Current HIV/AIDS Reports

, Volume 15, Issue 1, pp 49–59 | Cite as

Adherence Measurements in HIV: New Advancements in Pharmacologic Methods and Real-Time Monitoring

HIV Pathogenesis and Treatment (AL Landay and N Utay, Section Editors)
Part of the following topical collections:
  1. Topical Collection on HIV Pathogenesis and Treatment

Abstract

Purpose of Review

In this review, we present new developments in antiretroviral adherence, focusing on pharmacological measures and real-time adherence monitoring. In addition, new strategies on how to incorporate these new measures into research and clinical care are proposed.

Recent Findings

Antiretroviral drug concentrations in hair and dried blood spots are two novel pharmacological measures of cumulative drug adherence and exposure that have been recently evaluated in HIV treatment and pre-exposure prophylaxis. Real-time adherence monitoring using electronic devices has also proven highly informative, feasible, and well accepted, offering the possibility for an immediate intervention when non-adherence is detected. Both approaches offer considerable advantages over traditional adherence measures in predicting efficacy.

Summary

New methods to objectively monitor adherence in real-time and over long time periods have been developed. Further research is required to better understand how these measures can optimize adherence and, ultimately, improve clinical outcomes in HIV treatment and prevention.

Keywords

ART Adherence Hair drug levels Dried blood spots Real-time adherence monitoring 

Notes

Compliance with ethical standards

Conflict of Interest

Jose R. Castillo-Mancilla reports grants K23AI104315 and R21AI124859 from NIH. Jessica E. Haberer reports grants from NIH, Gates Foundation, USAID; has served as a consultant for NIH, Merck, and WHO; and has received stock from Natera.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

