Training rhesus macaques to take daily oral antiretroviral therapy for preclinical evaluation of HIV prevention and treatment strategies

English version

Autoři: Michele B. Daly ^aff001; April M. Clayton ^aff002; Susan Ruone ^aff001; James Mitchell ^aff001; Chuong Dinh ^aff001; Angela Holder ^aff001; Julian Jolly ^aff002; J. Gerardo García-Lerma ^aff001; James L. Weed ^aff002
Působiště autorů: Laboratory Branch, Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America ^aff001; Comparative Medicine Branch, Division of Scientific Resources, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America ^aff002
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0225146

Souhrn

Background

Macaque models of simian or simian/human immunodeficiency virus (SIV or SHIV) infection are critical for the evaluation of antiretroviral (ARV)-based HIV treatment and prevention strategies. However, modelling human oral ARV administration is logistically challenging and fraught by limited adherence. Here, we developed a protocol for administering daily oral doses of ARVs to macaques with a high rate of compliance.

Methods

Parameters of positive reinforcement training (PRT), behavioral responses and optimal drug delivery foods were defined in 7 male rhesus macaques (Macaca mulatta). Animals were trained to sit in a specified cage location prior to receiving ARVs, emtricitabine (FTC) and tenofovir alafenamide (TAF), in a blended food mixture, which was followed immediately with a juice chaser. Consistency of daily oral adherence was evaluated in 4 trained macaques receiving clinically equivalent doses of FTC and TAF (20 and 1.5 mg/kg, respectively) in a short-term (1 month) and an extended (6 month) trial. Adherence was monitored using medication diaries and by quantifying intracellular FTC-triphosphate (FTC-TP) and tenofovir-diphosphate (TFV-DP) concentrations in peripheral mononuclear blood cells (PBMCs).

Results

Trained macaques quickly and consistently took daily oral ARVs for 1 month with an average 99.8% observed adherence. Intracellular concentrations of TFV-DP (median = 845.8 fmol/million cells [range, 620.8–1031.3]) and FTC-TP (median = 367.0 fmol/million cells [range, 289.5–413.5) in PBMCs were consistent with high adherence. Extended treatment with select subjects yielded similar observations for three months (99.5% adherence, 352/356 complete doses taken), although a sudden drop in adherence was observed after splenic biopsy surgery.

Conclusions

We demonstrate that trained macaques reliably adhere to a daily oral ARV regimen, although unexpected adherence issues are possible. Our approach, using clinical doses of oral FTC and TAF daily, further refines macaque models of HIV treatment and prevention by mimicking the human route and timing of ARV administration.

Klíčová slova:

Taste – Drug administration – Macaque – Rhesus monkeys – Biopsy – Drug delivery – Oral administration

Zdroje

1. UNAIDS. Global HIV & AIDS statistics—2018 fact sheet 2018 [cited 2019 March 11]. http://www.unaids.org/en/resources/fact-sheet.

2. Del Prete GQ, Lifson JD. Nonhuman Primate Models for Studies of AIDS Virus Persistence During Suppressive Combination Antiretroviral Therapy. Curr Top Microbiol Immunol. 2018;417:69–109. doi: 10.1007/82_2017_73 29026923.

3. Weiss HA, Wasserheit JN, Barnabas RV, Hayes RJ, Abu-Raddad LJ. Persisting with prevention: the importance of adherence for HIV prevention. Emerg Themes Epidemiol. 2008;5:8. Epub 2008/07/11. doi: 10.1186/1742-7622-5-8 18620578.

4. Otten RA, Adams DR, Kim CN, Jackson E, Pullium JK, Lee K, et al. Multiple vaginal exposures to low doses of R5 simian-human immunodeficiency virus: strategy to study HIV preclinical interventions in nonhuman primates. J Infect Dis. 2005;19:164–73.

5. Subbarao S, Otten RA, Ramos A, Kim C, Jackson E, Monsour M, et al. Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in macaques given multiple virus challenges. J Infect Dis. 2006;194:904–11. doi: 10.1086/507306 16960777

6. Makarova N, Henning T, Taylor A, Dinh C, Lipscomb J, Aubert R, et al. Topical tenofovir protects against vaginal simian HIV infection in macaques coinfected with Chlamydia trachomatis and Trichomonas vaginalis. AIDS. 2017;31(6):745–52. doi: 10.1097/QAD.0000000000001389 28060011.

7. Radzio J, Henning T, Jenkins L, Ellis S, Farshy C, Phillips C, et al. Combination emtricitabine and tenofovir disoproxil fumarate prevents vaginal Simian/Human Immunodeficiency virus infection in macaques harboring Chlamydia trachomatis and Trichomonas vaginalis. J Infect Dis. 2016;213:1541–5. doi: 10.1093/infdis/jiw002 26743846

8. García-Lerma JG, Otten RA, Qari SH, Jackson E, Cong M, Masciotra S, et al. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med. 2008;5:e28. doi: 10.1371/journal.pmed.0050028 18254653

9. Massud I, Mitchell J, Babusis D, Deyounks F, Ray AS, Rooney JF, et al. Chemoprophylaxis with oral emtricitabine and tenofovir alafenamide combination protects macaques from rectal SHIV infection. J Infect Dis. 2016;Jul 27. [Epub ahead of print].

