Session - Safety of DTG in Pregnancy: Late

Session - Safety of DTG in Pregnancy: Late

Session - Safety of DTG in Pregnancy: Late Breaking Findings, Interpretations, Implications July 24 2018 Overview on Safety of HIV Treatment in Pregnancy Lynne M. Mofenson MD Senior HIV Technical Advisor Elizabeth Glaser Pediatric AIDS Foundation HIV, Pregnancy and ART HIV is associated with significant morbidity/mortality for the pregnant woman and her fetus/infant treatment is required for both maternal health and to prevent MTCT Only limited data on ARVs in pregnancy/lactation; of the 31 approved ARVs, mean lag between approvalany pregnancy data is 5 years (no data 3/7 drugs approved since 2010) Big unknowns, particularly for newer drugs: Pharmacokinetics and safety in pregnancy (and lactation) Fetal/infant safety Unanticipated findings with preconception DTG demonstrate importance of pharmacovigilance when new drugs introduced into adult population ARVs and Pregnancy

What can we learn from preclinical studies? Are there differences in pregnancy outcomes between ART regimens? Why is timing of exposure - critical and often neglected variable - important? Do birth outcomes vary by timing of ART start? Are there differences in DTG and EFV started during pregnancy? Evaluation of safety re: birth defects What Can We Learn From Pre-Clinical Reproductive Toxicology Studies What is Predictive Value of Pre-Clinical Animal Studies? The molecular basis of birth defects with drug exposure is known for only a few drugs Most human teratogens were first identified by clinical/epidemiologic studies (e.g., thalidomide, diethylstibesterol, valproate) Animals can be differentially sensitive to drugs: Thalidomide was negative in mice/rat embryo-fetal studies and only positive for limb malformation in rabbit studies This is why currently FDA requires studies in >2 animal species What is Predictive Value of Pre-Clinical

Animal Studies? To date, drugs known to be teratogenic in humans have shown teratogenic activity in mouse, rat or rabbit studies (often retrospectively) (van der Laan JW et al. Reg Toxicol Pharmacol 2012;63:115-23). However, while negative tests are reassuring, there is no absolute assurance that negative results obtained by testing drugs in these species can definitively predict that an agent will lack teratogenic effects in humans (Ujhazy E et al. Developmental Toxicology: Safety Evaluation of New Drugs 2005) Similarly, it cannot be said that agents teratogenic in in animals will necessarily produce teratogenic effects in humans at therapeutic dose levels (e.g., EFV and CNS defects in monkeys but not in humans) Do Pregnancy Outcomes Vary by ART Regimen? Do Pregnancy Outcomes Vary By ART Regimen? % o f p re g n a n c y o u tc o m e s Any Adverse/Severe Adverse Outcome By Preconception ART, Botswana Zash R et al. JAMA Pediatr. 2017;171:e172222 Compared to EFV ART, aRR of adverse outcomes with other ART regimens 1.15 (1.0-1.3) 1.30

(1.2-1.4) 1.31 (1.1-1.5) 1.21 (1.0-1.5) 60% 50% 42% 30% 1.44 (1.2-1.7) 20% 18% 40% 36% 48% 47%

1.68 (1.4-2.0) 21% 45% 1.58 (1.2-2.1) 20% 12% 10% 0% Any adverse outcome (PTD, SGA, SB, neonatal death) Any severe outcome (VPTD, VSGA, SB, neonatal death) 1.93 (1.4-2.6) 23% P e r c e n t o f p r e g n a n c y o u tc o m e s Regardless of ART Regimen, Pregnancy Outcomes Were

Worse in HIV+ Women On ART than HIV-Uninfected Women Zash R et al. JAMA Pediatr. 2017;171:e172222 Compared to HIV-uninfected, aRR of adverse outcomes for HIV+ woman on ART Any: 1.40 (1.3-1.4) Severe: 1.50 (1.4-1.6) 60% 50% 42% 45% 29% 18% 20% 10% 49% 36% 40% 30% 47%

10% 21% 20% 12% 0% Any adverse outcome (PTD, SGA, SB, neonatal death) Any severe outcome (VPTD, VSGA, SB, neonatal death) 23% P e r c e n t o f p r e g n a n c y o u tc o m e s Regardless of ART Regimen, Pregnancy Outcomes Were Worse in HIV+ Women On ART than HIV-Uninfected Women Zash R et al. JAMA Pediatr. 2017;171:e172222 EFV-based ART appears safer than NVP or LPV-r-based ART Compared to HIV-uninfected, aRR of adverse outcomes for HIV+ woman on ART

