Comparison of safety and effectiveness of antiretroviral therapy regimens among pregnant women living with HIV at preconception or during pregnancy: a systematic review and network meta-analysis of randomized trials.
Antiretroviral agents
HIV infection
Infant
Pregnant women
Vertical transmission
Journal
BMC infectious diseases
ISSN: 1471-2334
Titre abrégé: BMC Infect Dis
Pays: England
ID NLM: 100968551
Informations de publication
Date de publication:
19 Apr 2024
19 Apr 2024
Historique:
received:
02
01
2024
accepted:
08
04
2024
medline:
20
4
2024
pubmed:
20
4
2024
entrez:
19
4
2024
Statut:
epublish
Résumé
Mother-to-child transmission is the primary cause of HIV cases among children. Antiretroviral therapy (ART) plays a critical role in preventing mother-to-child transmission and reducing HIV progression, morbidity, and mortality among mothers. However, after more than two decades of ART during pregnancy, the comparative effectiveness and safety of ART medications during pregnancy are unclear, and existing evidence is contradictory. This study aimed to assess the effectiveness and safety of different ART regimens among pregnant women living with HIV at preconception or during pregnancy. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science. We included randomized trials that enrolled pregnant women living with HIV and randomized them to receive ART for at least four weeks. Pairs of reviewers independently completed screening for eligible studies, extracted data, and assessed the risk of bias using the Cochrane risk of bias tool. Our outcomes of interest included low birth weight, stillbirth, preterm birth, mother-to-child transmission of HIV, neonatal death, and congenital anomalies. Network meta-analysis was performed using a random-effects frequentist model, and the certainty of evidence was evaluated using the GRADE approach. We found 14 eligible randomized trials enrolling 9,561 pregnant women. The median duration of ART uptake ranged from 6.0 to 17.4 weeks. No treatment was statistically better than a placebo in reducing the rate of neonatal mortality, stillbirth, congenital defects, preterm birth, or low birth weight deliveries. Compared to placebo, zidovudine (ZDV)/lamivudine (3TC) and ZDV monotherapy likely reduce mother-to-child transmission (odds ratio (OR): 0.13; 95% CI: 0.05 to 0.31, high-certainty; and OR: 0.50; 95% CI: 0.33 to 0.74, moderate-certainty). Moderate-certainty evidence suggested that ZDV/3TC was associated with decreased odds of stillbirth (OR: 0.47; 95% CI: 0.09 to 2.60). Our analysis provides high- to moderate-certainty evidence that ZDV/3TC and ZDV are more effective in reducing the odds of mother-to-child transmission, with ZDV/3TC also demonstrating decreased odds of stillbirth. Notably, our findings suggest an elevated odds of stillbirth and preterm birth associated with all other ART regimens.
Sections du résumé
BACKGROUND
BACKGROUND
Mother-to-child transmission is the primary cause of HIV cases among children. Antiretroviral therapy (ART) plays a critical role in preventing mother-to-child transmission and reducing HIV progression, morbidity, and mortality among mothers. However, after more than two decades of ART during pregnancy, the comparative effectiveness and safety of ART medications during pregnancy are unclear, and existing evidence is contradictory. This study aimed to assess the effectiveness and safety of different ART regimens among pregnant women living with HIV at preconception or during pregnancy.
METHODS
METHODS
We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science. We included randomized trials that enrolled pregnant women living with HIV and randomized them to receive ART for at least four weeks. Pairs of reviewers independently completed screening for eligible studies, extracted data, and assessed the risk of bias using the Cochrane risk of bias tool. Our outcomes of interest included low birth weight, stillbirth, preterm birth, mother-to-child transmission of HIV, neonatal death, and congenital anomalies. Network meta-analysis was performed using a random-effects frequentist model, and the certainty of evidence was evaluated using the GRADE approach.
RESULTS
RESULTS
We found 14 eligible randomized trials enrolling 9,561 pregnant women. The median duration of ART uptake ranged from 6.0 to 17.4 weeks. No treatment was statistically better than a placebo in reducing the rate of neonatal mortality, stillbirth, congenital defects, preterm birth, or low birth weight deliveries. Compared to placebo, zidovudine (ZDV)/lamivudine (3TC) and ZDV monotherapy likely reduce mother-to-child transmission (odds ratio (OR): 0.13; 95% CI: 0.05 to 0.31, high-certainty; and OR: 0.50; 95% CI: 0.33 to 0.74, moderate-certainty). Moderate-certainty evidence suggested that ZDV/3TC was associated with decreased odds of stillbirth (OR: 0.47; 95% CI: 0.09 to 2.60).
