1. Meg Doherty, MD, MPH, PhD WHO Geneva 22 July 2018
Potential safety issue affecting women living with HIV using dolutegravir at the time of conception
Meg Doherty, MD, MPH, PhD
WHO Geneva
22 July 2018

2. incidence and mortality since 2010
Global HIV epidemic
incidence and mortality since 2010
- 18%
New infections annually
relative to 2010
2017
Globally
36.9 million
People living with HIV
- 34%
Deaths annually
relative to 2010
Source: UNAIDS/WHO estimates

3. ART coverage over time
Source: UNAIDS/WHO estimates

4. HIV testing and care continuum (2017)
Source: UNAIDS/WHO estimates

5. World Health Organization
15 February 2019
2016 WHO recommendations for 1st Line ART in Adults and Adolescents
National surveys on EFV/NVP pretreatment drug resistance showed resistance >10% in 6 out of 11 countries
WHO recommends that:
1) Countries with national pretreatment HIVDR to EFV or NVP ≥10% should consider a RAPID transition to non-NNRTI for all new ART starters
2) ART starters with reported prior exposure to ARVs: start a non-NNRTI (i.e. DTG), regardless of level of PDR
In EECA: already included in national guidelines in 9 countries

6. Approach to ARV Drug Optimization: Key Principles
Reduce toxicity
Improve palatability/pill burden
Reduce drug interactions
Increase resistance barrier
Safe use across different age groups and populations (“Harmonization”)
Reduce cost → Increase availability
IMPROVE ADHERENCE TO TREATMENT
BETTER VIRAL SUPPRESSION AND HEALTH
INCREASE AVAILABILITY AND FEASIBILITY

7. Dolutegravir – overall drug profile
Integrase inhibitor (once daily dose)
Effective (rapid viral load suppression)
Well tolerated
High genetic barrier to resistance
Few drug interactions
Single and fixed dose generic formulations
Comparable price to current regimens in LMICs

8. Gaps on clinical use of dolutegravir
CNS side effects: higher than expected rate of DTG discontinuation due insomnia in some cohort studies (higher rates compared with RCTs) but very low occurrence of other side effects.
IRIS in PLHIV with advanced HIV disease: increased risk observed in some cohort studies but not detected in RCTs with other INSTIs (REALITY trial).
HIV-associated TB: need to double dose if rifampin is used (INSPIRING – 50 mg BID)
Pregnant/BF women: limited safety data, very high DTG concentrations in blood cord at birth (clinical studies ongoing)
Infants and children: safety and dose finding trial underway.
Very limited clinical experience

9. Botswana, Brazil and Kenya have adopted DTG as preferred 1st line option in 2016/17 & have implemented a programmatic transition to DTG
Country
Transition start
PLHIV on DTG
M/F
ratio
DTG eligibility criteria
% of reported DTG adverse events
Major DTG AEs reported (top 3)
DTG monitoring tools
Use of VL for DTG substitution
ART naive
NNRTI intolerance
Stable on ART non EFV regimens
Stable on ART EFV regimen PW TB
2nd line
3rd line
PEP
Toxicity (PV)
APR
HIVDR
Botswana
May 2016
57,000
40/60   1%
GI symptoms
Skin reactions
Insomnia
Brazil
Jan 2017
100,000
70/30 2%
Kenya
July 2017
15,000
25/75 7%
Headache
Abnormal dreams
Source: MoH Botswana, Brazil & Kenya, 2018

10. (progress from November 2017 to July 2018)
Progress in transition to Dolutegravir (DTG) as a preferred first line ARV regimen in LMIC
(progress from November 2017 to July 2018)
98 (51%) of LMIC are making shifts to DTG containing regimens
87 countries (45%) of LMIC adopted TDF/[3TC or FTC]/EFV as the preferred first-line therapy, whereas an additional 98 (51%) of LMIC are making shifts to DTG containing regimens (measured as  composite indicator of countries that have introduced or are introducing DTG in their guidelines and procurement of DTG has been initiated).
# LMIC JULY 2018
Data not reported 5
DTG introduced in national guidelines 26 DTG introduced in national guidelines and procurement initiated 24
DTG introduction in national guidelines planned 21
TDF/[3TC or FTC]/EFV first line ARVs only 63
Grand Total 139
In November 2017: 72% of LMIC adopted TDF/3TC or FTC)/EFV as the preferred first-line therapy, whereas an additional 40% of LMIC are making shifts to DTG containing regimens.

