2. Dolutegravir use at conception: Additional surveillance data from Botswana
Mmakgomo Mimi Raesima, MD, MPH, MHA
Botswana Ministry of Health and Wellness
On behalf of the Botswana NTD Surveillance Team good morning/afternoon.

3. Disclosure: No conflicts of interest to declare
For disclosure, I have no conflicts of interest to declare.

4. Botswana poised to provide data on dolutegravir (DTG)
Implemented DTG-based ART as first-line therapy in May 2016
Tsepamo study findings raised concerns about a possible association between neural tube defects (NTDs) and DTG use at conception
More data needed
Botswana was uniquely positioned as it had sufficient numbers of women with DTG exposure at conception
In 2018, Botswana was poised to provide data on dolutegravir.
The country implemented DTG-based ART as first-line therapy for all adults, including pregnant women, in May 2016.
Tsepamo study findings, raised concerns about a possible neural tube defect (NTD) association.
More data was needed to understand the possible association.
Botswana was uniquely positioned to provide needed data on the safety of DTG as it had sufficient numbers of women with DTG exposure at conception.
______________________________________________________
More than 95% of Botswana’s women deliver in facilities.
*Zash, et al. N Engl J Med. 2018;379(10):

5. Expanding birth outcomes surveillance
Botswana’s Ministry of Health and Wellness (MoHW) initiated the NTD Surveillance Study
Conducted in collaboration with:
US Centers for Disease Control and Prevention (CDC) – Atlanta and Botswana offices
Botswana University of Maryland School of Health Initiative (BUMMHI)
Funding support from the US President’s Emergency Plan for AIDS Relief (PEPFAR)
Informed by Tsepamo study methods
To expand birth surveillance in Botswana, the Ministry of Health and Wellness (MoHW) initiated the NTD Surveillance Study.
This study was conducted in collaboration with the US Centers for Disease Control and Prevention (CDC) –Atlanta and Botswana offices, and Botswana University of Maryland School of Health Initiative (BUMMHI).
Study funding support came from the US President’s Emergency Plan for AIDS Relief (PEPFAR) and the study’s design was informed by the Tsepamo study methods.

6. Coverage of birth outcomes surveillance
Tsepamo
original
(8 sites: 45%)
After May 2018, coverage of birth outcomes in Botswana increased.
Tsepamo added to its original 8 sites.

7. Coverage of birth outcomes surveillance
72 %
Tsepamo
original
(8 sites: 45%)
Tsepamo expansion
(10 sites: 27%) = +
Tsepamo added another 10 sites; together the original and expansion sites covered 72% of Botswana’s births.

8. Coverage of birth outcomes surveillance
72 %
Tsepamo
original
(8 sites: 45%)
Tsepamo expansion
(10 sites: 27%) = +
NTD
Surveillance Study
(22 sites)
19 % =
The MoHW NTD Surveillance Study, which was conducted at 22 sites health facilities with highest delivery volume outside of Tsepamo study sites, added coverage for 19% of Botswana’s births.

9. Coverage of birth outcomes surveillance
72 %
Tsepamo
original
(8 sites: 45%)
Tsepamo expansion
(10 sites: 27%) = +
NTD
Surveillance Study
(22 sites)
19 % =
Together, Tsepamo and MoHW studies provided birth outcome surveillance for more than 90% of births in Botswana.
91 %
TOTAL:

10. Study methods Prospective NTD surveillance
Enrolled mothers who delivered infants (live births and stillbirths) >24 weeks gestation at the study sites from October 2018–March 2019
IRB-approved protocol
The study used prospective NTD surveillance. Site locations are shown in red on the country map.
Prospective surveillance watches for outcomes among a cohort of subjects.
In our study, we enrolled mothers who delivered infants (live births and stillbirths) greater than 24 weeks gestation at the study sites from October 2018 through March 2019.
The study used an IRB-approved protocol.
_________________________________________
Site selection cut-off: deliveries ≥ 100 births/year (using 2017 data)
There are 2 back-up slides explaining why retrospective approach not used.