CONCLUSIONS
CONCLUSIONS
Our analysis provides high- to moderate-certainty evidence that ZDV/3TC and ZDV are more effective in reducing the odds of mother-to-child transmission, with ZDV/3TC also demonstrating decreased odds of stillbirth. Notably, our findings suggest an elevated odds of stillbirth and preterm birth associated with all other ART regimens.
Identifiants
pubmed: 38641597
doi: 10.1186/s12879-024-09303-2
pii: 10.1186/s12879-024-09303-2
doi:
Types de publication
Systematic Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
417Informations de copyright
© 2024. The Author(s).
Références
Santosa WB, Staines-Urias E, Tshivuila-Matala COO, Norris SA, Hemelaar J. Perinatal outcomes associated with maternal HIV and antiretroviral therapy in pregnancies with accurate gestational age in South Africa. AIDS. 2019;33(10):1623–33.
pubmed: 30932959
doi: 10.1097/QAD.0000000000002222
Alemu FM, Yalew AW, Fantahun M, Ashu EE. Antiretroviral therapy and pregnancy outcomes in developing countries: a systematic review. Int J MCH AIDS. 2015;3(1):31–43.
pubmed: 27621984
pmcid: 4948169
Wedi COO, Kirtley S, Hopewell S, Corrigan R, Kennedy SH, Hemelaar J. Perinatal outcomes associated with maternal HIV infection: a systematic review and meta-analysis. Lancet HIV. 2016;3(1):e33-48.
pubmed: 26762992
doi: 10.1016/S2352-3018(15)00207-6
Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants: Recommendations for a Public Health Approach: 2010 Version. Geneva: World Health Organization; 2010. Available from: https://www.ncbi.nlm.nih.gov/books/NBK304944/ . Cited 2022.
Malaba TR, Phillips T, Le Roux S, Brittain K, Zerbe A, Petro G, et al. Antiretroviral therapy use during pregnancy and adverse birth outcomes in South African women. Int J Epidemiol. 2017;46(5):1678–89.
pubmed: 29040569
pmcid: 5837407
doi: 10.1093/ije/dyx136
Guideline on When to Start Antiretroviral Therapy and on Pre-Exposure Prophylaxis for HIV. Geneva: World Health Organization. 2015. https://www.ncbi.nlm.nih.gov/books/NBK327115/ . Cited 2022.
Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. 2nd edition. Geneva: World Health Organization; 2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK374294/ . Cited 2022.
Eke AC, Lockman S, Mofenson LM. Antiretroviral treatment of HIV/AIDS during pregnancy. JAMA. 2023;329(15):1308–9.
pubmed: 37010862
pmcid: 10390091
doi: 10.1001/jama.2023.5076
Policy brief: update of recommendations on first-and second-line antiretroviral regimens. Geneva: World Health Organization. 2019. https://iris.who.int/handle/10665/273632 . Cited 2022.
Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States. [Updated 2023 Jan 31]. https://www.ncbi.nlm.nih.gov/books/NBK586310/ . Cited 2023.
Tukei VJ, Hoffman HJ, Greenberg L, Thabelo R, Nchephe M, Mots’oane T, et al. Adverse pregnancy outcomes among HIV-positive women in the era of universal antiretroviral therapy remain elevated compared with HIV-negative women. Pediatr Infect Dis J. 2021;40(9):821–6.
pubmed: 33990522
pmcid: 8357042
doi: 10.1097/INF.0000000000003174
Uthman OA, Nachega JB, Anderson J, Kanters S, Mills EJ, Renaud F, et al. Timing of initiation of antiretroviral therapy and adverse pregnancy outcomes: a systematic review and meta-analysis. Lancet HIV. 2017;4(1):e21-30.
pubmed: 27864000
doi: 10.1016/S2352-3018(16)30195-3
Saleska JL, Turner AN, Maierhofer C, Clark J, Kwiek JJ. Use of antiretroviral therapy during pregnancy and adverse birth outcomes among women living with HIV-1 in low- and middle-income countries: A systematic review. JAIDS. 2018;79(1):1–9.