11. Many countries already started DTG Transition Plans
TLD transition plan in Mozambique
DTG transition plans in countries supported by PEPFAR
ARV Population and Regimen throughout TLD Transition in Eswatini

12. When Started During Pregnancy, No Difference Pregnancy Outcomes EFV vs DTG-Based ART Zash R et al. Lancet Global Health 2018;6:e804-10
No difference:
Major Birth Defects with
First Trimester Exposure
EFV: 1/395 (0.3%)
DTG: 0/280 (0%)
(no NTD either drug)

13. First 2.5 Weeks Post-Fertilization:
Timing of In Utero ARV Exposure and Fetal Risk
First 2.5 Weeks Post-Fertilization:
Pre-Organogenic Period
generally not sensitive to teratogens
Courtesy L. Mofenson 2018

14. Timing of In Utero ARV Exposure and Fetal Risk
Examples:
Neural Tube Closure by
Day 28
(e.g. myelomeningocele)
Oral Structure Formation by
Day 36
(e.g. cleft palate)
Weeks 3 to 8-12 Post Fertilization
Embryogenesis: Active Organogenesis
most sensitive period to teratogens
Courtesy L. Mofenson 2018

15. Timing of In Utero ARV Exposure and Fetal Risk
Greatest risk for serious defects is not in women starting during pregnancy but in those who conceive while receiving drug -
but most studies do not distinguish between 1st trimester and preconception exposure
Courtesy L. Mofenson 2018

16. Tsepamo Study – Birth Surveillance
NIH study specifically designed to evaluate the risk of neural tube defects (NTD) with preconception EFV exposure.
Well-designed prospective birth outcomes surveillance for major surface birth defects, population based (45% of births in Botswana).
Good denominator with control groups and ability to distinguish between ARV regimens
HIV-uninfected
HIV-infected ART preconception
HIV-infected ART started during pregnancy
Courtesy L. Mofenson & R Zash, 2018

17. Tsepamo Study: Neural Tube Defect (NTD) See Rebecca Zash Late Breaker Tues July 24
Preconception DTG exposure: 4 NTD/426 exposures, 0.94% (0.37, 2.4%)
Preconception non-DTG exposure: 14 NTD/11,200 (0.12%)
HIV-uninfected women: 61 NTD/66,057 (0.09%)
Preliminary signal of significantly increased risk of NTD with preconception DTG exposure
No clear time trend
No other (obvious) explanation in data
Controlled for polydactyly (1% in each group)
Programme and study ongoing – more women exposed to DTG
Expected more information by April 2018
Courtesy L. Mofenson & R Zash, 2018

18. Drug Safety Alert vs. Policy Guidelines
DOCUMENT
CARACTHERITICS
EXAMPLES
DRUG SAFETY ALERTS
Drug centered, more restrictive, consider major clinical scenarios
WHO (EMP), FDA, EMA, PEPFAR, SAHCS, ViiV, Brazilian MoH
GUIDELINES
Patient centered, consider a clinical and programmatic aspects in decision making
WHO (HIV), CDC, DHHS, BHIVA

19. New Directions on WHO Guidelines - 2018
DTG based regimen may be used as a preferred first-line regimen for people living with HIV initiating ART
Adults
Women and adolescent girls of childbearing potential - note of caution
Infants and children with approved DTG dosing

20. Note of caution for using DTG in women and adolescent girls of childbearing potential
Exposure to DTG at the time of conception may be associated with NTD risk among infants.
DTG appears to be safe when started after the period of risk of neural tube defects (ie, up to 8 weeks after conception).
Adolescent girls and women of childbearing potential who do not currently want to become pregnant can receive DTG together with consistent contraception (hormonal contraception and DTG have no reported or expected drug–drug interactions).
An EFV-based regimen is a safe and effective first-line regimen and can be used among women of childbearing potential during the period of potential risk for developing NTDs.
National programmes should consider the balance of benefits and risks when selecting the optimal ARV regimen for women and adolescent girls of childbearing potential (fertility levels, contraceptive availability and coverage, pretreatment resistance to NNRTIs at the population level, drug availability and the maternal and infant toxicity profile).

21. Example of an algorithm for programmatic implementation of the new DTG recommendation
People living with HIV
Male
TLD
Female
Childbearing potential? No
Yes
Desiring pregnancy or pregnant a?
Access to consistent and reliable b contraception?
TLE c
Notes: a TLD could be considered for pregnant women identified as receiving or starting ART later in the pregnancy (second or third trimester), although the switch to TLE should be ensured after delivery in case the woman does not have access to reliable contraception. TLD can be safely used in adolescents weighing more than 30 kg.
b Women should be advised on the possible effects of TLD on the pregnancy outcome and on the available contraceptive methods. Consistent and reliable contraception implies that contraceptive methods are widely available and easily accessible to the population, especially long acting contraceptive methods and dual contraceptive methods with condoms.
c TLE is a safe and effective option for women desiring pregnancy or currently pregnant until the signal of potential risk of new tube defects associated with DTG use in periconception period is confirmed or refuted.