Any: 1.40 (1.3-1.4) Severe: 1.50 (1.4-1.6) 60% 50% 40% 30% 20% 10% 0% But ART - regardless of regimen - does not make pregnancy outcomes among HIV+ women the same as in HIV-uninfected women 42% 47% 49% 45% 36% 29%

18% 10% 21% 20% 12% Any adverse outcome (PTD, SGA, SB, neonatal death) Any severe outcome (VPTD, VSGA, SB, neonatal death) 23% Why is Timing of ART Exposure Important? Timing of In Utero ARV Exposure and Fetal Risk Timing of In Utero ARV Exposure and Fetal Risk First 2.5 Weeks Post-Fertilization:

Pre-Organogenic Period generally not sensitive to teratogens 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 Post Fertilization Embryogenesis: Period of Major Organ Development most sensitive period to teratogens Neural Tube Closure Normally Occurs by 28 Days Post-Conception Different phenotypes of neural tube defects Cranial neuropore closes on 25th day after conception; caudal neuropore normally closes ~ 2 days later ni Cra

al n NEJM Botto 1999 op o eur re multi-site closure process Fusion of the neural tube may have several origins of fusion Fusion proceeds in both cephalad and caudal directions, forming anterior and posterior neuropores Caud a

l n eur op or e Phenotype depends on location & level of the defect, whether crosses CNS segmental boundaries UpToDate Online 17.2: McLone DG, Bowman RM Multifactorial Pathogenesis of Neural Tube Defects Development of the neural tube is a multi-step process strictly controlled by genes but modulated by a host of environmental factors (including drugs) Exact etiology remains poorly understood It is generally agreed that most NTD cases are of multifactorial origin, having a genetic sensitivity to their etiology that interacts with a number of environmental risk factors (e.g., folate, drugs) Occurrence NTD in abortuses and stillbirths is many-fold higher than that in live births Neural Tube Defects Are Not One Defect but Many NTD is a spectrum of maldevelopment affecting the neural tube, associated meninges and axial skeleton; depending onset time during development, can affect different regions of neural tube and non-neural organs. Two types: Open and Closed Open: arise during process of primary neurulation, primary failure of neural tube closure (~17-20 post-fertilization days);

tissues of unclosed neural tube (brain, spinal cord) are exposed. Most frequent open NTD are anencephaly and open spina bifida. Closed: is neural tube defect which is covered by skin; may occur post-neurulation. Encephaloceles and other skin covered lesions are examples of closed NTD. Timing of In Utero ARV Exposure and Fetal Risk Examples: Alcohol after 24 weeks & fetal-alcohol syndrome Smoking after 20 weeks and IUGR After 8 Weeks Post-Fertilization Fetal Development Period Fetal growth; teeth; external genitalia; continued brain develop Timing of In Utero ARV Exposure s u o iRisk and Fetal r e s n

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e u n t e o s i t w t w t p s e e o b c m n h t bu inguis preco t d s e n

i r a d u r s e o t s p e x e m i tr Do Birth Outcomes (Other than Birth Defects) Differ if Starting ART Before or During Pregnancy? Preterm Delivery and Preconception ART Uthman OA et al. Lancet HIV 2016. Meta-analysis studies through 2016 Meta-analysis 10 studies: ART started preconception in 9,443; during pregnancy in 7,773 Preconception ART associated with increased risk PTD:

RR 1.20 (1.01-1.44); highest association LMIC Since 2016, 7 new publications address this; 6 of 7 also report association of preconception ART with PTD Start Before Start During Start before vs during pregnancy Ramokolo Open Forum Infect Dis 2017 616 780 Yes: AOR, 1.7 (1.12.5) Sebitloane Niger J Clin Prac 2018 312 423 Trend (not signif): OR 1.24 (0.9,1.8) Chetty PlosOne 2018 1002 1591

No Favarato AIDS 2018 3090 2983 Yes: AOR 1.27 (1.01, 1.61) Rough NEJM 2018 434 1187 Yes: Higher preconception Snijdewind PLosOne 2018 550 842 Yes: 1.38 (1.02,1.85) Zash JPIDS 2018 502