pubmed: 29847475
Tshivuila-Matala CO, Honeyman S, Nesbitt C, Kirtley S, Kennedy SH, Hemelaar J. Adverse perinatal outcomes associated with antiretroviral therapy regimens: systematic review and network meta-analysis. AIDS. 2020;34(11):1643–56.
pubmed: 32701581
doi: 10.1097/QAD.0000000000002593
Hutton BSG, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP, Mulrow C, Catalá-López F, Gøtzsche PC, Dickersin K, Boutron I, Altman DG, Moher D. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations. Ann Intern Med Clin Cases. 2015;162(11):777–84.
Guyatt GH, Oxman AD, Kunz R, Atkins D, Brozek J, Vist G, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol. 2011;64(4):395–400.
pubmed: 21194891
doi: 10.1016/j.jclinepi.2010.09.012
Møller MH. Patient-important outcomes and core outcome sets: increased attention needed! Br J Anaesth. 2019;122(4):408–10.
pubmed: 30857595
pmcid: 6435936
doi: 10.1016/j.bja.2019.02.007
Cowdell I, Beck K, Portwood C, Sexton H, Kumarendran M, Brandon Z, et al. Adverse perinatal outcomes associated with protease inhibitor-based antiretroviral therapy in pregnant women living with HIV: a systematic review and meta-analysis. EClinicalMedicine. 2022;46:101368.
pubmed: 35521067
pmcid: 9061981
doi: 10.1016/j.eclinm.2022.101368
DeSilva M, Munoz FM, Mcmillan M, Kawai AT, Marshall H, Macartney KK, et al. Congenital anomalies: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2016;34(49):6015.
pubmed: 27435386
pmcid: 5139892
doi: 10.1016/j.vaccine.2016.03.047
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
pubmed: 22008217
pmcid: 3196245
doi: 10.1136/bmj.d5928
Boutron I, Estellat C, Guittet L, Dechartres A, Sackett DL, Hróbjartsson A, et al. Methods of blinding in reports of randomized controlled trials assessing pharmacologic treatments: a systematic review. PLOS Med. 2006;3(10):e425.
pubmed: 17076559
pmcid: 1626553
doi: 10.1371/journal.pmed.0030425
Schulz KF, Grimes DA. Blinding in randomised trials: hiding who got what. Lancet. 2002;359(9307):696–700.
pubmed: 11879884
doi: 10.1016/S0140-6736(02)07816-9
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.
pubmed: 3802833
doi: 10.1016/0197-2456(86)90046-2
Dalton JE, Bolen SD, Mascha EJ. Publication bias: the elephant in the review. Anesth Analg. 2016;123(4):812–3.
pubmed: 27636569
pmcid: 5482177
doi: 10.1213/ANE.0000000000001596
White IR. Network meta-analysis. Stata J. 2015;15(4):951–85.
doi: 10.1177/1536867X1501500403
White IR, Barrett JK, Jackson D, Higgins JP. Consistency and inconsistency in network meta-analysis: Model estimation using multivariate meta-regression. Res Synth Methods. 2012;3(2):111–25.
pubmed: 26062085
pmcid: 4433771
doi: 10.1002/jrsm.1045
Chaimani A, Salanti G. Visualizing assumptions and results in network meta-analysis: the network graphs package. Stata J. 2015;15(4):905–50.
doi: 10.1177/1536867X1501500402
Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta-analysis in STATA. PLoS One. 2013;8(10):e76654.
pubmed: 24098547
pmcid: 3789683
doi: 10.1371/journal.pone.0076654
Puhan MA, Schünemann HJ, Murad MH, Li T, Brignardello-Petersen R, Singh JA, et al. A GRADE working group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ. 2014;349:g5630.
pubmed: 25252733
doi: 10.1136/bmj.g5630
Brignardello-Petersen R, Bonner A, Alexander PE, Siemieniuk RA, Furukawa TA, Rochwerg B, et al. Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis. J Clin Epidemiol. 2018;93:36–44.
pubmed: 29051107
doi: 10.1016/j.jclinepi.2017.10.005
Fowler MG, Qin M, Fiscus SA, Currier JS, Flynn PM, Chipato T, et al. Benefits and risks of antiretroviral therapy for perinatal HIV prevention. NEJM. 2016;375(18):1726–37.
