Tenofovir diphosphate and emtricitabine triphosphate concentrations in blood cells compared with isolated peripheral blood mononuclear cells: a new measure of antiretroviral adherence?
Jessica L Adams, Craig Sykes, Prema Menezes, Heather M A Prince, Kristine B Patterson, Katrien Fransen, Tania Crucitti, Irith De Baetselier, Lut Van Damme, Angela D M Kashuba, Jessica L Adams, Craig Sykes, Prema Menezes, Heather M A Prince, Kristine B Patterson, Katrien Fransen, Tania Crucitti, Irith De Baetselier, Lut Van Damme, Angela D M Kashuba
Abstract
Background: The active metabolites of tenofovir (TFV) and emtricitabine (FTC) in peripheral blood mononuclear cells (PBMCs) have been used as markers of long-term antiretroviral (ARV) adherence. However, the process of isolating PBMCs is expensive, complex, and not feasible in many settings. We compared concentrations of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in the upper layer packed cells (ULPCs) obtained after whole blood centrifugation to isolated PBMCs as a possible alternative marker of adherence.
Methods: Ten HIV+ adults with HIV RNA <50 copies/mL on a TDF/FTC-containing regimen provided 5 paired PBMC and ULPC samples over 6 hours. TFV-DP and FTC-TP concentrations were analyzed by liquid chromatography/mass spectrometry. Partial areas under the curve were calculated using noncompartmental methods and Spearman Rank Correlations (rho) between PBMC and ULPC were determined.
Results: The median (25th-75th percentile) concentration of TFV-DP in PBMCs was 143 (103-248) fmol/10(6) cells and in ULPC was 227 (160-394) fmol/10(6) cells (rho = 0.65; P < 0.0001). The concentration of FTC-TP in PBMCs was 6660 (5650-10,000) fmol/10(6) cells and in ULPC was 19.0 (12.0-27.8) fmol/10(6) cells (rho = 0.55; P < 0.0001). Compared to PBMCs, ULPC TFV-DP was 64% higher and FTC-TP was 99.7% lower. ULPC concentrations of TFV-DP and FTC-TP in one additional subject receiving a single dose of TDF/FTC were only 0.05% and 25%, of the other 10 subjects, respectively.
Conclusions: ULPC concentrations significantly correlated with PBMC concentrations. Preliminary single-dose data suggest some discrimination between intermittent versus consistent dosing. ULPC concentrations of TFV-DP and FTC-TP should be further investigated as a simply collected surrogate measure of ARV adherence.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4042836/bin/nihms-589712-f0001.jpg)
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Individual concentration/time points plotted for…
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Individual concentration/time points plotted for TFV-DP (figure 1a) and FTC-TP (figure 1b) concentrations…
Figure 1
Individual concentration/time points plotted for…
Figure 1
Individual concentration/time points plotted for TFV-DP (figure 1a) and FTC-TP (figure 1b) concentrations…
Figure 2
Individual subject concentration/time profiles for…
Figure 2
Individual subject concentration/time profiles for TFV-DP (figure 2a) and FTC-TP (figure 2b) in…
Figure 2
Individual subject concentration/time profiles for…
Figure 2
Individual subject concentration/time profiles for TFV-DP (figure 2a) and FTC-TP (figure 2b) in…
Figure 3
The median (range) concentration/time profiles…
Figure 3
The median (range) concentration/time profiles of TFV-DP and FTC-TP in ULPC with comparison…
Figure 4
ULPC Concentrations of TFV-DP or…
Figure 4
ULPC Concentrations of TFV-DP or FTC-TP in ULPC at a single time point…
- Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure.Castillo-Mancilla JR, Zheng JH, Rower JE, Meditz A, Gardner EM, Predhomme J, Fernandez C, Langness J, Kiser JJ, Bushman LR, Anderson PL. Castillo-Mancilla JR, et al. AIDS Res Hum Retroviruses. 2013 Feb;29(2):384-90. doi: 10.1089/AID.2012.0089. Epub 2012 Oct 10. AIDS Res Hum Retroviruses. 2013. PMID: 22935078 Free PMC article.