11. Methods: Prospective Surveillance for All Deliveries
At Maternity Unit
Examination of infant
Completion of Coversheet and Maternal Obstetrical Record +
MIDWIFE
Delivery
The next several slides show the surveillance procedures.
At the maternity unit, after delivery, midwives systematically examined the infant. They then completed study coversheets that asked for specific HIV information and documented the head, neck and spine examination, as this was not routinely documented in the standard ANC/delivery Obstetrical Record.

12. Methods: Prospective Surveillance for All Deliveries
At Maternity Unit +
MIDWIFE
Delivery
Examination of infant
Completion of Coversheet and Maternal Obstetrical Record
Abstraction of data and entry into electronic data collection tool
Designated facility Study Surveillance Assistants abstracted data from the coversheet and Obstetrical Record and entered it into the REDCap electronic data base via a tablet.
SURVEILLANCE ASSISTANT
Review of de-identified information and classification of the suspected NTD

13. Methods: Prospective Surveillance for Suspected NTDs
At Maternity Unit +
MIDWIFE
Suspected NTD
Delivery
Examination of infant
Completion of Coversheet and Maternal Obstetrical Record
Consent for photographs and abstraction of additional information
Abstraction of data and entry into electronic data collection tool
If an infant with a suspected NTD was delivered, in addition to standard documentation done for all deliveries, maternal consent was requested to photograph the infant and extra information was abstracted from the mother’s Obstetrical Record.
SURVEILLANCE ASSISTANT

14. Methods: Prospective Surveillance for Suspected NTDs
At Maternity Unit +
MIDWIFE
Suspected NTD
Delivery
Examination of infant
Completion of Coversheet and Maternal Obstetrical Record
Consent for photographs and abstraction of additional information
Abstraction of data and entry into electronic data collection tool
Suspected NTDs were reviewed and classified by the clinical geneticist at CDC-Atlanta, who was blinded to ART exposure and other clinical history.
SURVEILLANCE ASSISTANT
Review of de-identified information and classification of the suspected NTD
Review of de-identified information and classification of the suspected NTD

15. Methods: Prospective Surveillance for All Deliveries
At Maternity Unit +
MIDWIFE
Delivery
Examination of infant
Completion of Coversheet and Maternal Obstetrical Record
Abstraction of data and entry into electronic data collection tool
Teams of the study staff regularly visited sites to thoroughly review documents and assure data quality.
SURVEILLANCE ASSISTANT
Review of de-identified information and classification of the suspected NTD
Data quality review for deliveries at all sites

16. Methods: Exposure definition
Exposure of interest = ART at conception
HIV-positive women categorized as ART: exposed/not exposed/unknown
Last menstrual period used to determine periconceptional time frame
Non-DTG based regimen
EFV-based regimen
Non- EFV-based regimen
DTG-based regimen
HIV-positive women exposed to ART at conception
The study exposure of interest was ART at conception. HIV-positive women were categorized as ART exposed, not exposed, or unknown . The ART regimen categories were DTG-based, non-DTG-based and efavirenz-based, shown on the right.
The mother’s last menstrual period was used to determine the periconception time frame.

17. Methods: Outcome definition
Outcome of interest = NTD classification
Not NTD — photo/description/drawing sufficient to rule out NTD
Possible — description/drawing insufficient to determine NTD status
Probable — clear description/drawing and indication of surgical referral, if live-born
Confirmed — photo or clear description/drawing and/or surgical records, if live-born
The outcome of interest was NTD classification.
The four NTD categories were:
Not an NTD.
Possible NTD--applied when the description or drawing was insufficient to determine NTD status.
Probable and confirmed NTD classifications were made when detailed documentation of the defect was provided; but a confirmed NTD had photos or surgical records available.