pubmed: 27806243
doi: 10.1056/NEJMoa1511691
Group KBS. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect Dis. 2011;11(3):171–80.
doi: 10.1016/S1473-3099(10)70288-7
Koss CA, Natureeba P, Plenty A, Luwedde F, Mwesigwa J, Ades V, et al. Risk factors for preterm birth among HIV-infected pregnant Ugandan women randomized to lopinavir/ritonavir-or efavirenz-based antiretroviral therapy. JAIDS. 2014;67(2):128–35.
pubmed: 25072616
Waitt C, Orrell C, Walimbwa S, Singh Y, Kintu K, Simmons B, et al. Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: a randomised trial (DolPHIN-1 study). PLoS Med. 2019;16(9):e1002895.
pubmed: 31539371
pmcid: 6754125
doi: 10.1371/journal.pmed.1002895
Kintu K, Malaba TR, Nakibuka J, Papamichael C, Colbers A, Byrne K, et al. Dolutegravir versus Efavirenz in women starting HIV therapy in late pregnancy (DolPHIN-2): an open-label, randomised controlled trial. Lancet HIV. 2020;7(5):e332-339.
pubmed: 32386721
pmcid: 10877544
doi: 10.1016/S2352-3018(20)30050-3
Team PS. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet. 2002;359(9313):1178–86.
doi: 10.1016/S0140-6736(02)08214-4
Shapiro RL, Hughes M, Ogwu A, Kitch D, Lockman S, Moffat C, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. NEJM. 2010;362(24):2282–94.
pubmed: 20554983
doi: 10.1056/NEJMoa0907736
Natureeba P, Ades V, Luwedde F, Mwesigwa J, Plenty A, Okong P, et al. Lopinavir/ritonavir-based antiretroviral treatment (ART) versus efavirenz-based ART for the prevention of malaria among HIV-infected pregnant women. J Infect Dis. 2014;210(12):1938–45.
pubmed: 24958908
pmcid: 4296178
doi: 10.1093/infdis/jiu346
Tubiana R, Mandelbrot L, Le Chenadec J, Delmas S, Rouzioux C, Hirt D, et al. Lopinavir/Ritonavir monotherapy as a nucleoside analogue–sparing strategy to prevent HIV-1 mother-to-child transmission: the ANRS 135 PRIMEVA Phase 2/3 randomized trial. Clin Infect Dis. 2013;57(6):891–902.
pubmed: 23766338
doi: 10.1093/cid/cit390
Lallemant M, Le Coeur S, Sirirungsi W, Cressey TR, Nicole N, Traisathit P, et al. Randomized non-inferiority trial of two maternal single-dose nevirapine sparing regimens to prevent perinatal HIV in Thailand (PHPT-5). AIDS. 2015;29(18):2497.
pubmed: 26372485
doi: 10.1097/QAD.0000000000000865
Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. NEJM. 1994;331(18):1173–80.
pubmed: 7935654
doi: 10.1056/NEJM199411033311801
João EC, Morrison RL, Shapiro DE, Chakhtoura N, Gouvèa MIS, Maria de Lourdes BT, et al. Raltegravir versus Efavirenz in antiretroviral-naive pregnant women living with HIV (NICHD P1081): an open-label, randomised, controlled, phase 4 trial. Lancet HIV. 2020;7(5):e322-331.
pubmed: 32386720
pmcid: 7323582
doi: 10.1016/S2352-3018(20)30038-2
Lockman S, Brummel SS, Ziemba L, Stranix-Chibanda L, McCarthy K, Coletti A, et al. Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. 2021;397(10281):1276–92.
pubmed: 33812487
pmcid: 8132194
doi: 10.1016/S0140-6736(21)00314-7
Favarato G, Townsend CL, Peters H, Sconza R, Bailey H, Cortina-Borja M, et al. Stillbirth in women living with HIV delivering in the United Kingdom and Ireland: 2007–2015. JAIDS. 2019;82(1):9–16.
pubmed: 31149953
Mofenson LM. Antiretroviral therapy and adverse pregnancy outcome: the Elephant in the room? J Infect Dis. 2016;213(7):1051–4.
pubmed: 26265779
doi: 10.1093/infdis/jiv390
Stringer EM, Kendall MA, Lockman S, Campbell TB, Nielsen-Saines K, Sawe F, et al. Pregnancy outcomes among HIV-infected women who conceived on antiretroviral therapy. PLoS One. 2018;13(7):e0199555.