550 Yes: 1.33 (1.04, 1.7) vs 2/3rd trim Preterm Delivery and Preconception ART Uthman OA et al. Lancet HIV 2016. Meta-analysis studies through 2016 10 studies: 9443 start ART preconception, 7773 during pregnancy Preterm delivery (and Preconception ART associated with increased risk PTD: very preterm delivery) RR 1.20 (1.01-1.44); highest association LMIC Since 2016, may be increased 7 new publications address this;with 5 of 7 also report association of preconception ART with PTD. preconception ART compared to first starting

ART during pregnancy Start Before Start During Start before vs during pregnancy Ramokolo Open Forum Infect Dis 2017 616 780 Yes: AOR, 1.7 (1.12.5) Sebitloane Niger J Clin Prac 2018 312 423 No (trend): OR 1.24 (0.9,1.8) Chetty PlosOne 2018 1002 1591 No

Favarato AIDS 2018 3090 2983 Yes: AOR 1.27 (1.01, 1.61) Rough NEJM 2018 434 1187 Yes: Higher preconception Snijdewind PLosOne 2018 550 842 Yes: 1.38 (1.02,1.85) Zash JPIDS 2018 502 550

Yes: 1.33 (1.04, 1.7) vs 2/3rd trim When Started During Pregnancy, Do Pregnancy Outcomes Differ Between Women on DTG vs EFV-Based ART Regimens? When Started During Pregnancy, No Difference Pregnancy Outcomes EFV vs DTG-Based ART Zash R et al. Lancet Global Health 2018;6:e804-10 35.0% Any adverse outcome 33.2% 11.3% Any severe adverse outcome 10.7% 18.5% Preterm <37 wk GA Very preterm <32 wk GA No difference: Major Birth Defects with

First Trimester Exposure 18.5% EFV: 1/395 (0.3%) 17.4% DTG: 0/280 (0%) (no NTD either drug) 18.0% 3.5% 3.8% SGA 10%ile wt for GA 6.7% Very SGA 3%ile wt for GA Stillbirth Neonatal death 0% 6.1% 2.3% 2.3% 1.3% 1.2% 5%

DTG/TDF/FTC (N=1,729) EFV/TDF/FTC (N=4,593) 10% 15% 20% 25% 30% 35% 40% However, HIV-Uninfected Women Still Have Better Outcomes than HIV+ Women on EFV or DTG ART Zash R et al. Lancet Global Health 2018;6:e804-10 28.9% Any adverse outcome 9.9% Any severe adverse outcome 11.3% 10.7%

15.6% Preterm <37 wk GA Very preterm <32 wk GA 18.5% 18.0% 3.6% 3.8% 3.5% 14.8% SGA 10%ile wt for GA Neonatal death 0% 18.5% 17.4% 5.4% 6.7% 6.1% Very SGA 3%ile wt for GA Stillbirth

35.0% 33.2% 2.1% 2.3% 2.3% DTG/TDF/FTC (N=1,729) Column1 1.4% 1.2% HIV-UNINFECTED (N=51,156) 1.3% 5% 10% 15% 20% 25% 30%

35% 40% However, HIV-Uninfected Women Still Have Better Outcomes than HIV+ Women on DTG or EFV ART When started during pregnancy, EFV and DTG appear equivalent in terms of pregnancy outcomes (including birth defects) Zash R et al. Lancet Global Health 2018;6:e804-10 28.9% Any adverse outcome 9.9% Any severe adverse outcome 11.3% 10.7% 15.6% Preterm <37 wk GA

Very preterm <32 wk GA 35.0% 33.2% 18.5% 18.0% 3.6% 3.8% 3.5% 14.8% SGA 10%ile wt for GA 18.5% 17.4% But adverse outcomes with EFV or DTG ART are still higher than in HIV-uninfected women 5.4% 6.7% 6.1%

Very SGA 3%ile wt for GA Stillbirth Neonatal death 0% 2.1% 2.3% 2.3% DTG/TDF/FTC (N=1,729) Column1 1.4% 1.2% HIV-UNINFECTED (N=51,156) 1.3% 5% 10% 15% 20%

