Journal Club, 17. Mai 2021 Mihaela Sava Klinik für Infektiologie und Spitalhygiene

Efficacy and safety of (1) with and fumarate or (2) fumarate, and (3) , emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/ VESTED)

Lockman S, Brummel S et al. April 3, 2021; The Lancet Background

• 38 millionen people living with HIV in 2019, 51% women • 1.3 million pregnant women were receiving antiretroviral therapy (ART) in 2018 • Antiretroviral therapy during pregnancy • Important for mother`s health • Prevention of perinatal HIV transmission • ART during pregnancy: safety of the woman and fetus must be considered • High-quality data on safety and efficacy of ART in pregnancy is scarce

2 Dolutegravir (DTG), Efavirenz (EFV), Emtricitabine (FTC), Tenofovir alafenamide fumarate (TAF), Tenofovir disoproxil fumarate (TDF) Antiretroviral regimen for ART-naïve pregnant women

• In 2018 WHO replaced efavirenz (EFV) with dolutegravir (DTG) as 1st line ART in adults and adolecents, including pregnant women • DTG + 3TC () or FTC (emtricitabine) + TDF (tenofovir disoproxil fumarate)

• DTG: potent, well-tolerated INSTI, high-barrier to drug resistance • Tsepamo study: unexpected safety signal (neural tube defects in neonates exposed to DTG at conception) • Tenofovir alafenamide fumarate (TAF): prodrug of tenofovir (TFV) • achieves high levels of tenofovir-diphosphate in lymphoid cells and hepatocytes • 90% lower systemic concentrations of TFV compared to TDF -> less renal & bone toxicity • TAF: recommended ARV regimen > W14 of pregnancy by EACS (10/2020)

3 Dolutegravir (DTG), Efavirenz (EFV), Emtricitabine (FTC), Tenofovir alafenamide fumarate (TAF), Tenofovir disoproxil fumarate (TDF) Methods

• Multicentre, open-label, randomised, phase 3 trial • 9 countries: Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, Zimbabwe

Population Randomisation 1:1:1 • Pregnant women, ≥18years • (1) DTG + FTC + TAF • Confirmed HIV-1 infection • (2) DTG + FTC + TDF • Gestation weeks 14-28 at enrolment • (3) EFV 600mg + FTC + TDF • ART-naive participants (exeption: ART<14d) • Stratified by gestational age & by country • Exclusion: multiple fetuses, fetal anomaly, psichiatric illness • Procedures • Efficacy & Satefy testing: every 4 weeks antepartum, delivery, postpartum • Outcomes: • (1) Efficacy: viral suppression (HIV-1 RNA <200cp/ml) at/within 14 days of delivery • (1) Safety: composite pregnancy outcome: spontaneus abortion (<20W), stillbirth (≥20W), preterm delivery (<37W), infant born small for gestational age (<10th percentile) • (2/3) Safety: grade 3 or higher adverse events for mothers and infants

4 Dolutegravir (DTG), Efavirenz (EFV), Emtricitabine (FTC), Tenofovir alafenamide fumarate (TAF), Tenofovir disoproxil fumarate (TDF) Methods • Statistical analysis • Sample size calculation: 639 participants • -10% non-inferiority margin for primary efficacy outcome in DTG- vs. EFV- containing regimens • Primary safety outcomes compared pairwise among treatment groups • After establishing non-inferiority: superiority of DTG-containing regimens was assessed

5 Dolutegravir (DTG), Efavirenz (EFV), Emtricitabine (FTC), Tenofovir alafenamide fumarate (TAF), Tenofovir disoproxil fumarate (TDF) Screening 01/2018 – 02/2019 Dolutegravir (DTG), Efavirenz (EFV), Emtricitabine (FTC), Results Tenofovir alafenamide fumarate(TAF), Tenofovir disoproxil fumarate (TDF)

Randomisation DTG + FTC + TAF DTG + FTC + TDF EFV + FTC + TDF

643 participants started treatment

617 participants continued treatment

Pregnancy outcome 99.5% of participants

Efficacy analysis 94% of participants Safety analysis 6 All randomised participants Baseline characteristics

7 Dolutegravir (DTG), Efavirenz (EFV), Emtricitabine (FTC), Tenofovir alafenamide fumarate (TAF), Tenofovir disoproxil fumarate (TDF) Primary efficacy outcome: viral suppresion at delivery

8 Dolutegravir (DTG), Efavirenz (EFV), Emtricitabine (FTC), Tenofovir alafenamide fumarate(TAF), Tenofovir disoproxil fumarate (TDF) Pregnancy outcome

9 Dolutegravir (DTG), Efavirenz (EFV), Emtricitabine (FTC), Tenofovir alafenamide fumarate (TAF), Tenofovir disoproxil fumarate (TDF) Adverse events grade 3 or higher Maternal outcome: until d14 postpartum Infant outcome: until age 28d

10 Dolutegravir (DTG), Efavirenz (EFV), Emtricitabine (FTC), Tenofovir alafenamide fumarate (TAF), Tenofovir disoproxil fumarate (TDF) Strengths/limitations/discussion • Strengths • One of the few RTC including pregnant women living with HIV • High rates of retention and completeness • Largest RTC assessing safety and efficacy of DTG in pregnancy • First RTC assessing TAF in pregnancy • Limitations • Advanced median gestational age at enrolment (21.9W IQR 18.3-25.3) • Not powered for rare adverse events (perinatal HIV transmission) • No resistence testing • Discussion • DTG/FTC/TAF superior efficacy compared to DTG/FTC/TDF and EFV/FTC/TDF • DTG/FTC/TAF - regimen least adverse pregnancy outcome and neonatal deaths • DTG is safe in pregnancy • TAF (+FTC/DTG) preferred to TDF in pregnancy (>14W)

11 Dolutegravir (DTG), Efavirenz (EFV), Emtricitabine (FTC), Tenofovir alafenamide fumarate (TAF), Tenofovir disoproxil fumarate (TDF)