  1. 1.
    Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr. 2006;43(1):27–34.  https://doi.org/10.1097/01.qai.0000233310.90484.16.CrossRefPubMedGoogle Scholar
  2. 2.
    Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, Eron JJ, Yazdanpanah Y, Podzamczer D, et al. Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial. Lancet. 2017;390(10101):1499–510.  https://doi.org/10.1016/S0140-6736(17)31917-7.CrossRefPubMedGoogle Scholar
  3. 3.
    Garrison LE, Haberer JE. Technological methods to measure adherence to antiretroviral therapy and preexposure prophylaxis. Curr Opin HIV AIDS. 2017;12(5):467–74.  https://doi.org/10.1097/COH.0000000000000393.CrossRefPubMedGoogle Scholar
  4. 4.
    Pearson CR, Simoni JM, Hoff P, Kurth AE, Martin DP. Assessing antiretroviral adherence via electronic drug monitoring and self-report: an examination of key methodological issues. AIDS Behav. 2007;11(2):161–73.  https://doi.org/10.1007/s10461-006-9133-3.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Simoni JM, Kurth AE, Pearson CR, Pantalone DW, Merrill JO, Frick PA. Self-report measures of antiretroviral therapy adherence: a review with recommendations for HIV research and clinical management. AIDS Behav. 2006;10(3):227–45.  https://doi.org/10.1007/s10461-006-9078-6.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Turner BJ. Adherence to antiretroviral therapy by human immunodeficiency virus-infected patients. J Infect Dis. 2002;185(Suppl 2):S143–51.  https://doi.org/10.1086/340197.CrossRefPubMedGoogle Scholar
  7. 7.
    Arnsten JH, Demas PA, Farzadegan H, Grant RW, Gourevitch MN, Chang CJ, et al. Antiretroviral therapy adherence and viral suppression in HIV-infected drug users: comparison of self-report and electronic monitoring. Clin Infect Dis. 2001;33(8):1417–23.  https://doi.org/10.1086/323201.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Okatch H, Beiter K, Eby J, Chapman J, Marukutira T, Tshume O, et al. Brief report: apparent antiretroviral overadherence by pill count is associated with HIV treatment failure in adolescents. J Acquir Immune Defic Syndr. 2016;72(5):542–5.  https://doi.org/10.1097/QAI.0000000000000994.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Bisson GP, Gross R, Bellamy S, Chittams J, Hislop M, Regensberg L, et al. Pharmacy refill adherence compared with CD4 count changes for monitoring HIV-infected adults on antiretroviral therapy. PLoS Med. 2008;5(5):e109.  https://doi.org/10.1371/journal.pmed.0050109.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Grabar S, Le Moing V, Goujard C, Leport C, Kazatchkine MD, Costagliola D, et al. Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy. Ann Intern Med. 2000;133(6):401–10.  https://doi.org/10.7326/0003-4819-133-6-200009190-00007.CrossRefPubMedGoogle Scholar
  11. 11.
    Cohen MS, McCauley M, Gamble TR. HIV treatment as prevention and HPTN 052. Curr Opin HIV AIDS. 2012;7(2):99–105.  https://doi.org/10.1097/COH.0b013e32834f5cf2.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133(1):21–30.  https://doi.org/10.7326/0003-4819-133-1-200007040-00004.CrossRefPubMedGoogle Scholar
  13. 13.
    Bangsberg DR, Hecht FM, Charlebois ED, Zolopa AR, Holodniy M, Sheiner L, et al. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS. 2000;14(4):357–66.  https://doi.org/10.1097/00002030-200003100-00008.CrossRefPubMedGoogle Scholar
  14. 14.
    Viswanathan S, Detels R, Mehta SH, Macatangay BJ, Kirk GD, Jacobson LP. Level of adherence and HIV RNA suppression in the current era of highly active antiretroviral therapy (HAART). AIDS Behav. 2015;19(4):601–11.  https://doi.org/10.1007/s10461-014-0927-4.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bangsberg DR. Less than 95% adherence to nonnucleoside reverse-transcriptase inhibitor therapy can lead to viral suppression. Clin Infect Dis. 2006;43(7):939–41.  https://doi.org/10.1086/507526.CrossRefPubMedGoogle Scholar
  16. 16.
    Shuter J, Sarlo JA, Kanmaz TJ, Rode RA, Zingman BS. HIV-infected patients receiving lopinavir/ritonavir-based antiretroviral therapy achieve high rates of virologic suppression despite adherence rates less than 95%. J Acquir Immune Defic Syndr. 2007;45(1):4–8.  https://doi.org/10.1097/QAI.0b013e318050d8c2.CrossRefPubMedGoogle Scholar
  17. 17.
    Martin M, Del Cacho E, Codina C, Tuset M, De Lazzari E, Mallolas J, et al. Relationship between adherence level, type of the antiretroviral regimen, and plasma HIV type 1 RNA viral load: a prospective cohort study. AIDS Res Hum Retrovir. 2008;24(10):1263–8.  https://doi.org/10.1089/aid.2008.0141.CrossRefPubMedGoogle Scholar
  18. 18.
    Maggiolo F, Airoldi M, Kleinloog HD, Callegaro A, Ravasio V, Arici C, et al. Effect of adherence to HAART on virologic outcome and on the selection of resistance-conferring mutations in NNRTI- or PI-treated patients. HIV Clin Trials. 2007;8(5):282–92.  https://doi.org/10.1310/hct0805-282.CrossRefPubMedGoogle Scholar
  19. 19.