- Tenofovir, emtricitabine intracellular and plasma, and efavirenz plasma concentration decay following drug intake cessation: implications for HIV treatment and prevention.Jackson A, Moyle G, Watson V, Tjia J, Ammara A, Back D, Mohabeer M, Gazzard B, Boffito M. Jackson A, et al. J Acquir Immune Defic Syndr. 2013 Mar 1;62(3):275-81. doi: 10.1097/QAI.0b013e3182829bd0. J Acquir Immune Defic Syndr. 2013. PMID: 23274933
- Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates.Chen X, Seifert SM, Castillo-Mancilla JR, Bushman LR, Zheng JH, Kiser JJ, MaWhinney S, Anderson PL. Chen X, et al. PLoS One. 2016 Nov 10;11(11):e0165505. doi: 10.1371/journal.pone.0165505. eCollection 2016. PLoS One. 2016. PMID: 27832147 Free PMC article.
- Emtricitabine/tenofovir in the treatment of HIV infection: current PK/PD evaluation.Uglietti A, Zanaboni D, Gnarini M, Maserati R. Uglietti A, et al. Expert Opin Drug Metab Toxicol. 2012 Oct;8(10):1305-14. doi: 10.1517/17425255.2012.714367. Epub 2012 Sep 4. Expert Opin Drug Metab Toxicol. 2012. PMID: 22943210 Review.
- Emtricitabine/tenofovir disoproxil fumarate: a review of its use in HIV-1 pre-exposure prophylaxis.Plosker GL. Plosker GL. Drugs. 2013 Mar;73(3):279-91. doi: 10.1007/s40265-013-0024-4. Drugs. 2013. PMID: 23444256 Review.
- REverSe TRanscrIptase chain termination (RESTRICT) for selective measurement of nucleotide analogs used in HIV care and prevention.Olanrewaju AO, Sullivan BP, Gim AH, Craig CA, Sevenler D, Bender AT, Drain PK, Posner JD. Olanrewaju AO, et al. Bioeng Transl Med. 2022 Jul 14;8(1):e10369. doi: 10.1002/btm2.10369. eCollection 2023 Jan. Bioeng Transl Med. 2022. PMID: 36684094 Free PMC article.
- Tenofovir, Lamivudine, and Dolutegravir Among Rural Adolescents in Zimbabwe: A Cautionary Tale.Kouamou V, Machekano R, Mapangisana T, Maposhere C, Munyati S, Mutsvangwa J, Shamu T, McCarty K, Katzenstein D, Manasa J. Kouamou V, et al. AIDS Res Hum Retroviruses. 2022 Oct;38(10):774-778. doi: 10.1089/AID.2021.0140. Epub 2022 Sep 7. AIDS Res Hum Retroviruses. 2022. PMID: 35959737 Clinical Trial.
- Feasibility, Acceptability, and Preliminary Efficacy of a Gamified Mobile Health Contingency Management Intervention for PrEP Adherence Among Black MSM.Mitchell JT, Burns CM, Atkinson B, Cottrell M, Frye JK, McKellar MS, Kashuba ADM, McClernon FJ, Okeke NL. Mitchell JT, et al. AIDS Behav. 2022 Oct;26(10):3311-3324. doi: 10.1007/s10461-022-03675-9. Epub 2022 Apr 13. AIDS Behav. 2022. PMID: 35416595
- Two-dose emtricitabine/tenofovir alafenamide plus bictegravir prophylaxis protects macaques against SHIV infection.Bekerman E, Cox S, Babusis D, Campigotto F, Das M, Barouch DH, Cihlar T, Callebaut C. Bekerman E, et al. J Antimicrob Chemother. 2021 Feb 11;76(3):692-698. doi: 10.1093/jac/dkaa476. J Antimicrob Chemother. 2021. PMID: 33202006 Free PMC article.
