Tenofovir Diphosphate Concentrations in Dried Blood Spots From Pregnant and Postpartum Adolescent and Young Women Receiving Daily Observed Pre-exposure Prophylaxis in Sub-Saharan Africa

Lynda Stranix-Chibanda, Peter L Anderson, Deborah Kacanek, Sybil Hosek, Sharon Huang, Teacler G Nematadzira, Frank Taulo, Violet Korutaro, Clemensia Nakabiito, Maysebole Masenya, Kathryn Lypen, Emily Brown, Mustafa E Ibrahim, Jenna Yager, Lubbe Wiesner, Benjamin Johnston, K Rivet Amico, James F Rooney, Nahida Chakhtoura, Hans M L Spiegel, Benjamin H Chi, IMPAACT 2009 Team, Vongai Chanaiwa, Suzen Maonera, Lucia Mungate, Sharon Kunkanga Mambiya, Abigail Mnemba, Flora Chithila, Phionah Nakabuye, Muzamil Nsibuka Kisekka, Victoria Ndyanabangi, Brenda Gati Mirembe, Phionah Kibalama Ssemambo, Annette Miwanda Ssekasi, Elizea Horne, Siphokazi Sibisi, Janet Grab, Lynda Stranix-Chibanda, Peter L Anderson, Deborah Kacanek, Sybil Hosek, Sharon Huang, Teacler G Nematadzira, Frank Taulo, Violet Korutaro, Clemensia Nakabiito, Maysebole Masenya, Kathryn Lypen, Emily Brown, Mustafa E Ibrahim, Jenna Yager, Lubbe Wiesner, Benjamin Johnston, K Rivet Amico, James F Rooney, Nahida Chakhtoura, Hans M L Spiegel, Benjamin H Chi, IMPAACT 2009 Team, Vongai Chanaiwa, Suzen Maonera, Lucia Mungate, Sharon Kunkanga Mambiya, Abigail Mnemba, Flora Chithila, Phionah Nakabuye, Muzamil Nsibuka Kisekka, Victoria Ndyanabangi, Brenda Gati Mirembe, Phionah Kibalama Ssemambo, Annette Miwanda Ssekasi, Elizea Horne, Siphokazi Sibisi, Janet Grab

Abstract

Background: Intracellular tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is used to monitor cumulative pre-exposure prophylaxis (PrEP) adherence. We evaluated TFV-DP in DBSs following daily oral PrEP (emtricitabine 200 mg/tenofovir diphosphate 300 mg) among pregnant and postpartum adolescent girls and young women (AGYW).

Methods: Directly observed PrEP was administered for 12 weeks in a pregnancy (14-24 weeks' gestation, n = 20) and postpartum (6-12 weeks postpartum, n = 20) group of AGYW aged 16-24 years in sub-Saharan Africa. Weekly DBS TFV-DP was measured by validated liquid chromatography-tandem mass spectrometry assay. Week 12 TFV-DP distributions were compared between groups with Wilcoxon test. Population pharmacokinetic models were fit to estimate steady-state concentrations and create benchmarks for adherence categories. Baseline correlates of TFV-DP were evaluated.

Results: Median age was 20 (IQR, 19-22) years. Of 3360 doses, 3352 (>99%) were directly observed. TFV-DP median (IQR) half-life was 10 (7-12) days in pregnancy and 17 (14-21) days postpartum, with steady state achieved by 5 and 8 weeks, respectively. Observed median (IQR) steady-state TFV-DP was 965 fmol/punch (691-1166) in pregnancy versus 1406 fmol/punch (1053-1859) postpartum (P = .006). Modeled median steady-state TFV-DP was 881 fmol/punch (667-1105) in pregnancy versus 1438 fmol/punch (1178-1919) postpartum. In pooled analysis, baseline creatinine clearance was associated with observed TFV-DP concentrations.

Conclusions: TFV-DP in African AGYW was approximately one-third lower in pregnancy than postpartum. These Population-specific benchmarks can be used to guide PrEP adherence support in pregnant/postpartum African women.

Clinical trials registration: NCT03386578.

Keywords: PrEP in pregnancy; adolescence; intracellular TFV-DP.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Observed and fitted TFV-DP concentrations in pregnant and postpartum women by study week (A and B, observed; C and D, modeled). Dashed line = USA median; gray shading represents the 95% confidence interval for Loess curve. Abbreviation: TFV-DP, tenofovir diphosphate.
Figure 2.
Figure 2.
Proposed adherence thresholds for study groups. Abbreviations: DBS, dried blood spot; ROC, receiver operating characteristic curve; TFV-DP, tenofovir diphosphate.