    Viswanathan S, Justice AC, Alexander GC, Brown TT, Gandhi NR, McNicholl IR, et al. Adherence and HIV RNA suppression in the current era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2015;69(4):493–8.  https://doi.org/10.1097/QAI.0000000000000643.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Thirumurthy H, Siripong N, Vreeman RC, Pop-Eleches C, Habyarimana JP, Sidle JE, et al. Differences between self-reported and electronically monitored adherence among patients receiving antiretroviral therapy in a resource-limited setting. AIDS. 2012;26(18):2399–403.  https://doi.org/10.1097/QAD.0b013e328359aa68.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Liu H, Golin CE, Miller LG, Hays RD, Beck CK, Sanandaji S, et al. A comparison study of multiple measures of adherence to HIV protease inhibitors. Ann Intern Med. 2001;134(10):968–77.  https://doi.org/10.7326/0003-4819-134-10-200105150-00011.CrossRefPubMedGoogle Scholar
  22. 22.
    Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS. 2001;15(1):71–5.  https://doi.org/10.1097/00002030-200101050-00011.CrossRefPubMedGoogle Scholar
  23. 23.
    Gunda DW, Kasang C, Kidenya BR, Kabangila R, Mshana SE, Kidola J, et al. Plasma concentrations of efavirenz and nevirapine among HIV-infected patients with immunological failure attending a tertiary hospital in North-western Tanzania. PLoS One. 2013;8(9):e75118.  https://doi.org/10.1371/journal.pone.0075118.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Anderson PL, Liu AY, Castillo-Mancilla JR, Gardner EM, Seifert SM, McHugh C, et al. Intracellular tenofovir-diphosphate and emtricitabine-triphosphate in dried blood spots following directly observed therapy: the DOT-DBS study. Antimicrob Agents Chemother. 2017;62(1):e01710–7.  https://doi.org/10.1128/AAC.01710-17.PubMedGoogle Scholar
  25. 25.
    Podsadecki TJ, Vrijens BC, Tousset EP, Rode RA, Hanna GJ. “White coat compliance” limits the reliability of therapeutic drug monitoring in HIV-1-infected patients. HIV Clin Trials. 2008;9(4):238–46.  https://doi.org/10.1310/hct0904-238.CrossRefPubMedGoogle Scholar
  26. 26.
    Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
  27. 27.
    Koenig RJ, Peterson CM, Jones RL, Saudek C, Lehrman M, Cerami A. Correlation of glucose regulation and hemoglobin AIc in diabetes mellitus. N Engl J Med. 1976;295(8):417–20.  https://doi.org/10.1056/NEJM197608192950804.CrossRefPubMedGoogle Scholar
  28. 28.
    Lehmann S, Delaby C, Vialaret J, Ducos J, Hirtz C. Current and future use of “dried blood spot” analyses in clinical chemistry. Clin Chem Lab Med. 2013;51(10):1897–909.  https://doi.org/10.1515/cclm-2013-0228.CrossRefPubMedGoogle Scholar
  29. 29.
    Castillo-Mancilla JR, Zheng JH, Rower JE, Meditz A, Gardner EM, Predhomme J, et al. Tenofovir, emtricitabine, and tenofovir diphosphate in dried blood spots for determining recent and cumulative drug exposure. AIDS Res Hum Retrovir. 2013;29(2):384–90.  https://doi.org/10.1089/AID.2012.0089.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Johannessen A. Dried blood spots in HIV monitoring: applications in resource-limited settings. Bioanalysis. 2010;2(11):1893–908.  https://doi.org/10.4155/bio.10.120.CrossRefPubMedGoogle Scholar
  31. 31.
    Balmaseda A, Saborio S, Tellez Y, Mercado JC, Perez L, Hammond SN, et al. Evaluation of immunological markers in serum, filter-paper blood spots, and saliva for dengue diagnosis and epidemiological studies. J Clin Virol. 2008;43(3):287–91.  https://doi.org/10.1016/j.jcv.2008.07.016.CrossRefPubMedGoogle Scholar
  32. 32.
    Conroy JM, Trivedi G, Sovd T, Caggana M. The allele frequency of mutations in four genes that confer enhanced susceptibility to venous thromboembolism in an unselected group of New York State newborns. Thromb Res. 2000;99(4):317–24.  https://doi.org/10.1016/S0049-3848(00)00254-1.CrossRefPubMedGoogle Scholar
  33. 33.
    Snijdewind IJ, van Kampen JJ, Fraaij PL, van der Ende ME, Osterhaus AD, Gruters RA. Current and future applications of dried blood spots in viral disease management. Antivir Res. 2012;93(3):309–21.  https://doi.org/10.1016/j.antiviral.2011.12.011.CrossRefPubMedGoogle Scholar
  34. 34.
    Lakshmi V, Sudha T, Dandona R, Teja VD, Kumar GA, Dandona L. Application of human immunodeficiency virus type 1 BED enzyme immunoassay on dried blood spots in India. J Med Microbiol. 2009;58(Pt 3):312–7.  https://doi.org/10.1099/jmm.0.005249-0.CrossRefPubMedGoogle Scholar
  35. 35.
    Chang J, de Sousa A, Sabatier J, Assane M, Zhang G, Bila D, et al. Performance characteristics of finger-stick dried blood spots (DBS) on the determination of human immunodeficiency virus (HIV) treatment failure in a pediatric population in Mozambique. PLoS One. 2017;12(7):e0181054.  https://doi.org/10.1371/journal.pone.0181054.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zeh C, Ndiege K, Inzaule S, Achieng R, Williamson J, Chih-Wei Chang J, et al. Evaluation of the performance of Abbott m2000 and Roche COBAS Ampliprep/COBAS Taqman assays for HIV-1 viral load determination using dried blood spots and dried plasma spots in Kenya. PLoS One. 2017;12(6):e0179316.  https://doi.org/10.1371/journal.pone.0179316.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Duthaler U, Berger B, Erb S, Battegay M, Letang E, Gaugler S et al. Automated high throughput analysis of antiretroviral drugs in dried blood spots. J Mass Spectrom. 2017.Google Scholar
