AIDS and Behavior

, Volume 17, Issue 1, pp 298–306 | Cite as

Oral Adherence Monitoring Using a Breath Test to Supplement Highly Active Antiretroviral Therapy

  • Timothy E. Morey
  • Matthew Booth
  • Scott Wasdo
  • Judith Wishin
  • Brian Quinn
  • Daniel Gonzalez
  • Hartmut Derendorf
  • Susan P. McGorray
  • Jane Simoni
  • Richard J. Melker
  • Donn M. Dennis
Original Paper


A breath-based adherence system to document ingestion of oral medications (e.g., HAART) was investigated. Specifically, the food additive 2-butanol, which can be easily packaged with a drug, is converted via alcohol dehydrogenase to the volatile metabolite 2-butanone that rapidly appears in breath, indicating adherence. In healthy adults using a portable sensor and GC–MS, the following experiments were performed: yield of 2-butanone in breath following ingestion of 2-butanol, adherence system accuracy, and potential interference of the adherence system by food or misplacement of 2-butanol on the tongue. During feasibility testing, every subject exhaled 2-butanone with 6.6 ± 1.5 min to peak concentrations of 548 ± 235 ppb following ingestion of 2-butanol (40 mg). ROC areas at 5 and 10 min were 0.95 (0.86–1.00) and 1.00 (1.00–1.00). Food did not interfere. Tongue application resulted in large concentrations of 2-butanol, but not 2-butanone. A breath test to provide definitive evidence of oral medication adherence appears technically feasible.


Adherence Antiretroviral therapy Behavioral interventions Prevention of sexual transmission Sexual behavior 


Un sistema de la adherencia basada en el aliento, para documentar la ingestión de medicamentos por vía oral (por ejemplo, HAART), se investigo. Específicamente el aditivo alimentario 2-butanol, el cual puede ser fácilmente empaquetado con un fármaco, se convierte mediante el alcohol deshidrogenasa en el metabolito volátil 2-butanona que rápidamente aparece en la respiración, indicando la adherencia. En adultos sanos utilizando un sensor portátil y GC–MS, los siguientes experimentos se llevaron a cabo: rendimiento de 2-butanona en el aliento tras la ingestión de 2-butanol, la precisión del sistema de adherencia, y la interferencia potencial del sistema de adherencia por medio de la comida o extravió de 2-butanol en la lengua. Durante los ensayos de viabilidad, cada sujeto exhaló 2-butanona con 6.6 ± 1.5 min a concentraciones máximas de 548 ± 235 ppb tras la ingestión de 2-butanol (40 mg). Áreas ROC a 5 y 10 minutos fueron de 0.95 (0.86–1.00) y 1.00 (1.00–1.00). La comida no interfiere. La aplicación en la lengua dió por resultado altas concentraciones de 2-butanol, pero no la 2-butanona. Una prueba de aliento para proporcionar evidencia definitiva de la adherencia a los medicamentos oral parece técnicamente factible.



The project described was supported by Award Number R44MH081767 (“A Breath-based Medication Adherence Monitoring System for HIV/AIDS Therapies”) from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health. This work was also supported by Xhale, Inc. (Gainesville, FL, USA), the Department of Anesthesiology, University of Florida College of Medicine (Gainesville, FL, USA), and the Joachim S. Gravenstein, M.D. Professorship in Anesthesiology. Drs. Melker and Dennis are employees of Xhale, Inc., the company that sponsored the study. Drs. Morey and Derendorf are consultants for Xhale, Inc. Drs. Melker, Dennis, and Morey also own equity in Xhale, Inc. In addition, the University of Florida owns equity in Xhale, Inc.If a device is sold commercially, then the authors listed above and the University of Florida could benefit financially. For the remaining authors and institutions, no conflict is declared.