- Antiretroviral Penetration and Drug Transporter Concentrations in the Spleens of Three Preclinical Animal Models and Humans.Devanathan AS, Fallon JK, White NR, Schauer AP, Van Horne B, Blake K, Sykes C, Kovarova M, Adamson L, Remling-Mulder L, Luciw P, Garcia JV, Akkina R, Pirone JR, Smith PC, Kashuba ADM. Devanathan AS, et al. Antimicrob Agents Chemother. 2020 Sep 21;64(10):e01384-20. doi: 10.1128/AAC.01384-20. Print 2020 Sep 21. Antimicrob Agents Chemother. 2020. PMID: 32661005 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Adenine / analogs & derivatives*
- Adenine / blood
- Adenine / pharmacokinetics
- Adult
- Anti-HIV Agents / blood*
- Anti-HIV Agents / pharmacokinetics
- Blood Cells / metabolism*
- Deoxycytidine / analogs & derivatives*
- Deoxycytidine / blood
- Deoxycytidine / pharmacokinetics
- Diphosphates / blood
- Diphosphates / pharmacokinetics
- Emtricitabine
- Female
- HIV Infections / drug therapy*
- Humans
- Leukocytes, Mononuclear / metabolism
- Male
- Medication Adherence*
- Middle Aged
- Organophosphonates / blood*
- Organophosphonates / pharmacokinetics
- Polyphosphates / blood
- Polyphosphates / pharmacokinetics
- Tenofovir
- Anti-HIV Agents
- Diphosphates
- Organophosphonates
- Polyphosphates
- Deoxycytidine
- Tenofovir
- Emtricitabine
- Adenine
- triphosphoric acid
- Full Text Sources
- Other Literature Sources
- Medical
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![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4042836/bin/nihms-589712-f0002.jpg)
Figure 1
Individual concentration/time points plotted for…
Figure 1
Individual concentration/time points plotted for TFV-DP (figure 1a) and FTC-TP (figure 1b) concentrations…
Figure 2
Individual subject concentration/time profiles for…
Figure 2
Individual subject concentration/time profiles for TFV-DP (figure 2a) and FTC-TP (figure 2b) in…
Figure 2
Individual subject concentration/time profiles for…
Figure 2
Individual subject concentration/time profiles for TFV-DP (figure 2a) and FTC-TP (figure 2b) in…
Figure 3
The median (range) concentration/time profiles…
Figure 3
The median (range) concentration/time profiles of TFV-DP and FTC-TP in ULPC with comparison…
Figure 4
ULPC Concentrations of TFV-DP or…
Figure 4
ULPC Concentrations of TFV-DP or FTC-TP in ULPC at a single time point…
- Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure.Castillo-Mancilla JR, Zheng JH, Rower JE, Meditz A, Gardner EM, Predhomme J, Fernandez C, Langness J, Kiser JJ, Bushman LR, Anderson PL. Castillo-Mancilla JR, et al. AIDS Res Hum Retroviruses. 2013 Feb;29(2):384-90. doi: 10.1089/AID.2012.0089. Epub 2012 Oct 10. AIDS Res Hum Retroviruses. 2013. PMID: 22935078 Free PMC article.
- Tenofovir, emtricitabine intracellular and plasma, and efavirenz plasma concentration decay following drug intake cessation: implications for HIV treatment and prevention.Jackson A, Moyle G, Watson V, Tjia J, Ammara A, Back D, Mohabeer M, Gazzard B, Boffito M. Jackson A, et al. J Acquir Immune Defic Syndr. 2013 Mar 1;62(3):275-81. doi: 10.1097/QAI.0b013e3182829bd0. J Acquir Immune Defic Syndr. 2013. PMID: 23274933
- Model Linking Plasma and Intracellular Tenofovir/Emtricitabine with Deoxynucleoside Triphosphates.Chen X, Seifert SM, Castillo-Mancilla JR, Bushman LR, Zheng JH, Kiser JJ, MaWhinney S, Anderson PL. Chen X, et al. PLoS One. 2016 Nov 10;11(11):e0165505. doi: 10.1371/journal.pone.0165505. eCollection 2016. PLoS One. 2016. PMID: 27832147 Free PMC article.
- Emtricitabine/tenofovir in the treatment of HIV infection: current PK/PD evaluation.Uglietti A, Zanaboni D, Gnarini M, Maserati R. Uglietti A, et al. Expert Opin Drug Metab Toxicol. 2012 Oct;8(10):1305-14. doi: 10.1517/17425255.2012.714367. Epub 2012 Sep 4. Expert Opin Drug Metab Toxicol. 2012. PMID: 22943210 Review.
- Emtricitabine/tenofovir disoproxil fumarate: a review of its use in HIV-1 pre-exposure prophylaxis.Plosker GL. Plosker GL. Drugs. 2013 Mar;73(3):279-91. doi: 10.1007/s40265-013-0024-4. Drugs. 2013. PMID: 23444256 Review.
- REverSe TRanscrIptase chain termination (RESTRICT) for selective measurement of nucleotide analogs used in HIV care and prevention.Olanrewaju AO, Sullivan BP, Gim AH, Craig CA, Sevenler D, Bender AT, Drain PK, Posner JD. Olanrewaju AO, et al. Bioeng Transl Med. 2022 Jul 14;8(1):e10369. doi: 10.1002/btm2.10369. eCollection 2023 Jan. Bioeng Transl Med. 2022. PMID: 36684094 Free PMC article.