18. Results: Pregnancies by HIV and ART status
in 22 surveillance sites
Between October 2018 and March 2019, our surveillance system captured 3076 pregnancies who delivered at the 22 sites.

19. Results: Pregnancies by HIV and ART status
in 22 surveillance sites
742 (24%) with
HIV-positive mother
2328 (76%) with HIV-negative mother
6 (<0.1%) with mother’s HIV status unknown
742 mothers (24%) were HIV positive.
2328 mothers were HIV negative and 6 mothers had unknown HIV status.

20. Results: Pregnancies by HIV and ART status
in 22 surveillance sites
742 (24%) with
HIV-positive mother
2328 (76%) with HIV-negative mother
6 (<0.1%) with mother’s HIV status unknown
544 (73%) with HIV-positive mother on ART at conception
176 (24%) with HIV- positive mother not on ART at conception
22 (3%) with HIV-positive mother with unknown ART status at conception
Of the 742 HIV positive mothers, 544, about three-quarters, were on ART at conception.

21. Results: Pregnancies by HIV and ART status
in 22 surveillance sites
742 (24%) with
HIV-positive mother
2328 (76%) with HIV-negative mother
6 (<0.1%) with mother’s HIV status unknown
544 (73%) with HIV-positive mother on ART at conception
176 (24%) with HIV- positive mother not on ART at conception
22 (3%) with HIV-positive mother with unknown ART status at conception
Of the 544 HIV-positive mothers who were on ART at conception, 152, or about 28% were on a DTG-based ART regimen at conception.
381 mothers were on non-DTG regimens and 11 were on unknown regimens at conception.
152 (28%) on DTG-based regimen
at conception
381 (70%) on non-DTG- based regimen at conception
11 (2%) on unknown regimen at conception

22. Results: Pregnancies by HIV and ART status
in 22 surveillance sites
742 (24%) with
HIV-positive mother
2328 (76%) with HIV-negative mother
6 (<0.1%) with mother’s HIV status unknown
544 (73%) with HIV-positive mother on ART at conception
176 (24%) with HIV- positive mother not on ART at conception
22 (3%) with HIV-positive mother with unknown ART status at conception
Of those on non-DTG based regimens at conception, 261 were on efavirenz-based regimens.
152 (28%) on DTG-based regimen
at conception
381 (70%) on non-DTG- based regimen at conception
11 (2%) on unknown regimen at conception
261 (69%) on EFV-based regimen at conception
120 (31%) on non-EFV-based regimen at conception

23. Results: Pregnancies by HIV and ART status
in 22 surveillance sites
742 (24%) with
HIV-positive mother
2328 (76%) with HIV-negative mother
6 (<0.1%) with mother’s HIV status unknown
544 (73%) with HIV-positive mother on ART at conception
176 (24%) with HIV- positive mother not on ART at conception
22 (3%) with HIV-positive mother with unknown ART status at conception
The colored boxes on this slide represent the different exposure groups that we analyzed.
152 (28%) on DTG-based regimen
at conception
381 (70%) on non-DTG- based regimen at conception
11 (2%) on unknown regimen at conception
261 (69%) on EFV-based regimen at conception
120 (31%) on non-EFV-based regimen at conception

24. Results: Six suspected NTDs identified
The surveillance system identified 6 suspected NTDs within the participating facilities. These cases were reviewed by the CDC clinical geneticist. Determinations were:

25. Results: Six suspected NTDs identified
2 not NTDs: sacral dimples
2 were not NTDs, both cases were sacral dimples.

26. Results: Six suspected NTDs identified
2 not NTDs: sacral dimples
1 possible NTD: unspecified lesion on side of head
1 possible NTD, which was an unspecified lesion on the side of the head.

27. Results: Six suspected NTDs identified
2 not NTDs: sacral dimples
1 possible NTD: unspecified lesion on side of head
2 probable NTDs: 1 spina bifida and 1 spina bifida with frontal encephalocele
2 probable NTDs, one spina bifida alone; and one spina bifida with frontal encephalocele.