22. Approach to use of DTG across different guidelines making bodies
ART history
Clinical scenarios
DHHS
BHIVA
WHO
ART naive or on using a non-DTG containing regimen
Early pregnancy
Late pregnancy
Childbearing age potential, not using contraception
Childbearing age potential, using effective/consistent contraception
On DTG containing regimen
Childbearing age potential , not using contraception
Childbearing age potential, using contraception
* The definition of early pregnancy period varies in different guidelines. DHHS: < 8 weeks from LMP; BHIVA : 1st trimester; WHO: < up to 8 weeks from conception.
Do not initiate DTG/ switch to other effective options
Initiate /continue to DTG or switch to other effective options
initiate/ switch to DTG

23. Programmes should strengthen the integration of sexual and reproductive health services within HIV treatment programmes to ensure reliable and consistent access to contraception for women and adolescent girls living with HIV.

24. Recommendations for use of hormonal contraception for women living with HIV using antiretroviral therapy (ART)
ARV Class
COCs
CICs
Patches & rings
POPs
POIs
LNG & ETG
implants
LNG-IUD
DMPA
NET-EN
WHO clinical stage
WHO stage
1 or 2
3 or 4
WHO stage 3 or 4
NRTI
NNRTI
EFV or NVP
ETR or RIL PI
INSTI (RAL)
MEC Category 2
(benefits > risks)
MEC Category 3
(risks > benefits)
MEC Category 1
(no restriction)
GRADE assessment for quality of evidence: LOW to VERY LOW
Adapted from : Medical Eligibility Criteria for Contraceptive Use (5th edition). WHO 2015
Available from : 

25. Common concerns Contraception:
Definition of “consistent” or “long term” contraception
Injectable method have not be considered long term methods in most of the countries
Pregnant women:
Difficulty to correctly dating the pregnancy in the first trimester
If using DTG during pregnancy and switching afterwards how to ensure that the switching happen before new pregnancy
Most countries chose EFV for PW: what about women identified late in pregnancy when DTG could give the higher benefit?
Adolescents girls:
Group with higher risk of low adherence and low viral suppression
Group at higher risk of unplanned pregnancies and lower uptake of contraception

26. WHO Global Surveillance of drug safety in pregnancy
WHO / TDR
Central registry for epidemiological surveillance of drug safety in pregnancy
South Africa
Botswana
Others : MSF Mozambique
Uganda
Malawi
ARV pregnancy registry : National Department of Health and WHO technical support
Plan: Gauteng Province
With UCT in Western Cape Province
University of Cape Town
MoH Gauteng Province
Birth defect surveillance project with CDC funding and WHO technical support,
Queen Elizabeth Hospital in Blantyre 8000 deliveries, 1000 HIV positive, 37 babies with major birth defects - at end July 2017
Expansion in September 2017 at Mangochi and Ntcheu, and Bwaila Hospital, Lilongwe – 4 sites
Methodo: (i) surveillance maternal and birth outcomes (ii) case –control study examining risk factors associated with major BDs
MoH Botswana Harvard Partnership
Tsepamo study
Approximately 88,000 births , HIV positive on ART, as of April 2018
12,000 exposed to DTG based regimen
NTD signal May 2018
More sites
Pregnancy registry starting MSF in Malawi, Mozambique initiating, Uganda (CDC protocol) , Kenya, …

27. Conclusions
Faced with an unexpected signal of risk in a high value and much anticipated ARV
WHO along with other regulatory issued drug safety warnings
Now WHO will be releasing updated guidelines at this conference on the policy direction
DTG can be used and WHO emphasizes that women and adolescents of child bearing potential will need informed choices; and use DTG with consistent and reliable contraception
Communities need to be at the table to discuss policy translation at country level
Silver lining is an opportunity for integration and real linkages between HIV and SHR; FP choices need to be available in HIV clinics (and vice - versa)

28. Join us on AIDS 2018

29. Acknowledgements Lynne Mofenson WHO Treatment and Care team
Marco Vitoria
Martina Penazzato
Serena Brusamento
Chantal Migone
Nathan Ford
Lara Vojnov
Systematic reviewers
Silvia Bertagnolio
Guidelines Development Group members
Wole Ameyan
External Review Committee