pubmed: 30020964
pmcid: 6051581
doi: 10.1371/journal.pone.0199555
Kourtis AP, Schmid CH, Jamieson DJ, Lau J. Use of antiretroviral therapy in pregnant HIV-infected women and the risk of premature delivery: a meta-analysis. AIDS. 2007;21(5):607–15.
pubmed: 17314523
doi: 10.1097/QAD.0b013e32802ef2f6
Delicio AM, Lajos GJ, Amaral E, Cavichiolli F, Polydoro M, Milanez H. Adverse effects in children exposed to maternal HIV and antiretroviral therapy during pregnancy in Brazil: a cohort study. Reprod Health. 2018;15(1):76.
pubmed: 29747664
pmcid: 5946413
doi: 10.1186/s12978-018-0513-8
Romero R, Espinoza J, Kusanovic JP, Gotsch F, Hassan S, Erez O, et al. The preterm parturition syndrome. BJOG. 2006;113:17–42.
pubmed: 17206962
pmcid: 7062298
doi: 10.1111/j.1471-0528.2006.01120.x
Barros FC, Papageorghiou AT, Victora CG, Noble JA, Pang R, Iams J, et al. The distribution of clinical phenotypes of preterm birth syndrome: implications for Prevention. JAMA Pediatr. 2015;169(3):220–9.
pubmed: 25561016
doi: 10.1001/jamapediatrics.2014.3040
Kramer MS, Papageorghiou A, Culhane J, Bhutta Z, Goldenberg RL, Gravett M, et al. Challenges in defining and classifying the preterm birth syndrome. Am J Obstet Gynecol. 2012;206(2):108–12.
pubmed: 22118964
doi: 10.1016/j.ajog.2011.10.864
Patel K, Shapiro DE, Brogly SB, Livingston EG, Stek AM, Bardeguez AD, et al. Prenatal protease inhibitor use and risk of preterm birth among HIV-infected women initiating antiretroviral drugs during pregnancy. J Infect Dis. 2010;201(7):1035–44.
pubmed: 20196654
doi: 10.1086/651232
Duryea E, Nicholson F, Cooper S, Roberts S, Rogers V, McIntire D, et al. The use of protease inhibitors in pregnancy: maternal and fetal considerations. Infect Dis Obstet Gynecol. 2015;2015:563727.
pubmed: 26617456
pmcid: 4651704
doi: 10.1155/2015/563727
Cotter AM, Garcia AG, Duthely ML, Luke B, O’Sullivan MJ. Is antiretroviral therapy during pregnancy associated with an increased risk of preterm delivery, low birth weight, or stillbirth? J Infect Dis. 2006;193(9):1195–201.
pubmed: 16586354
doi: 10.1086/503045
Kumar R, Uduman S, Khurranna A. Impact of maternal HIV-1 infection on perinatal outcome. Int J Gynaecol Obstet. 1995;49(2):137–43.
pubmed: 7649317
doi: 10.1016/0020-7292(95)02356-H
Graves C, Porter R, Ma K, Byrum B, Barkanic G, Raffanti S, et al. Preterm labor in pregnancies complicated by HIV. Am J Obstet Gynecol. 2006;195(6):S55.
Tuomala RE, Yawetz S. Protease inhibitor use during pregnancy: is there an obstetrical risk? J Infect Dis. 2006;193(9):1191–4.
pubmed: 16586353
doi: 10.1086/503049
Castetbon K, Ladner J, Leroy V, Chauliac M, Karita E, De Clercq A, et al. Low birthweight in infants born to African HIV-infected women: relationship with maternal body weight during pregnancy. J Trop Pediatr. 1999;45(3):152–7.
pubmed: 10401193
doi: 10.1093/tropej/45.3.152
Menza TW, Hixson LK, Lipira L, Drach L, editors. Social determinants of health and care outcomes among people with HIV in the United States. Open Forum Infectious Diseases; 2021: Oxford University Press US.
Lorch SA, Enlow E. The role of social determinants in explaining racial/ethnic disparities in perinatal outcomes. Pediatr Res. 2016;79(1):141–7.
pubmed: 26466077
doi: 10.1038/pr.2015.199