28. Results: Six suspected NTDs identified
2 not NTDs: sacral dimples
1 possible NTD: unspecified lesion on side of head
2 probable NTDs: 1 spina bifida and 1 spina bifida with frontal encephalocele
1 confirmed NTD: spina bifida
And 1 confirmed NTD, spina bifida.

29. Results: Six suspected NTDs identified
2 not NTDs: sacral dimples
1 possible NTD: unspecified lesion on side of head
2 probable NTDs: 1 spina bifida and 1 spina bifida with frontal encephalocele
1 confirmed NTD: spina bifida
Probable and confirmed NTD cases (n=3) were included in the analysis
The two probable and one confirmed NTD cases were the outcomes included in the analysis.

30. Results: NTD prevalence by maternal exposure
Percentage (95% CI) with NTD
Number of NTDs 1 2
Number of Exposures
152
381
261
2328
% with NTD (95% CI)
0.66% (0.02%, 3.69%)
0 (0, 0.79%)
0 (0, 1.15%)
0.09% (0.01%, 0.31%)
Prevalence Difference (95% CI)
ref
0.66% (-0.73%, 4.16%)
0.66% (-1.25%, 4.16%)
0.58% (-0.10%, 4.10%)
Of the three (3) NTDs included in the final analysis.
One occurred among the 152 DTG-exposed HIV-positive mothers.
The other two NTDs occurred among the 2328 HIV-negative mothers.
Slide adapted from Rebecca Zash

31. Results: NTD prevalence by maternal exposure
DTG
0.66%
(1/152)
HIV-negative
0.09% (2/2328)
Percentage (95% CI) with NTD
Number of NTDs 1 2
Number of Exposures
152
381
261
2328
% with NTD (95% CI)
0.66% (0.02%, 3.69%)
0 (0, 0.79%)
0 (0, 1.15%)
0.09% (0.01%, 0.31%)
Prevalence Difference (95% CI)
ref
0.66% (-0.73%, 4.16%)
0.66% (-1.25%, 4.16%)
0.58% (-0.10%, 4.10%)
The NTD prevalence among the DTG-exposed HIV-positive mothers was 0.66% (with 95% Confidence Interval: 0.02% – 3.69%).
NTD prevalence among the HIV-negative mothers was 0.09% (with 95% Confidence Interval: 0.01% – 0.31%).
Slide adapted from Rebecca Zash

32. Consideration: How do we monitor birth outcomes?
As the dolutegravir-based ART regimen (TLD) is rolled out, countries will be interested in how best to monitor birth outcomes.

33. Consideration: How do we monitor birth outcomes?
Surveillance
Pharmacovigilance
They will consider two approaches, surveillance and pharmacovigilance. To choose well, decision makers will need to understand and consider the differences between these two approaches.

34. Consideration: Surveillance
Surveillance is a reliable method to establish the DTG-NTD association
Data collection methodology is continuous and systematic
Provides a denominator to estimate the magnitude and scope of birth defects
Starting point = outcome (delivery, NTD)
Requires large sample size to detect rare outcome of birth defects
Complex and resource-intensive
Surveillance is a reliable method to establish the DTG-NTD association. Its advantages include data collection methodology that is continuous and systematic; the approach provides a denominator to estimate the magnitude and scope of birth defects, and the starting point is the outcome (delivery or NTD).
Surveillance can be challenging because it requires a large sample size to detect rare outcomes of birth defects; it is complex and resource-intensive.*
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*Back-up slide “Surveillance is complex/resource-intensive” lists components of surveillance.

35. Consideration: Pharmacovigilance
Pharmacovigilance is a common post-marketing approach to capture adverse drug effects
No comparison group
Not designed to collect data from maternity wards
Starting point = exposure (DTG at conception)
Pharmacovigilance is a common post-marketing approach to capture adverse drug effects.
Pharmacovigilance provides no comparison group, meaning that no information would be collected on HIV-negative women.
It is not designed to collect data from maternity wards because its starting point is the exposure (DTG at conception), not the NTD outcome.

