
50
6
5
Length (cm)
Weight (kg)
45
60
4
3
2
40
30
20
1
10
40
35
30
25
20
15
10
5
0
Birth
1 month
6 Months
0
Birth
1 Month
6 Months
0
Birth
1 month
6 months
Newborns Exposed In Utero – RAL
Levels
Patient
RAL level (mg/L)
Age of first RAL
level(days)
1
< 0.01 (undetectable)
13
2
0.9345
1 (16 hours of life)
3
Not available
-
4
< 0.01 (undetectable)
5
5
< 0.01 (undetectable)
4
6
0.0381
1 (30 hours of life)
7
Not 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
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))
Neonatal Prophylaxis of Infants Born
to Multidrug-Resistant Mothers

New challenge – Pregnancy among perinataly-infected women

Lifetime of ARV exposure + difficulties with adherence = multidrugresistance

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)
Newborn 1
Indication for RAL: Detectable maternal VL in 3rd trimester (480 copies/ml), history
of non-adherence, and multidrug resistance (NNRTI, NRTI and PIs)
Day of Life
AZT Dolutegravir,
ALTEtravirine, Darunavir/Ritonavir,
Bilirubin
Hemoglobin
Maternal
Regimen:
TDF/FTC Neutrophils
Total/Direct
Infant Regimen: AZT 4mg/kg/ BID, 3TC 2mg/kg/BID, RAL 1.5mg/kg/BID for 6 weeks
Birth
Day of 37 Weight
Life
(kg)
2
6
49 3.115
12
9
29 3.220
19
26
20
27
40
75
123
37
29
3.565
3.835
40
-
4.275
Dose9
mg/kg/
dose
Trough
32/6
(hours)
Trough
Level
Peak
175
Adjusted
Peak 15.7
Level
5 mg8
BID
1.61
53/6
11.67
0.36
160
1.97
0.87
10 No
1.55
19/4
11.25
0.75
136
1.25
0.15
2.3No
5 mg
BID
1.40
12
5 mg
BID 10
1.30
6 mg
BID 15
1.40
5 mg12
BID
11
8
-
(hours)
24.1/9.2
110
16.7/6.4
100
13.1/4.3
96
11
N/A
0.07
0.06
N/A
1.17
1.15
N/A
18.5/5.6
101
-
-
0.33
0.02
2
No
1.8
Increased to
6 mg BID
0.9
N/A
Stopped
0.9
4.3
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)
2
Day ofRegimen:
Life
ALT
Bilirubin
Hemoglobin 300mg/m
Neutrophils
Infant
AZT
4mg/kg/ BID, 3TC
2mg/kg/BID, Lopinavir/Ritonavir
BID, RAL 1.5mg/kg/BID for 6 weeks Total/Direct
Birth
4
13
22
29
36
43
56
Day of
Life
Weight Dose
(kg)
26
mg/
kg/
dose
Troug Trough
h 37.3/9.9
Level
(hours
)
Peak
Peak
(hours) Level
178
13
3.710
5.4 mg
BID
1.46
12.75
NA
22
4.175
5.4 mg
BID
1.29
15.2
29
4.075
12.6
mg
BID
3.09
15.4
36
4.16
24
24.6
mg
BID
6.15
16.33
0.02
7.2/3.0
43
4.60
24.6
mg
BID
5.32
N/A
23
20
18
22
19
25
22.7/6.7
0.07
14.9/6.2
<0.01
7/9.2
<0.01
6.6/3.6
5.3/2.1
4.6/
N/A
Adjusted
16.1
165
139
5.5
1.17
0.39
1.17
0.38
Increased
6mg/kg
BID
1.17
2.31
108
No
N/A
N/A
120
100
116
109
Yes
Stopped
Increased
3mg/kg
BID
2.3
1.2
1.1
0.9
1.5
1.4
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
Summary: RAL for PMTCT
 Raltegravir in pregnancy may have a role to play in prevention of motherchild-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
Acknowledgements
Merck Product Development
Dr Hedy Teppler
Dr Jeff Fortin
Dr. Nancy Sheehan