  38. 38.
    Kromdijk W, Mulder JW, Smit PM, ter Heine R, Beijnen JH, Huitema AD. Short communication therapeutic drug monitoring of antiretroviral drugs at home using dried blood spots: a proof-of-concept study. Antivir Ther. 2013;18(6):821–5.  https://doi.org/10.3851/IMP2501.CrossRefPubMedGoogle Scholar
  39. 39.
    Zheng J-H, Guida LA, Rower C, Castillo-Mancilla J, Meditz A, Klein B, et al. Quantitation of tenofovir and emtricitabine in dried blood spots (DBS) with LC–MS/MS. J Pharm Biomed Anal. 2014;88:144–51.  https://doi.org/10.1016/j.jpba.2013.08.033.CrossRefPubMedGoogle Scholar
  40. 40.
    Amara AB, Else LJ, Tjia J, Olagunju A, Puls RL, Khoo S, et al. A validated method for quantification of efavirenz in dried blood spots using high-performance liquid chromatography–mass spectrometry. Ther Drug Monit. 2015;37(2):220–8.  https://doi.org/10.1097/FTD.0000000000000127.CrossRefPubMedGoogle Scholar
  41. 41.
    Koal T, Burhenne H, Roemling R, Svoboda M, Resch K, Kaever V. Quantification of antiretroviral drugs in dried blood spot samples by means of liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2005;19(21):2995–3001.  https://doi.org/10.1002/rcm.2158.CrossRefPubMedGoogle Scholar
  42. 42.
    Meesters RJ, van Kampen JJ, Reedijk ML, Scheuer RD, Dekker LJ, Burger DM, et al. Ultrafast and high-throughput mass spectrometric assay for therapeutic drug monitoring of antiretroviral drugs in pediatric HIV-1 infection applying dried blood spots. Anal Bioanal Chem. 2010;398(1):319–28.  https://doi.org/10.1007/s00216-010-3952-9.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ter Heine R, Rosing H, Van Gorp E, Mulder J, Van der Steeg W, Beijnen J, et al. Quantification of protease inhibitors and non-nucleoside reverse transcriptase inhibitors in dried blood spots by liquid chromatography–triple quadrupole mass spectrometry. J Chromatogr B. 2008;867(2):205–12.  https://doi.org/10.1016/j.jchromb.2008.04.003.CrossRefGoogle Scholar
  44. 44.
    Ter Heine R, Hillebrand M, Rosing H, van Gorp E, Mulder J, Beijnen J, et al. Quantification of the HIV-integrase inhibitor raltegravir and detection of its main metabolite in human plasma, dried blood spots and peripheral blood mononuclear cell lysate by means of high-performance liquid chromatography tandem mass spectrometry. J Pharm Biomed Anal. 2009;49(2):451–8.  https://doi.org/10.1016/j.jpba.2008.11.025.CrossRefPubMedGoogle Scholar
  45. 45.
    Ter Heine R, Rosing H, Van Gorp E, Mulder J, Beijnen J, Huitema A. Quantification of etravirine (TMC125) in plasma, dried blood spots and peripheral blood mononuclear cell lysate by liquid chromatography tandem mass spectrometry. J Pharm Biomed Anal. 2009;49(2):393–400.  https://doi.org/10.1016/j.jpba.2008.10.040.CrossRefPubMedGoogle Scholar
  46. 46.
    Van Schooneveld T, Swindells S, Nelson SR, Robbins BL, Moore R, Fletcher CV. Clinical evaluation of a dried blood spot assay for atazanavir. Antimicrob Agents Chemother. 2010;54(10):4124–8.  https://doi.org/10.1128/AAC.00297-10.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Amara AB, Else LJ, Carey D, Khoo S, Back DJ, Amin J et al. A comparison of dried blood spots versus conventional plasma collection for the characterisation of efavirenz pharmacokinetics in a large-scale global clinical trial-The ENCORE1 study. Therapeutic Drug Monitoring. 2017.Google Scholar
  48. 48.
    Alcaide ML, Ramlagan S, Rodriguez VJ, Cook R, Peltzer K, Weiss SM et al. Self-report and dry blood spot measurement of antiretroviral medications as markers of adherence in pregnant women in rural South Africa. AIDS and Behavior. 2017;1–6.Google Scholar
  49. 49.
    Wilhelm AJ, den Burger JC, Swart EL. Therapeutic drug monitoring by dried blood spot: progress to date and future directions. Clin Pharmacokinet. 2014;53(11):961–73.  https://doi.org/10.1007/s40262-014-0177-7.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Zheng JH, Rower C, McAllister K, Castillo-Mancilla J, Klein B, Meditz A, 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.  https://doi.org/10.1016/j.jpba.2016.01.038.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Castillo-Mancilla J, Seifert S, Campbell K, Coleman S, McAllister K, Zheng JH, et al. Emtricitabine-triphosphate in dried blood spots as a marker of recent dosing. Antimicrob Agents Chemother. 2016;60(11):6692–7.  https://doi.org/10.1128/AAC.01017-16.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Castillo-Mancilla J, Coyle RP, Zheng JH, Ellison L, Roon L, Fey J et al. Tenofovir diphosphate arising from TAF is quantifiable in dried blood spots. Poster Presented at CROI 2017 Seattle, WA Abstract 405.Google Scholar
  53. 53.