36. Conclusions
Small increased NTD prevalence among infants born to HIV-positive mothers on DTG at conception compared to infants born to HIV-negative mothers
Study was conducted for only 6 months, resulting in small number of deliveries
Data suggest that NTD risk with DTG exposure at conception remains <1%, consistent with Tsepamo study findings reported in 2018
In conclusion, we found a small increased NTD prevalence among infants born to HIV-positive mothers on DTG at conception compared to infants born to HIV-negative mothers.
The study was conducted for only 6 months, resulting in a small number of deliveries. Consequently, our NTD prevalence estimates have wide confidence intervals.
However, our data suggest that NTD risk with DTG exposure at conception remains <1%, consistent with the Tsepamo study findings reported in 2018.

37. Acknowledgements Botswana MoHW: CDC Atlanta: CDC Botswana BUMMHI
Eldah Dintwa
Chipo Petlo
Sifelani Malima
Omphemetse Mmunyane
Kelame Kefitlhile
Thusoetsile Modise
CDC Botswana
Vasavi Thomas
Michelle Roland
Catherine Motswere-Chirwa
Kunle Dare
Shifawu Odunsi
Mpho Letebele
CDC Atlanta:
Sara Forhan
Dhelia Williamson
Elizabeth Rabold
Sarah Tinker
Cynthia Moore
Surbhi Modi
BUMMHI
Gadzikanani Gokatweng
Chibuike Mark Ogbuabo
Ndwapi Ndwapi
I would like to acknowledge my colleagues from MoHW, CDC Botswana and Atlanta, and BUMMHI for making this study possible.

38. Ke a leboga! Thank you!

39. EXTRA SLIDES

40. Retrospective study not feasible
Prospective
2016
2017
2018
Using standard obstetrical records:
Unreliable outcome data unable to validate NTDs
Missing records, unreliable exams, missing exams, unable to validate
Incomplete exposure data—ART regimen at conception not captured
In the study planning stages, a review of the standard obstetrical records from more than 200 deliveries at 4 facilities showed that a retrospective study would not be feasible.
We found unreliable outcome data, thus we would be unable to validate NTDs; exposure data--specific ART regimen and date of initiation--was incomplete.

41. Prospective approach chosen
Retrospective
Prospective
2016
2017
2018
Reasons:
Able to capture needed data elements with additional tool
Provides an accurate denominator
Can compare NTD ratios among other groups of women (e.g., HIV negative and HIV-positive on other ARVs)
Thus a prospective approach was chosen. The needed data elements were captured with an additional data collection tool.
Moreover, the prospective approach provided an accurate denominator and the ability to compare NTD ratios among other groups of women, for example between HIV-negative and HIV-positive mothers on ARVs other than DTG.

42. Would the results be different if the analysis had included the possible NTD case?
Possible NTD case occurred in an HIV-negative woman
We conducted a sensitivity analysis to assess how inclusion of the possible NTD would affect the prevalence difference estimate and found there was no meaningful change
The possible NTD case occurred in an HIV-negative woman.
We conducted a sensitivity analysis to assess how inclusion of the possible NTD would affect the prevalence difference estimate and found there was no meaningful change.

43. Birth surveillance is complex and resource-intensive
Designated leadership
New data tools
Midwife training
Cadre dedicated to data collection
Commodities
Logistics
Ongoing oversight for procedural and data quality
Data collection system
We learned that setting up a birth surveillance system, even at a few sites, is complex and resource-intensive. It required significant planning, coordination, and monetary and human resources. Among the needed components for such a system are:
Designated leadership
New data tools to capture exposure and outcome-related information may be needed
Midwife training
A cadre dedicated to data collection
Commodities (such as storage files, collection forms, and tablets)
Logistics
Ongoing oversight for procedural and data quality and a
Data collection system