- Tenofovir, Lamivudine, and Dolutegravir Among Rural Adolescents in Zimbabwe: A Cautionary Tale.Kouamou V, Machekano R, Mapangisana T, Maposhere C, Munyati S, Mutsvangwa J, Shamu T, McCarty K, Katzenstein D, Manasa J. Kouamou V, et al. AIDS Res Hum Retroviruses. 2022 Oct;38(10):774-778. doi: 10.1089/AID.2021.0140. Epub 2022 Sep 7. AIDS Res Hum Retroviruses. 2022. PMID: 35959737 Clinical Trial.
- Feasibility, Acceptability, and Preliminary Efficacy of a Gamified Mobile Health Contingency Management Intervention for PrEP Adherence Among Black MSM.Mitchell JT, Burns CM, Atkinson B, Cottrell M, Frye JK, McKellar MS, Kashuba ADM, McClernon FJ, Okeke NL. Mitchell JT, et al. AIDS Behav. 2022 Oct;26(10):3311-3324. doi: 10.1007/s10461-022-03675-9. Epub 2022 Apr 13. AIDS Behav. 2022. PMID: 35416595
- Two-dose emtricitabine/tenofovir alafenamide plus bictegravir prophylaxis protects macaques against SHIV infection.Bekerman E, Cox S, Babusis D, Campigotto F, Das M, Barouch DH, Cihlar T, Callebaut C. Bekerman E, et al. J Antimicrob Chemother. 2021 Feb 11;76(3):692-698. doi: 10.1093/jac/dkaa476. J Antimicrob Chemother. 2021. PMID: 33202006 Free PMC article.
- Antiretroviral Penetration and Drug Transporter Concentrations in the Spleens of Three Preclinical Animal Models and Humans.Devanathan AS, Fallon JK, White NR, Schauer AP, Van Horne B, Blake K, Sykes C, Kovarova M, Adamson L, Remling-Mulder L, Luciw P, Garcia JV, Akkina R, Pirone JR, Smith PC, Kashuba ADM. Devanathan AS, et al. Antimicrob Agents Chemother. 2020 Sep 21;64(10):e01384-20. doi: 10.1128/AAC.01384-20. Print 2020 Sep 21. Antimicrob Agents Chemother. 2020. PMID: 32661005 Free PMC article.
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Adenine / analogs & derivatives*
- Adenine / blood
- Adenine / pharmacokinetics
- Adult
- Anti-HIV Agents / blood*
- Anti-HIV Agents / pharmacokinetics
- Blood Cells / metabolism*
- Deoxycytidine / analogs & derivatives*
- Deoxycytidine / blood
- Deoxycytidine / pharmacokinetics
- Diphosphates / blood
- Diphosphates / pharmacokinetics
- Emtricitabine
- Female
- HIV Infections / drug therapy*
- Humans
- Leukocytes, Mononuclear / metabolism
- Male
- Medication Adherence*
- Middle Aged
- Organophosphonates / blood*
- Organophosphonates / pharmacokinetics
- Polyphosphates / blood
- Polyphosphates / pharmacokinetics
- Tenofovir
- Anti-HIV Agents
- Diphosphates
- Organophosphonates
- Polyphosphates
- Deoxycytidine
- Tenofovir
- Emtricitabine
- Adenine
- triphosphoric acid
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4042836/bin/nihms-589712-f0003.jpg)
Figure 2
Individual subject concentration/time profiles for…
Figure 2
Individual subject concentration/time profiles for TFV-DP (figure 2a) and FTC-TP (figure 2b) in…
Figure 2
Individual subject concentration/time profiles for…
Figure 2
Individual subject concentration/time profiles for TFV-DP (figure 2a) and FTC-TP (figure 2b) in…
Figure 3
The median (range) concentration/time profiles…
Figure 3
The median (range) concentration/time profiles of TFV-DP and FTC-TP in ULPC with comparison…
Figure 4
ULPC Concentrations of TFV-DP or…
Figure 4
ULPC Concentrations of TFV-DP or FTC-TP in ULPC at a single time point…
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4042836/bin/nihms-589712-f0004.jpg)
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![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4042836/bin/nihms-589712-f0006.jpg)
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4042836/bin/nihms-589712-f0007.jpg)
Source: PubMed