Congenital anomalies following

antenatal exposure

to dolutegravir: a Canadian

surveillance study

1

Money D, Lee T, O’Brien C, Brophy J, Bitnun A, Kakkar F, Boucoiran

I, Alimenti A, Vaudry W Singer J and Sauve LJ, for the Canadian

Perinatal HIV Surveillance Program.

Presenter Disclosure

I have received funding for clinical trials from Merck, GSK,

Novartis, Sanofi, Gilead

Merck has supported our investigator driven studies of the

HPV vaccine in women living with HIV

The funding support for this study is from the Public

Health Agency of Canada, the Provincial Health Services

Authority and the Canadian Institutes for Health Research,

Clinical Trials Network

BACKGROUND: Congenital anomalies & neural

tube defects in general

4-5% of ALL infants have congenital anomalies

Neural tube closes by approximately 28 days of embryogenesis which

is approx. 6 weeks post LMP

Incidence of neural tube defects in BC and Canada is 0.04%

Decreased from 0.78% prior to initiation of folic fortification of grains

in Canada since 1998

Also prenatal diagnosis lowers # of live births of infants with

congenital anomalies

Global data on rates of neural tube defects – African countries report

0.05% to 0.75% with typical rates in Botswana reported as 0.1%

Eras of antiretroviral prescribing in pregnant

WLWH in Canada

0

10

20

30

40

50

60

70

80

90

100

90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14

Perc

enta

ge

Year

ART

HAART

Total treated

Infected

ACTG 076Dual nuc

PI and NNRI

combinations

Integrase inhibitors

The information on potential

teratogenicity of an integrase inhibitor

May 18, 2018 – new data released from Botswana

25% of the adult population living with HIV IN Botswana

In 2016, Botswana rolled out a ‘Treat All’ campaign with standard drug

regimens to manage cost and complexity. All adults (regardless or

pregnancy status) were to receive Truvada and Dolutegravir resulting

in a country-wide shift in prescribing

Surveillance data on pregnancy outcomes were reviewed to assess for

any complications

Neural tube defect data from Botswana, May

2018 A surveillance cohort of 11, 558 women living with HIV who became

pregnant were evaluated:

Of 426 women taking dolutegravir there were 4 cases of neural

tube defects (0.9%)

Of 11,173 women who were on other ARV regimens, 14 had a

neural tube defect (0.1%)

Comparison is statistically significantly different (p=0.003)

This information was considered a ‘safety signal’

Data at IAS, July 2018 - 4/596 (0.67%, 95% CI 0.26%, 1.7%)

Methods

Canadian Perinatal HIV Surveillance Program (CPHSP) consists of 22 sites in

Canada with annual data entry

Data are collected on all mother infant pairs with a live birth

Data collected includes maternal country of birth, self-reported

race/ethnicity, suspected mode of maternal HIV acquisition, antiretroviral

regimen and duration of therapy in pregnancy (including dates of ART

commencement and changes), mode of delivery, gestational age and birth

weight and any congenital anomalies and any adverse infant outcomes.

Congenital anomaly data was categorized using ICD-10 and classified by organ

system involved

Oracle was the data capture system and summary statistics were conducted

Proportions of affected infants between groups are compared using Chi-

square or Fisher’s exact test as appropriate. Analyses were conducted using

SAS 9.4 (SAS Institute, Cary NC).

Canadian Perinatal HIV Surveillance Program (CPHSP)

Vancouver

Edmonton

Calgary

Saskatoon

Winnipeg

Ottawa

Toronto

HamiltonLondon

Windsor

Sudbury

Montréal

(2 sites)

Québec city

Whitehorse

Iqaluit

St John’sHalifax

Fredericton

Charlottetown

Yellowknife

Kingston

Regina

Demographics of cohort for congenital

anomalies analysis (N= 2,423 from 22 sites)

Insert the data from our paper here!