References

    1. Drake AL, Wagner A, Richardson B, John-Stewart G. Incident HIV during pregnancy and postpartum and risk of mother-to-child HIV transmission: a systematic review and meta-analysis. PLoS Med 2014; 11:e1001608.
    1. Graybill LA, Kasaro M, Freeborn K, et al. . Incident HIV among pregnant and breast-feeding women in sub-Saharan Africa: a systematic review and meta-analysis. AIDS 2020; 34:761–76.
    1. Tippett Barr BA, van Lettow M, van Oosterhout JJ, et al. . National estimates and risk factors associated with early mother-to-child transmission of HIV after implementation of option B+: a cross-sectional analysis. Lancet HIV 2018; 5:e688–95.
    1. UNICEF; UNAIDS; World Health Organization. Key considerations for programming and prioritization. Going the “Last Mile” to EMTCT: a road map for ending the HIV epidemic in children. New York: UNICEF; 2020. Available at: . Accessed 16 February 2020.
    1. Fonner VA, Dalglish SL, Kennedy CE, et al. . Effectiveness and safety of oral HIV preexposure prophylaxis for all populations. AIDS 2016; 30:1973–83.
    1. Joseph Davey DL, Pintye J, Baeten JM, et al. ; PrEP in Pregnancy Working Group . Emerging evidence from a systematic review of safety of pre-exposure prophylaxis for pregnant and postpartum women: where are we now and where are we heading? J Int AIDS Soc 2020; 23:e25426.
    1. Davies N, Heffron R. Global and national guidance for the use of pre-exposure prophylaxis during peri-conception, pregnancy and breastfeeding. Sex Health 2018; 15:501–12.
    1. Blumenthal J, Pasipanodya EC, Jain S, et al. . Comparing self-report pre-exposure prophylaxis adherence questions to pharmacologic measures of recent and cumulative pre-exposure prophylaxis exposure. Front Pharmacol 2019; 10:721.
    1. Pyra M, Anderson PL, Hendrix CW, et al. ; Partners Demonstration Study Team . Tenofovir and tenofovir-diphosphate concentrations during pregnancy among HIV-uninfected women using oral preexposure prophylaxis. AIDS 2018; 32:1891–8.
    1. Montgomery MC, Oldenburg CE, Nunn AS, et al. . Adherence to pre-exposure prophylaxis for HIV prevention in a clinical setting. PLoS One 2016; 11:e0157742.
    1. Grant RM, Anderson PL, McMahan V, et al. ; iPrEx Study Team . Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis 2014; 14:820–9.
    1. Pyra M, Anderson P, Haberer JE, et al. . Tenofovir-diphosphate as a marker of HIV pre-exposure prophylaxis use among East African men and women. Front Pharmacol 2019; 10:401.
    1. Liu AY, Cohen SE, Vittinghoff E, et al. . Preexposure prophylaxis for HIV infection integrated with municipal- and community-based sexual health services. JAMA Intern Med 2016; 176:75–84.
    1. Blumenthal J.Results from a PrEP demonstration project for at-risk cisgender women in the US. PrEP in cisgender women; Conference on Retroviruses and Opportunistic Infections, Boston, MA; 2020. Available at: . Accessed 1 April 2020.
    1. Celum CL.PrEP adherence and effect of drug level feedback among young African Women in HPTN 082. Mexico City, Mexico. 2019. Available at: . Accessed 1 April 2020.
    1. Anderson PL, Liu AY, Castillo-Mancilla JR, et al. . Intracellular tenofovir-diphosphate and emtricitabine-triphosphate in dried blood spots following directly observed therapy. Antimicrob Agents Chemother 2018; 62:e01710–17.
    1. Castillo-Mancilla JR, Zheng JH, Rower JE, et al. . Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure. AIDS Res Hum Retroviruses 2013; 29:384–90.
    1. Zheng JH, Rower C, McAllister K, et al. . Application of an intracellular assay for determination of tenofovir-diphosphate and emtricitabine-triphosphate from erythrocytes using dried blood spots. J Pharm Biomed Anal 2016; 122:16–20.
    1. Anderson PL, Glidden DV, Liu A, et al. ; iPrEx Study Team . Emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. Sci Transl Med 2012; 4:151ra125.
    1. Pariente G, Leibson T, Carls A, Adams-Webber T, Ito S, Koren G. Pregnancy-associated changes in pharmacokinetics: a systematic review. PLoS Med 2016; 13:e1002160.
    1. Best BM, Burchett S, Li H, et al. ; International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s Team . Pharmacokinetics of tenofovir during pregnancy and postpartum. HIV Med 2015; 16:502–11.
    1. Cressey TR, Harrison L, Achalapong J, et al. . Tenofovir exposure during pregnancy and postpartum in women receiving tenofovir disoproxil fumarate for the prevention of mother-to-child transmission of hepatitis B virus. Antimicrob Agents Chemother 2018; 62:e01686-18.
    1. Bierhoff M, Smolders EJ, Tarning J, et al. . Pharmacokinetics of oral tenofovir disoproxil fumarate in pregnancy and lactation: a systematic review. Antivir Ther 2019; 24:529–40.
    1. Committee on Obstetric Practice American Institute of Ultrasound in Medicine Society for Maternal–Fetal Medicine. Committee opinion no 700: methods for estimating the due date. Obstet Gynecol 2017; 129:e150–4. doi: 10.1097/AOG.0000000000002046.
    1. Amico KR, Miller J, Balthazar C, et al. . Integrated next step counseling (iNSC) for sexual health and PrEP use among young men who have sex with men: implementation and observations from ATN110/113. AIDS Behav 2019; 23:1812–23.
    1. Division of AIDS (DAIDS). Table for grading the severity of adult and pediatric adverse events, corrected version 2.1.2017. Available at: . Accessed 16 February 2020.
    1. Pintye J, Kinuthia J, Roberts DA, et al. . Brief report: integration of PrEP services into routine antenatal and postnatal care: experiences from an implementation program in Western Kenya. J Acquir Immune Defic Syndr 2018; 79:590–5.
    1. World Health Organization. WHO technical brief: preventing HIV during pregnancy and breastfeeding in the context of pre-exposure prophylaxis (PrEP).2017. Available at: . Accessed 16 February 2020.
    1. Pintye J, Kinuthia J, Abuna F, et al. . Frequency and predictors of tenofovir-diphosphate detection among young Kenyan women in a real-world pre-exposure prophylaxis implementation program. Clin Infect Dis 2020; 71:e509–12. doi: 10.1093/cid/ciaa181.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere