Evaluation of Neural Tube Defects (NTD) after Exposure to Raltegravir

(RAL) in Pregnancy

Hala Shamsuddin MD

Evaluation of NTDs after RAL Exposure

►Raltegravir (RAL) was the first integrase strand transfer inhibitor (INSTI), approved in 2007 for the treatment of HIV-1 infection

►An unplanned interim analysis of Botswana birth outcomes surveillance study suggested potential risk of NTD associated with periconception dolutegravir (DTG) exposure1.

►To evaluate the risk of NTDs after exposure to RAL during pregnancy.

1NEJM 2018;379:979-981 doi:10.1056/NEJMc1807653

2

Neural Tube Defects

3

► Birth defects of the brain, spine, or spinal cord

► Neural tube closes by 28 days post-conception

► Include spinal bifida, myelomeningocele, anencephaly, iniencephaly, encephalocele

► Worldwide prevalence highly variable but globally account for estimated 18.6 per 10,000 live births

► 70% of the variance in prevalence attributed to genetic factors

► Risk factors: exposure to certain medications in pregnancy, obesity, poorly controlled diabetes and folate deficiency.

J Prenat Med 2008;2(4):40–41.

https://www.cdc.gov/ncbddd/folicacid/index.html

PLoS One. 2016;11(4):e0151586.

Lancet Neurol. 2013;12:799–810

Sources of Data

► Merck Adverse Event Review and Reporting System (MARRS)

– Adverse events spontaneously reported to the company in the post-marketing period and in non-interventional studies

– All serious adverse events (including all pregnancies) reported in company-sponsored and company-supported investigational clinical trials.

– Includes all reports received from the antiretroviral pregnancy registry (APR).

► Publicly available cohort results - not reported to or included in MARRS

– United Kingdom (UK)/Ireland Cohort (National Study of HIV in Pregnancy and Childhood - NSHPC)

– French Perinatal Cohort (the ANRS-French Perinatal Cohort (EPF).

4

Results - MARRS

► Reports classified as prospective or retrospective

– Prospective is a report received prior to knowledge of pregnancy outcome or prior to the detection of a congenital malformation at prenatal examination.

– Retrospective is a report received after knowledge of pregnancy outcome or after detection of a congenital malformation or any fetal event during prenatal testing.

► Only prospective reports are used to calculate prevalence estimates.

► Calculation of prevalence from retrospective reports is inappropriate:

– Biased toward reporting of more unusual and severe cases

– Lack of denominator data

– Poor case documentation

https://www.fda.govwww.APRegistry.com

5

Results – MARRS

► As of 31 May 2018, 1238 pregnancies that reported 1256 outcomes in women exposed to RAL 400 mg twice daily

– United States (47%), European Union (25%), African countries (7%) and rest of world countries (21%)

– Prospectively reported in 803 (65%) and retrospectively reported in 435 (35%).

► Among the 803 prospective reports, 443 (55%) documented first trimester as the earliest exposure, 302 (38%) had second/third trimester exposure, and 58 (7%) had an unknown trimester of exposure.

► Of the 443 first trimester exposures (451 outcomes), 295 (66%) were in women receiving RAL in the periconception period (within 28 days of conception).

6

7

47%

25%

7%

21%

MARRS - RAL Pregnancy ReportsN = 1238

United States

EU

African Countries

ROW

7

8

803; 65%

435; 35%

MARRS - RAL Pregnancy ReportsN = 1238

Prospective

Retrospective

8

9

295; 37%

148; 18%

302; 38%

58; 7%

MARRS - Prospective ReportsN = 803

Periconception

Other First trimester

second/thirdtrimester

Unknown

9

Results – MARRS – Prospective Reports

►No reports of NTDs were identified among infants born to prospectively reported pregnancies, regardless of the earliest time of raltegravir exposure.

– Periconception Exposure: 0/295

– Any exposure: 0/803

10

Results – MARRS – Retrospective Reports

► Periconception exposure:

– Myelomeningocele (live birth)

– Encephalocele (spontaneous abortion)

► Exposure later in pregnancy

– Anencephaly (induced abortion)

– Myelomeningocele (live birth)

► Incidence rates are not calculated from retrospective reports.