    Grant RM, Anderson PL, McMahan V, Liu A, Amico KR, Mehrotra M, et al. 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(9):820–9.  https://doi.org/10.1016/S1473-3099(14)70847-3.CrossRefPubMedGoogle Scholar
  54. 54.
    Hosek S, Rudy B, Landovitz RJ, Kapogiannis BG, Siberry G, Rutledge B et al. An HIV-pre-exposure prophylaxis (PrEP) demonstration project and safety study for young men who have sex with men in the united states (ATN 110). IAS 2015: 8th IAS Conference on HIV Pathogenesis Treatment and Prevention. 2015.Google Scholar
  55. 55.
    Liu AY, Cohen SE, Vittinghoff E, Anderson PL, Doblecki-Lewis S, Bacon O, et al. Preexposure prophylaxis for HIV infection integrated with municipal- and community-based sexual health services. JAMA Intern Med. 2016;176(1):75–84.  https://doi.org/10.1001/jamainternmed.2015.4683.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Knox DC, Anderson PL, Harrigan PR, Tan DH. Multidrug-resistant HIV-1 infection despite preexposure prophylaxis. N Engl J Med. 2017;376(5):501–2.  https://doi.org/10.1056/NEJMc1611639.CrossRefPubMedGoogle Scholar
  57. 57.
    Hoornenborg E, Prins M, Achterbergh RC, Woittiez LR, Cornelissen M, Jurriaans S et al. Acquisition of wild-type HIV-1 infection in a patient on pre-exposure prophylaxis with high intracellular concentrations of tenofovir diphosphate: a case report. Lancet HIV. 2017.Google Scholar
  58. 58.
    Markowitz M, Grossman H, Anderson PL, Grant R, Gandhi M, Horng H et al. Newly acquired infection with multi-drug resistant HIV-1 in a patient adherent to pre-exposure prophylaxis. JAIDS J Acquired Immune Deficiency Syndromes. 2017.Google Scholar
  59. 59.
    Castillo-Mancilla JR, Searls K, Caraway P, Zheng JH, Gardner EM, Predhomme J, et al. Short communication: tenofovir diphosphate in dried blood spots as an objective measure of adherence in HIV-infected women. AIDS Res Hum Retrovir. 2015;31(4):428–32.  https://doi.org/10.1089/AID.2014.0229.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Warne P, Robbins R, Anderson P, Gouse H, Joska J, Leu CS et al. Utility of dried blood spot-derived ARV biomarkers as an objective measure of treatment adherence in South Africa. Poster Presented at IAPAC Adherence 2015 Miami, FL Abstract 241.Google Scholar
  61. 61.
    LeBeau MA, Montgomery MA, Brewer JD. The role of variations in growth rate and sample collection on interpreting results of segmental analyses of hair. Forensic Sci Int. 2011;210(1):110–6.  https://doi.org/10.1016/j.forsciint.2011.02.015.CrossRefPubMedGoogle Scholar
  62. 62.
    Beumer J, Bosman I, Maes R. Hair as a biological specimen for therapeutic drug monitoring. Int J Clin Pract. 2001;55(6):353–7.PubMedGoogle Scholar
  63. 63.
    Balabanova S, Homoki J. Determination of cocaine in human hair by gas chromatography/mass spectrometry. Int J Legal Med. 1987;98(4):235–40.Google Scholar
  64. 64.
    Mieczowski T, Newel R. Comparing hair and urine assays for cocaine and marijuana. Fed Probat. 1993;57:59.Google Scholar
  65. 65.
    Gandhi M, Greenblatt RM. Hair it is: the long and short of monitoring antiretroviral treatment. Ann Intern Med. 2002;137(8):696–7.  https://doi.org/10.7326/0003-4819-137-8-200210150-00016.CrossRefPubMedGoogle Scholar
  66. 66.
    Song SH, Jun SH, Park KU, Yoon Y, Lee JH, Kim JQ, et al. Simultaneous determination of first-line anti-tuberculosis drugs and their major metabolic ratios by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2007;21(7):1331–8.  https://doi.org/10.1002/rcm.2961.CrossRefPubMedGoogle Scholar
  67. 67.
    Williams J, Myson V, Steward S, Jones G, Wilson JF, Kerr MP, et al. Self-discontinuation of antiepileptic medication in pregnancy: detection by hair analysis. Epilepsia. 2002;43(8):824–31.  https://doi.org/10.1046/j.1528-1157.2002.38601.x.CrossRefPubMedGoogle Scholar
  68. 68.
    Sauvé B, Koren G, Walsh G, Tokmakejian S, Van Uum SH. Measurement of cortisol in human hair as a biomarker of systemic exposure. Clin Invest Med. 2007;30(5):183–91.  https://doi.org/10.25011/cim.v30i5.2894.CrossRefGoogle Scholar
  69. 69.
    Gao W, Stalder T, Foley P, Rauh M, Deng H, Kirschbaum C. Quantitative analysis of steroid hormones in human hair using a column-switching LC–APCI–MS/MS assay. J Chromatogr B. 2013;928:1–8.  https://doi.org/10.1016/j.jchromb.2013.03.008.CrossRefGoogle Scholar
  70. 70.
    Prasitsuebsai W, Kerr SJ, Truong KH, Ananworanich J, Do VC, Nguyen LV, et al. Using lopinavir concentrations in hair samples to assess treatment outcomes on second-line regimens among Asian children. AIDS Res Hum Retrovir. 2015;31(10):1009–14.  https://doi.org/10.1089/aid.2015.0111.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Hickey MD, Salmen CR, Tessler RA, Omollo D, Bacchetti P, Magerenge R, et al. Antiretroviral concentrations in small hair samples as a feasible marker of adherence in rural Kenya. J Acquir Immune Defic Syndr. 1999;66(3):311.CrossRefGoogle Scholar
  72. 72.
    Strano-Rossi S, Bermejo-Barrera A, Chiarotti M. Segmental hair analysis for cocaine and heroin abuse determination. Forensic Sci Int. 1995;70(1–3):211–6.  https://doi.org/10.1016/0379-0738(94)01620-K.CrossRefPubMedGoogle Scholar