25% 30% 35% 40% Safety Birth Defects Expected Incidence of Neural Tube Defects Blencowe H et al. Ann NY Aca Sci 2018;1414:31-46 Estimated prevalence of NTD in 2015 globally was 0.19% (0.15% to 0.23%) [19 (1523)/10,000 birth outcomes] About 50% of cases were elective terminations or stillbirths, so evaluation of only live births gives underestimation African Region: Data from 11 studies from 8 countries analyzed Median prevalence of NTD in Africa was 0.12% (range 0.06% to 0.23%) P Musoke CROI 2018 Abs 829 43,293 births (4,634 HIV+ women, 77% on EFV ART) in Uganda Prevalence NTD: HIV-uninfected 0.09%, HIV+ 0.04% Ability to Rule-Out Birth Defect is Related to Incidence Defect

and Number Observed Preconception/1st Trimester Exposures 200 exposures can rule out a 2-fold in overall birth defects (incidence 3%) Overall defects Incidence 3% Watts DH. Curr HIV/AIDS Rep 2007;4:135-140 RR 2.0 Ability to Rule-Out Birth Defect is Related to Incidence Defect and Number Observed Preconception/1st Trimester Exposures However, to rule-out a 3-fold increase in a relatively rare event like NTD (incidence 0.1%), need about 2,000 exposures Neural tube defect Incidence 0.1% RR 3.0 Overall defects Incidence 3% Watts DH. Curr HIV/AIDS Rep 2007;4:135-140 RR 2.0 Birth Defect Surveillance:

Antiretroviral Pregnancy Registry Antiretroviral Pregnancy Registry began in 1990 as Zidovudine in Pregnancy Registry Currently international registry including 128 antiretroviral drugs 49 brand, 79 generic drugs Provider prospectively reports women on ART during pregnancy to the APR prior to delivery outcome To provide early warning signal; estimates risk of major birth defects compared to general population Registry is only as good as reporting to it! Drug-Specific Birth Defect Rates* Prevalence of Birth Defects (95% CI): 1 January 1989 31 January 2018 First Trimester Exposure *For drug to be included for comparison with population rates, a drug must meet threshold of having 200 1st trimester exposed pregnancies Metropolitan Atlanta Congenital Defects Program (2.7%) Texas Birth Defects Registry (4.2%) 2.7% (CI 2.4-3.1%) MACDP: Metropolitan Atlanta Congenital Defects Program TBDR: Texas Birth Defects Registry

Drug-Specific Birth Defect Rates* Prevalence of Birth Defects (95% CI): 1 January 1989 31 January 2018 First Trimester Exposure Other than rilpivirine, raltegravir, *For drugs meeting threshold of 200 1 st trimester exposed pregnancies Metropolitan Atlanta Congenital Defects Program (2.7%) Texas Birth Defects Registry (4.2%) and cobicistat, there are insufficient data on newer ARV drugs (bictegravir, carbotegravir, dolutegravir, elvitegravir, etravirine tenofovir alafenamide.) to be able to rule out a 2-fold increase in overall birth defects, let alone rare events like NTD 2.7% (CI 2.4-3.1%) MACDP: Metropolitan Atlanta Congenital Defects Program TBDR: Texas Birth Defects Registry

Drug Therapy in Pregnancy Balancing act Benefit of Maternal Treatment Risk of Adverse Fetal Effects Unfortunately there are often only limited data to make recommendations Dolutegravir in Pregnancy Balancing act Benefit of Maternal Treatment DTG: Rapid VL decline Better tolerated Less expensive Risk of Adverse Fetal Effects DTG: Potential signal for

neural tube defect with preconception exposure Dolutegravir in Pregnancy Balancing act Benefit of Maternal Treatment DTG: Rapid VL decline Better tolerated Less expensive Risk of Adverse Fetal Effects DTG: Potential signal for neural tube defect with preconception exposure Maternal-baby boxing match! Dolutegravir in Pregnancy Benefit of Maternal Treatment

DTG: Rapid VL decline Better tolerated Less expensive Balancing act Risk of Adverse Fetal Effects DTG: Potential signal for neural tube defect with preconception exposure As you will hear, more data will be available to confirm/refute this signal in the next year In the meantime, we need to figure out how to maximize outcomes for both mother and child (without pitting one against the other) Thank you for your attention!

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