Journal Club, 17. Mai 2021 Mihaela Sava Klinik für Infektiologie und Spitalhygiene
Efficacy and safety of (1) dolutegravir with emtricitabine and tenofovir alafenamide fumarate or (2) tenofovir disoproxil fumarate, and (3) efavirenz, 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 (lamivudine) 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)