  73. 73.
    Olds PK, Kiwanuka JP, Nansera D, Huang Y, Bacchetti P, Jin C, et al. Assessment of HIV antiretroviral therapy adherence by measuring drug concentrations in hair among children in rural Uganda. AIDS Care. 2015;27(3):327–32.  https://doi.org/10.1080/09540121.2014.983452.CrossRefPubMedGoogle Scholar
  74. 74.
    Robbins R, Gouse H, Warne P, Mtingeni Y, Henry M, Lopez-Rios J et al. Feasibility and acceptability of hair and dried blood spot derived ARV biomarkers as objective measures of treatment adherence in South Africa. Poster Presented at IAPAC Adherence 2015 Miami, FL Abstract 210.Google Scholar
  75. 75.
    Bernard L, Vuagnat A, Peytavin G, Hallouin M-C, Bouhour D, Nguyen TH, et al. Relationship between levels of indinavir in hair and virologic response to highly active antiretroviral therapy. Ann Intern Med. 2002;137(8):656–9.  https://doi.org/10.7326/0003-4819-137-8-200210150-00009.CrossRefPubMedGoogle Scholar
  76. 76.
    Huang Y, Yang Q, Yoon K, Lei Y, Shi R, Gee W, et al. Microanalysis of the antiretroviral nevirapine in human hair from HIV-infected patients by liquid chromatography-tandem mass spectrometry. Anal Bioanal Chem. 2011;401(6):1923–33.  https://doi.org/10.1007/s00216-011-5278-7.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Huang Y, Gandhi M, Greenblatt RM, Gee W, Lin ET, Messenkoff N. Sensitive analysis of anti-HIV drugs, efavirenz, lopinavir and ritonavir, in human hair by liquid chromatography coupled with tandem mass spectrometry. Rapid Commun Mass Spectrom. 2008;22(21):3401–9.  https://doi.org/10.1002/rcm.3750.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Gandhi M, Yang Q, Bacchetti P, Huang Y. A low-cost method for analyzing nevirapine levels in hair as a marker of adherence in resource-limited settings. AIDS Res Hum Retrovir. 2014;30(1):25–8.  https://doi.org/10.1089/aid.2013.0239.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Gandhi M, Ameli N, Bacchetti P, Anastos K, Gange SJ, Minkoff H, et al. Atazanavir concentration in hair is the strongest predictor of outcomes on antiretroviral therapy. Clin Infect Dis. 2011;52(10):1267–75.  https://doi.org/10.1093/cid/cir131.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Saberi P, Neilands TB, Ming K, Johnson MO, Kuncze K, Koss CA et al. Strong correlation between concentrations of antiretrovirals in home-collected and study-collected hair samples: implications for adherence monitoring. JAIDS J Acquir Immune Defic Syndr. 2017.Google Scholar
  81. 81.
    Pintye J, Bacchetti P, Teeraananchai S, Kerr S, Prasitsuebsai W, Singtoroj T et al. Brief report: lopinavir hair concentrations are the strongest predictor of viremia in HIV-infected Asian children and adolescents on second-line antiretroviral therapy. JAIDS J Acquir Immune Defic Syndr. 2017.Google Scholar
  82. 82.
    Van Zyl GU, Van Mens TE, McIlleron H, Zeier M, Nachega JB, Decloedt E, et al. Low lopinavir plasma or hair concentrations explain second line protease inhibitor failures in a resource-limited setting. J Acquir Immune Defic Syndr. 1999;56(4):333.Google Scholar
  83. 83.
    Gandhi M, Ameli N, Bacchetti P, Gange SJ, Anastos K, Levine A, et al. Protease inhibitor levels in hair samples strongly predict virologic responses to HIV treatment. AIDS (London, England). 2009;23(4):471–8.  https://doi.org/10.1097/QAD.0b013e328325a4a9.CrossRefGoogle Scholar
  84. 84.
    Koss CA, Natureeba P, Mwesigwa J, Cohan D, Nzarubara B, Bacchetti P, et al. Hair concentrations of antiretrovirals predict viral suppression in HIV-infected pregnant and breastfeeding Ugandan women. AIDS (London, England). 2015;29(7):825–30.  https://doi.org/10.1097/QAD.0000000000000619.CrossRefGoogle Scholar
  85. 85.
    Baxi SM, Greenblatt RM, Bacchetti P, Jin C, French AL, Keller MJ, et al. Nevirapine concentration in hair samples is a strong predictor of Virologic suppression in a prospective cohort of HIV-infected patients. PLoS One. 2015;10(6):e0129100.  https://doi.org/10.1371/journal.pone.0129100.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Liu AY, Yang Q, Huang Y, Bacchetti P, Anderson PL, Jin C, et al. Strong relationship between oral dose and tenofovir hair levels in a randomized trial: hair as a potential adherence measure for pre-exposure prophylaxis (PrEP). PLoS One. 2014;9(1):e83736.  https://doi.org/10.1371/journal.pone.0083736.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Koss CA, Bacchetti P, Hillier SL, Livant E, Horng H, Mgodi N et al. Differences in cumulative exposure and adherence to tenofovir in the VOICE, iPrEx OLE, and PrEP demo studies as determined via hair concentrations. AIDS Res Human Retroviruses. 2017.Google Scholar
  88. 88.
    Dai JY, Hendrix CW, Richardson BA, Kelly C, Marzinke M, Chirenje ZM, et al. Pharmacological measures of treatment adherence and risk of HIV infection in the VOICE study. J Infect Dis. 2015;213(3):335–42.  https://doi.org/10.1093/infdis/jiv333.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Baxi SM, Liu A, Bacchetti P, Mutua G, Sanders EJ, Kibengo FM, et al. Comparing the novel method of assessing PrEP adherence/exposure using hair samples to other pharmacologic and traditional measures. J Acquir Immune Defic Syndr. 1999;68(1):13.CrossRefGoogle Scholar
