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 www.iasociety.org/HIV-Programmes/Campaigns/Generation-Now

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

ART coverage over time Source: UNAIDS/WHO estimates

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

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

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

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

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

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

(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.

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

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)

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

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

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

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

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 – 800 -1000 more women exposed to DTG Expected more information by April 2018 Courtesy L. Mofenson & R Zash, 2018

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

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

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).

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.  

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

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.

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 : http://www.who.int/reproductivehealth/publications/family_planning/MEC-5/en/

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

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, 2016 - 2020 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 , 19 000 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, … http://www.who.int/tdr/research/tb_hiv/drug-safety-pregnancy/en/

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)

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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