11

Cohorts – United Kingdom/Ireland-NSHPC1

► Active National Surveillance Study of HIV in Pregnancy and Childhood

► Monitors the prevalence of HIV infection in pregnant women and children and transmission of infection from mother to child.

► RAL exposure in 709 (7%) of 10,144 pregnancies reported through 2014.

► Earliest time of exposure was during the first trimester in 184 (26.5%), of which 161 (23%) were at conception.

► NTDs were not observed in this cohort.

1Sconza et al. Raltegravir in pregnancy: patterns of use and birth outcomes in the

UK & Ireland [Poster 806]. CROI 2018

12

Cohorts - ANRS-French Perinatal Cohort (EPF)

► National multicenter prospective cohort that enrolls approximately 70% of HIV infected pregnant women in 100 sites in France.

► 479 pregnancy exposures to RAL through 2015.

► 140 (29%) were exposed during the first trimester.

► The number of women exposed at conception was not reported.

► NTDs were not observed in this cohort.

Sibiude et al. Evaluation of the risk of birth defects among children exposed to

raltegravir in utero in the ANRS-French Perinatal Cohort EPF [Abstract MOAB0204].

IAS 2017.

13

RAL

Exposure

N = 2426

MARRS

N = 1238

Prospective

803

1st Trimester

443

Periconception

295**

NTD = 0

Retrospective

435

Cohort Data

1188

UK/Ireland (NSHPC)

709

1st Trimester

184

Periconception

161

NTD = 0

France (EPF)

479

1st Trimester

140

Periconception

NR

NTD = 0

Results Summary –

As of 31-May 2018

14

Updates

► MARRS Updated through 31-May 2018 Through 31-Jan 2019

– Additional 117 prospective reports (42 first trimester including 23 periconception)

– 60 retrospective reports (15 first trimester, including 8 periconception)

►NHSPC Updated* as of 2018

– 875 RAL pregnancy exposures (i.e., additional 166), of which 222 were at conception (additional 66)

► No NTDs

15

*J Acquir Immune Defic Syndr 2019 80(3):264-268

19

Conclusions

► Available data do not indicate an association between RAL exposure and NTDs

– Prospective Reports as of January 2019: No NTDs

• 2274 reports from MARRS and two cohorts, of which 540 were periconception exposures.

– Retrospective Reports periconception exposure

• One myelomeningocele (live birth) and one encephalocele (spontaneous abortion)

• Calculation of prevalence from retrospective reports is not appropriate

• Small number of cases despite market availability since 2007

16

Discussion

► Limitation: Pregnancy outcome data after RAL exposure are predominantly from Western countries.

– There is geographic variability in the background rate of NTDs due to dietary and genetic factors.

► RAL and DTG have distinctly different chemical structure

– Potentially different possible effects on neural tube development

17

https://pubchem.ncbi.nlm.nih.gov

Raltegravir Dolutegravir

18

19

DolutegravirRaltegravir

https://pubchem.ncbi.nlm.nih.gov/compound/46216142#s

ection=3D-Conformerhttps://pubchem.ncbi.nlm.nih.gov/compound/54671008#s

ection=3D-Conformer

Discussion – Practical Implications

► Lack of association of RAL exposure and NTDs has practical implications for the choice of antiretroviral therapy in HIV-1 infected pregnant individuals.

► DHHS and EACS treatment guidelines.

– RAL 400 mg twice daily may be used in women of reproductive potential and during pregnancy if clinically indicated.

https://aidsinfo.nih.gov/guidelines/html/3/perinatal/487/table-6---what-to-start--initial-combination-regimens-for-

antiretroviral-naive-pregnant-women

http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html

20

Thank You

21

Acknowledgments

22

►Brittany Leigh Sciba

►Casey Raudenbush

►Kim Strohmaier

►Yun-Ping Zhou

►Wayne Greaves

►George Hanna

►Ronald Leong

►Chris Mast

►Walter Straus