  1. 1.
    Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363:2587–99.PubMedCrossRefGoogle Scholar
  2. 2.
    Guidance Interim. Preexposure prophylaxis for the prevention of HIV infection in men who have sex with men. MMWR Morb Mortal Wkly Rep. 2011;60:65–8.Google Scholar
  3. 3.
    Hogg RS, Heath K, Bangsberg D, et al. Intermittent use of triple-combination therapy is predictive of mortality at baseline and after 1 year of follow-up. AIDS. 2002;16:1051–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Nachega JB, Leisegang R, Bishai D, et al. Association of antiretroviral therapy adherence and health care costs. Ann Intern Med. 2010;152:18–25.PubMedGoogle Scholar
  5. 5.
    Gardner EM, Hullsiek KH, Telzak EE, et al. Antiretroviral medication adherence and class-specific resistance in a large prospective clinical trial. AIDS. 2010;24:395–403.PubMedCrossRefGoogle Scholar
  6. 6.
    Morey T, Booth MM, Prather RA, et al. Measurement of ethanol in gaseous breath using a miniature gas chromatograph. J Anal Toxicol. 2011;35:134–42.PubMedCrossRefGoogle Scholar
  7. 7.
    Leffingwell, JC. GRAS chemicals in food; PPM Report: Flavor-Base. 2007.Google Scholar
  8. 8.
    Morey TE, Wasdo S, Wishin J, et al. Feasibility of a breath test for monitoring adherence to vaginal administration of anti-retroviral microbicide gels. J Clin Pharmacol. 2012 (in press).Google Scholar
  9. 9.
    Little TJ, Horowitz M, Feinle-Bisset C. Modulation by high-fat diets of gastrointestinal function and hormones associated with the regulation of energy intake: implications for the pathophysiology of obesity. Am J Clin Nutr. 2007;86:531–41.PubMedGoogle Scholar
  10. 10.
    Jones AW. Pharmacokinetics of ethanol: issues of forensic importance. Forensic Sci Rev. 2011;23:91–136.Google Scholar
  11. 11.
    Lieber CS. ALCOHOL: its metabolism and interaction with nutrients. Annu Rev Nutr. 2000;20:395–430.PubMedCrossRefGoogle Scholar
  12. 12.
    Stone CL, Li TK, Bosron WF. Stereospecific oxidation of secondary alcohols by human alcohol dehydrogenases. J Biol Chem. 1989;264:11112–6.PubMedGoogle Scholar
  13. 13.
    Yin SJ, Bosron WF, Magnes LJ, et al. Human liver alcohol dehydrogenase: purification and kinetic characterization of the beta 2 beta 2, beta 2 beta 1, alpha beta 2, and beta 2 gamma 1 “Oriental” isoenzymes. Biochemistry. 1984;23:5847–53.PubMedCrossRefGoogle Scholar
  14. 14.
    Duester G, Smith M, Bilanchone V, et al. Molecular analysis of the human class I alcohol dehydrogenase gene family and nucleotide sequence of the gene encoding the beta subunit. J Biol Chem. 1986;261:2027–33.PubMedGoogle Scholar
  15. 15.
    Reddy B, Reddy A, Nagaraja T, et al. Single nucleotide polymorphisms of the alcohol dehydrogenase genes among the 28 caste and tribal populations of India. Int J Human Genet. 2006;6:309–16.Google Scholar
  16. 16.
    Bosron WF, Magnes LJ, Li TK. Human liver alcohol dehydrogenase: ADH Indianapolis results from genetic polymorphism at the ADH2 gene locus. Biochem Genet. 1983;21:735–44.PubMedCrossRefGoogle Scholar
  17. 17.
    Edenberg H, Bosron WF. Alcohol dehydrogenases, In: Guengerich F, editor. Comprehensive toxicology: Biotransformation, Vol. 3. New York: Pergamon Press; 1997. p. 119–31.Google Scholar
  18. 18.
    Food and drug administration center for food safety and applied nutrition. Everything added to food in the United States (EAFUS). Accessed 28 Sep 2011.
  19. 19.
    Food and drug administration center for drug evaluation and research (CDER). Guidance for industry: Q3C—Tables and List.…/Guidances/ucm128282.pdf%20. Accessed 14 Dec 2011.
  20. 20.
    Food and drug administration. Q3c appendix 6 toxilogical data for class 3 solvents. Accessed 24 Sep 2011.
  21. 21.
    Food and drug administration center for drug evaluation and research. Inactive Ingredient search for approved drug products. Accessed 24 Sep 2011.
  22. 22.
    Food and Drug administration center for drug evaluation and research. Guidance for industry: Incorporation of physical-chemical identifiers into solid oral dosage form drug products for anticounterfeiting. Accessed 14 Dec 2011.
  23. 23.
    Herper, M. The truly staggering cost of inventing new drugs. Accessed 29 Aug 2012.
  24. 24.
    Grove A. Rethinking clinical trials. Science. 2011;333:1679.PubMedCrossRefGoogle Scholar
  25. 25.
    Choudhry NK, Avorn J, Glynn RJ, et al. Full coverage for preventive medications after myocardial infarction. N Engl J Med. 2011;365(22):2088–97.PubMedCrossRefGoogle Scholar
  26. 26.
    Au-Yeung KY, Moon GD, Robertson TL, et al. Early clinical experience with networked system for promoting patient self-management. Am J Manag Care. 2011;17:e277–87.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Timothy E. Morey
    • 1
  • Matthew Booth
    • 1
  • Scott Wasdo
    • 1
  • Judith Wishin
    • 1
  • Brian Quinn
    • 2
  • Daniel Gonzalez
    • 3
  • Hartmut Derendorf
    • 3
  • Susan P. McGorray
    • 4
  • Jane Simoni
    • 5
  • Richard J. Melker
    • 1
    • 2
  • Donn M. Dennis
    • 1
    • 2
    • 6
  1. 1.Department of AnesthesiologyUniversity of Florida College of MedicineGainesvilleUSA
  2. 2.Xhale, Inc.GainesvilleUSA
  3. 3.Department of PharmaceuticsUniversity of Florida College of PharmacyGainesvilleUSA
  4. 4.Department of BiostatisticsUniversity of Florida College of MedicineGainesvilleUSA
  5. 5.Department of PsychologyUniversity of WashingtonSeattleUSA
  6. 6.Departments of Pharmacology and Experimental Therapeutics, and PsychiatryUniversity of Florida College of MedicineGainesvilleUSA

Personalised recommendations