Rates of congenital anomalies by ART

exposure

*

Congenital anomalies by system

*

Congenital anomalies by type of ART

exposure

*

*

Results - summary From 2007-2017 there were 2,423 of 2,591 live born infants born with data

available on both congenital anomalies and antiretroviral therapy in

pregnancy

Of 98 cases of anomalies (4.04%; 95% CI: 3.30-4.91%), 12 were chromosomal

abnormalities (0.5%), resulting in a non-chromosomal congenital anomaly

prevalence of 3.5%.

The prevalence of congenital anomalies did not significantly differ across

gestational age exposure timing groups (p=0.915)

there have been 3 cases of neural tube defects since 2007, an overall

incidence rate of 0.12, of which 2 were on ARV’s in the first trimester

one was on tenofovir, emtricitabine, and ritonavir boosted atazanavir

the other was on zidovudine, lamivudine, abacavir, and ritonavir boosted

atazanavir.

Results summary - Integrase inhibitors

Raltegravir – 76 infants exposed, 3 anomalies – systems were respiratory,

genital or urinary (4.0%) [CI: 0.82%-11.1%].

Dolutegravir: 80 infants with dolutegravir exposure in the first trimester (69

cases with dolutegravir at conception) with 4 cases of non-chromosomal

congenital anomalies, giving a rate of 5.0% [CI: 1.4%-12.3%] (table 4) - urinary

tract (n=2), circulatory system (n=1) and musculoskeletal system (isolated

polydactyly)(n=1)

Elvitegravir: 28 infants exposed to elvitegravir – 3 had congenital anomalies;

-urinary (polycystic kidneys), musculoskeletal (polydactyly), and multiple

systems (including polycystic kidney, imperforate anus and hydronephrosis)

(10.7%)[CI:2.3%-28.2%] .

Discussion Limitations:

Relatively small cohort of mother infant pairs with only 80 exposures to

dolutegravir

No data on in utero anomalies that resulted in spontaneous loss, termination of

pregnancy or stillbirth

Strengths:

Comprehensive dataset of essentially all mother infant pairs with known HIV on

antiretrovirals in Canada

Comparison data in a country with folic acid supplementation and generally

comprehensive prenatal care

Conclusions of Canadian analysis

• Rate of congenital anomalies for infants exposed to any ART in the 1st

trimester (4.1%) was no different for rates in infants not exposed to ART

in the 1st trimester (3.9%)

• Rate of NTDs of those exposed to ART at conception was 2/1311 (0.15%)

was no different to those unexposed to ART in first trimester 1/690

(0.14%)

• No NTDs associated with dolutegravir in the 80 infants born to women

with first trimester exposure, including 69 who were on dolutegravir

at time of conception

• However, 3-fold higher rate of congenital anomalies in neonates with

elvitegravir exposure in the first trimester (10.7%) presenting some

potential concern although no specific system is identified

• Reinforces need for planning of antiretroviral therapy in women with the

potential to conceive pregnancy

Acknowledgements

Thank you to all CPHSP Contributors:

CPHSP Investigators:

Drs. Taj Jadavji, Joan Robinson, Ben Tan, Jarred Bullard, Sandi Siegel, Lindy Samson, Michael Silverman, Roger Sandre, Kirk Liefso, Jeff Cohen, François Boucher, Marie-Astrid Lefebvre, Chris Karatzios, Jeanette Cameau, Natalie Bridger, Debbie Kelly, Brendan Hanley, Kim Barker, Alex Wong, David Sabapathy, Scott Halperin, Dorothy Moore, Normand Lapointe, Susan King, ValérieLamarre

Thank you to all CPHSP Contributors:

Carolyn Denney, Debra Quinn, Alison Spry, Athena McConnell, Laura Puri, Cheryl Arneson, Jenna Craig, Jennifer Bowe, Michelle Ellis, Tammy Bourque, Dawn-Marie Spratt, Debbie Andrews, Isabelle Chabot, Suzanne Tallefer, Sylvie Valois, Ambrose Ardith, Rana Aslanova, Cathy Stannard, Andrea Schertzer, Elaine Randal, Dennaye Fuchs, Claire Allen, Sandi Kassir