  90. 90.
    Gandhi M, Murnane PM, Bacchetti P, Elion R, Kolber MA, Cohen SE, et al. Hair levels of preexposure prophylaxis drugs measure adherence and are associated with renal decline among men/transwomen. AIDS. 2017;31(16):2245–51.  https://doi.org/10.1097/QAD.0000000000001615.CrossRefPubMedGoogle Scholar
  91. 91.
    Gandhi M, Glidden DV, Mayer K, Schechter M, Buchbinder S, Grinsztejn B, et al. Association of age, baseline kidney function, and medication exposure with declines in creatinine clearance on pre-exposure prophylaxis: an observational cohort study. Lancet HIV. 2016;3(11):e521–e8.  https://doi.org/10.1016/S2352-3018(16)30153-9.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Vreeman RC, Nyandiko WM, Liu H, Tu W, Scanlon ML, Slaven JE et al. Measuring adherence to antiretroviral therapy in children and adolescents in western Kenya. J Int AIDS Soc. 2014;17(1).Google Scholar
  93. 93.
    Samet JH, Sullivan LM, Traphagen ET, Ickovics JR. Measuring adherence among HIV-infected persons: is MEMS consummate technology? AIDS Behav. 2001;5(1):21–30.  https://doi.org/10.1023/A:1009503320498.CrossRefGoogle Scholar
  94. 94.
    Haberer JE. Actionable adherence monitoring to optimise intervention. Lancet HIV. 2017;4(1):e5–6.  https://doi.org/10.1016/S2352-3018(16)30191-6.CrossRefPubMedGoogle Scholar
  95. 95.
    Gengiah TN, Upfold M, Naidoo A, Mansoor LE, Feldblum PJ, Karim QA, et al. Monitoring microbicide gel use with real-time notification of the container’s opening events: results of the CAPRISA Wisebag study. AIDS Behav. 2014;18(5):833–40.  https://doi.org/10.1007/s10461-014-0750-y.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Haberer JE, Sabin L, Amico KR, Orrell C, Galárraga O, Tsai AC et al. Improving antiretroviral therapy adherence in resource-limited settings at scale: a discussion of interventions and recommendations. J Int AIDS Soc. 2017;20(1).Google Scholar
  97. 97.
    Deschamps AE, Van Wijngaerden E, Denhaerynck K, De Geest S, Vandamme AM. Use of electronic monitoring induces a 40-day intervention effect in HIV patients. J Acquir Immune Defic Syndr. 2006;43(2):247–8.  https://doi.org/10.1097/01.qai.0000246034.86135.89.CrossRefPubMedGoogle Scholar
  98. 98.
    Ware NC, Pisarski EE, Tam M, Wyatt MA, Atukunda E, Musiimenta A, et al. The meanings in the messages: how SMS reminders and real-time adherence monitoring improve antiretroviral therapy adherence in rural Uganda. AIDS. 2016;30(8):1287–94.  https://doi.org/10.1097/QAD.0000000000001035.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Haberer JE, Kahane J, Kigozi I, Emenyonu N, Hunt P, Martin J, et al. Real-time adherence monitoring for HIV antiretroviral therapy. AIDS Behav. 2010;14(6):1340–6.  https://doi.org/10.1007/s10461-010-9799-4.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Haberer JE, Musinguzi N, Boum Y 2nd, Siedner MJ, Mocello AR, Hunt PW, et al. Duration of antiretroviral therapy adherence interruption is associated with risk of virologic rebound as determined by real-time adherence monitoring in rural Uganda. J Acquir Immune Defic Syndr. 1999;70(4):386–92.CrossRefGoogle Scholar
  101. 101.
    Haberer JE, Robbins GK, Ybarra M, Monk A, Ragland K, Weiser SD, et al. Real-time electronic adherence monitoring is feasible, comparable to unannounced pill counts, and acceptable. AIDS Behav. 2012;16(2):375–82.  https://doi.org/10.1007/s10461-011-9933-y.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Haberer JE, Kiwanuka J, Nansera D, Muzoora C, Hunt PW, So J et al. Real-time adherence monitoring of antiretroviral therapy among HIV-infected adults and children in rural Uganda. AIDS (London, England). 2013;27(13).Google Scholar
  103. 103.
    Bachman DeSilva M, Gifford AL, Keyi X, Li Z, Feng C, Brooks M et al. Feasibility and acceptability of a real-time adherence device among HIV-positive IDU patients in China. AIDS Res Treat. 2013;2013.Google Scholar
  104. 104.
    Campbell JI, Eyal N, Musiimenta A, Haberer JE. Ethical questions in medical electronic adherence monitoring. J Gen Intern Med. 2016;31(3):338–42.  https://doi.org/10.1007/s11606-015-3502-4.CrossRefPubMedGoogle Scholar
  105. 105.
    de Sumari-de Boer IM, van den Boogaard J, Ngowi KM, Semvua HH, Kiwango KW, Aarnoutse RE, et al. Feasibility of real time medication monitoring among HIV infected and TB patients in a resource-limited setting. AIDS Behav. 2016;20(5):1097–107.  https://doi.org/10.1007/s10461-015-1254-0.CrossRefGoogle Scholar
  106. 106.
    Wisepill Technologies. Real time adherence management. (Accessed November 18, 2017 at https://www.wisepill.com/).
  107. 107.
    Haberer JE, Musiimenta A, Atukunda EC, Musinguzi N, Wyatt MA, Ware NC, et al. Short message service (SMS) reminders and real-time adherence monitoring improve antiretroviral therapy adherence in rural Uganda. AIDS. 2016;30(8):1295–300.  https://doi.org/10.1097/QAD.0000000000001021.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Sabin LL, Bachman DeSilva M, Gill CJ, Zhong L, Vian T, Xie W, et al. Improving adherence to antiretroviral therapy with triggered real-time text message reminders: the China adherence through technology study. J Acquir Immune Defic Syndr. 2015;69(5):551–9.  https://doi.org/10.1097/QAI.0000000000000651.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Orrell C, Cohen K, Mauff K, Bangsberg DR, Maartens G, Wood R. A randomized controlled trial of real-time electronic adherence monitoring with text message dosing reminders in people starting first-line antiretroviral therapy. J Acquir Immune Defic Syndr. 2015;70(5):495–502.  https://doi.org/10.1097/QAI.0000000000000770.CrossRefPubMedGoogle Scholar
  110. 110.
    Protecting households on exposure to newly diagnosed index multidrug-resistant TB patients. Available at http://impaactnetwork.org/studies/IMPAACT2003B.asp Accessed 7 Nov 2017.
  111. 111.
    Gandhi M, Team iS, Glidden DV, Team iS, Liu A, Team iS et al. Strong correlation between concentrations of tenofovir (TFV) emtricitabine (FTC) in hair and TFV diphosphate and FTC triphosphate in dried blood spots in the iPrEx open label extension: implications for pre-exposure prophylaxis adherence monitoring. J Infect Dis 2015;212(9):1402–1406, DOI:  https://doi.org/10.1093/infdis/jiv239.
  112. 112.
    Abaasa A, Hendrix C, Gandhi M, Anderson P, Kamali A, Kibengo F et al. Utility of different adherence measures for PrEP: patterns and incremental value. AIDS Behav. 2017:1–9.Google Scholar
  113. 113.
    Kanters S, Park JJ, Chan K, Socias ME, Ford N, Forrest JI, et al. Interventions to improve adherence to antiretroviral therapy: a systematic review and network meta-analysis. Lancet HIV. 2017;4(1):e31–40.  https://doi.org/10.1016/S2352-3018(16)30206-5.CrossRefPubMedGoogle Scholar
  114. 114.
    Gwadz M, Cleland CM, Applegate E, Belkin M, Gandhi M, Salomon N, et al. Behavioral intervention improves treatment outcomes among HIV-infected individuals who have delayed, declined, or discontinued antiretroviral therapy: a randomized controlled trial of a novel intervention. AIDS Behav. 2015;19(10):1801–17.  https://doi.org/10.1007/s10461-015-1054-6.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Hickey MD, Salmen CR, Omollo D, Mattah B, Fiorella KJ, Geng EH, et al. Implementation and operational research: pulling the network together: quasiexperimental trial of a patient-defined support network intervention for promoting engagement in HIV care and medication adherence on Mfangano Island, Kenya. J Acquir Immune Defic Syndr. 2015;69(4):e127–34.  https://doi.org/10.1097/QAI.0000000000000664.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Golub SA, Pena S, Hilley A, Pachankis J, Radix A. Brief behavioral intervention increases PrEP drug levels in a real-world setting. Poster Presented at CROI 2017 Seattle, WA Abstract 965.Google Scholar
  117. 117.
    Li JZ, Gallien S, Ribaudo H, Heisey A, Bangsberg DR, Kuritzkes DR. Incomplete adherence to antiretroviral therapy is associated with higher levels of residual HIV-1 viremia. AIDS. 2014;28(2):181–6.  https://doi.org/10.1097/QAD.0000000000000123.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Podsadecki TJ, Vrijens BC, Tousset EP, Rode RA, Hanna GJ. Decreased adherence to antiretroviral therapy observed prior to transient human immunodeficiency virus type 1 viremia. J Infect Dis. 2007;196(12):1773–8.  https://doi.org/10.1086/523704.CrossRefPubMedGoogle Scholar
  119. 119.
    Castillo-Mancilla JR, Brown TT, Erlandson KM, Palella FJ Jr, Gardner EM, Macatangay BJ, et al. Suboptimal adherence to combination antiretroviral therapy is associated with higher levels of inflammation despite HIV suppression. Clin Infect Dis. 2016;63(12):1661–7.  https://doi.org/10.1093/cid/ciw650.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Castillo-Mancilla JR, Morrow M, Boum Y, Byakwaga H, Haberer JE, Martin JN et al. Higher Art adherence is associated with lower systemic inflammation in treatment-naïve Ugandans who achieve virologic suppression. J Acquir Immune Defic Syndr. 2018.  https://doi.org/10.1097/QAI.0000000000001629.
  121. 121.
    Castillo-Mancilla JR, Phillips AN, Neaton JD, Neuhaus J, Collins S, Mannheimer S, et al. Association of Suboptimal Antiretroviral Therapy Adherence With Inflammation in Virologically Suppressed Individuals Enrolled in the SMART Study. Open Forum Infect Dis. 2017 Dec 22;5(1):ofx275.  https://doi.org/10.1093/ofid/ofx275.

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jose R. Castillo-Mancilla
    • 1
  • Jessica E. Haberer
    • 2
  1. 1.Division of Infectious Diseases, Department of MedicineUniversity of Colorado Anschutz Medical Campus, Medicine/Infectious DiseasesAuroraUSA
  2. 2.Massachusetts General Hospital and Harvard Medical SchoolBostonUSA

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