CPHSP Steering committee:

Drs. Wendy Vaudry, Jason Brophy, Fatima Kakkar, Joel Singer, Isabelle Boucoiran, Deborah Money, Arianne Alimenti, Ari Bitnun and Laura Sauvé

CPHSP Research support: Arezou Azampanah & Evelyn Maan

Data management and statistical support: Dr. Terry Lee

Funding from Public Health Agency of Canada

Interim recommendations

1. Women who are taking dolutegravir and become pregnant should have their

antiretroviral regimen reviewed by their HIV and pregnancy care providers

and, if the pregnancy is at less than 10-12 weeks of gestation, should have

their regimen changed to a non-dolutegravir containing regimen if possible.

2. Women who are pregnant and have had dolutegravir exposure at conception

and/or through the first trimester, should have their pregnancy management

reviewed by experts at or affiliated with the Oak Tree Clinic and ensure that

prenatal screening for neural tube defects are completed. Because the

likelihood of a neural tube defect remains small (less than 1%),

recommendation for termination of pregnancy on the basis of dolutegravir

exposure alone is not appropriate.

3.Women who are pregnant and on dolutegravir beyond the first trimester

should NOT stop their antiretroviral regimen, but should discuss this with Oak

Tree Clinic associated care providers.

Interim recommendations cont’d

4. Reproductive aged women who are not on highly reliable methods of birth

control (e.g. intrauterine device) should not be prescribed dolutegravir

containing regimens if there are other reasonable treatment options.

5. Non-pregnant, reproductive aged women being considered for, or on,

dolutegravir containing regimens, should have their pregnancy intentions and

contraceptive use reviewed in each visit. If pregnancy is a possibility,

switching to non-dolutegravir containing regimen should be considered.

Perform a pregnancy test prior to starting a woman of reproductive potential

on dolutegravir and counsel on the risks of neural tube defects in the setting of

dolutegravir use. Encourage the use of highly reliable forms of contraception

(e.g. IUDs) prior to or at the time of initiating Dolutegravir based regimens.

Given the lack of safety information on any new antiretroviral formulations,

including but not limited to, raltegravir and elvitegravir containing regimens,

caution should be used in prescribing these in non-pregnant, reproductive aged

women and they should be avoided in the first trimester of pregnancy when

possible.

Summary

Newer antiretroviral therapies have the risk of insufficient safety data that

takes many years to accumulate

Consider all reproductive aged women potentially able to be pregnant soon

until proven otherwise!

Think of reproductive/sexual health issues when caring for women living with

HIV

References: WHO Statement on DTG – Geneva 18 May 2018.

European Medicines Agency statement. New study suggests risk of birth defects in babies born to women on HIV medicine dolutegravir. May 18, 2018.

Tivicay® Product Monograph, ViiV Healthcare ULC, February 3, 2017.

Hill A, Clayden P, Thorne C, Christie R, Zash R. Safety and pharmacokinetics of dolutegravir in HIV-positive pregnant women: a systematic review. Journal of Virus Eradication. 2018;4:66-71

Bornhede R, Soeria-Atmadja S, Westling K, Pettersson K, Naver L. Dolutegravir in pregnancy-effects on HIV-positive women. European Journal of Clinical Microbiology & Infectious Diseases. 2018;37:495-500.

Public Health Agency of Canada. Congenital Anomalies in Canada 2013 : A Perinatal Health Surveillance Report. Ottawa, 2013.

Wilson D et al. Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies. J Obstet Gynaecol Can 2015;37(6):534-549.

Zaganjor I, Sekkarie A, Tsang, BL, Williams J, Razzaghi H, Mulinare J, Sniezek JE, Cannon MJ, Rosenthal J. Describing the prevalence of neural tube defects worldwide: A systematic literature review. Plos One 2016;137:1-31.

Health Canada letter June 7, 2018. RA-66998