10. NIH. Drugs that fight HIV-1: A reference guide: The U.S. Department of Health and Human Services; 2016 [April 11, 2019]. https://aidsinfo.nih.gov/contentfiles/upload/HIV_Pill_Brochure.pdf.

11. Perlman J, Bloomsmith M, Whittaker M, McMillan J, Minier D, McCowan B. Implementing positive reinforcement animal training programs at primate laboratories2012. 114–26 p.

12. Gibaldi M. Biopharmaceutics and Clinical Pharmacokinetics. 3rd Edition. ed. Philadelphia: Lea & Febiger; 1984.

13. Van Rompay KK, Berardi CJ, Aguirre NL, Bischofberger N, Lietman PS, Pedersen NC, et al. Two doses of PMPA protect newborn macaques against oral simian immunodeficiency virus infection. AIDS. 1998;12:F79–83. doi: 10.1097/00002030-199809000-00001 9662190

14. García-Lerma JG, Cong M, Mitchell J, Youngpairoj AS, Martin A, Hanson D, et al. Prevention of Rectal SHIV Transmission in Macaques by Intermittent Pre-Exposure Prophylaxis (iPrEP) with Oral Truvada. 16th Conference on Retroviruses and Opportunistic Infections. 2009;(Abstract 47).

15. Van Rompay KK, Kearney BP, Sexton JJ, Colón R, Lawson JR, Blackwood EJ, et al. Evaluation of oral tenofovir disoproxil fumarate and topical tenofovir GS-7340 to protect infant macaques against repeated oral challenges with virulent simian immunodeficiency virus. J Acquir Immune Defic Syndr. 2006;43:6–14. doi: 10.1097/01.qai.0000224972.60339.7c 16810108

16. Van Rompay KK, Babusis D, Abbott Z, Geng Y, Jayashankar K, Johnson JA, et al. Compared to subcutaneous tenofovir, oral tenofovir disoproxyl fumarate administration preferentially concentrates the drug into gut-associated lymphoid cells in simian immunodeficiency virus-infected macaques. Antimicrobial agents and chemotherapy. 2012;56(9):4980–4. doi: 10.1128/AAC.01095-12 22777046.

17. Gaalema DE, Perdue BM, Kelling AS. Food preference, keeper ratings, and reinforcer effectiveness in exotic animals: the value of systematic testing. J Appl Anim Welf Sci. 2011;14(1):33–41. doi: 10.1080/10888705.2011.527602 21191846.

18. Martin AL, Franklin AN, Perlman JE, Bloomsmith MA. Systematic assessment of food item preference and reinforcer effectiveness: Enhancements in training laboratory-housed rhesus macaques. Behav Processes. 2018;157:445–52. Epub 2018/07/14. doi: 10.1016/j.beproc.2018.07.002 30003936.

19. Hopper LM, Egelkamp CL, Fidino M, Ross SR. An assessment of touchscreens for testing primate food preferences and valuations. Behav Res Methods. 2019;51(2):639–50. Epub 2018/06/28. doi: 10.3758/s13428-018-1065-0 29949070.

20. Mueller MM, Piazza CC, Patel MR, Kelley ME, Pruett A. Increasing variety of foods consumed by blending nonpreferred foods into preferred foods. J Appl Behav Anal. 2004;37(2):159–70. Epub 2004/08/06. doi: 10.1901/jaba.2004.37-159 15293635.

21. Vaz PC, Piazza CC, Stewart V, Volkert VM, Groff RA, Patel MR. Using a chaser to decrease packing in children with feeding disorders. J Appl Behav Anal. 2012;45(1):97–105. Epub 2012/03/10. doi: 10.1901/jaba.2012.45-97 22403452.

22. I.P. P. Conditioned Reflexes. Oxford University Press; 1927. p. 380–3.

23. McMillan JL, Perlman JE, Galvan A, Wichmann T, Bloomsmith MA. Refining the pole-and-collar method of restraint: emphasizing the use of positive training techniques with rhesus macaques (Macaca mulatta). J Am Assoc Lab Anim Sci. 2014;53(1):61–8. 24411781.

24. Ramirez K. Animal Training: Successful Animal Management Through Positive Reinforcement. Chicago: John G. Shedd Aquarium; 1999. p. pp.533–54.

25. Laule GE, Bloomsmith MA, Schapiro SJ. The Use of Positive Reinforcement Training Techniques to Enhance the Care, Management, and Welfare of Primates in the Laboratory. Journal of Applied Animal Welfare Science. 2003;6(3):163–73. doi: 10.1207/S15327604JAWS0603_02 14612265

26. Egger MD, Miller NE. When is a reward reinforcing? An experimental study of the information hypothesis. J J Comp Physiol Psychol. 1963;56(1):132.

27. García-Lerma JG, Aung W, Cong ME, Zheng Q, Youngpairoj AS, Mitchell J, et al. Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide HIV reverse transcriptase inhibitors. J Virol. 2011;85::6610–7. doi: 10.1128/JVI.00311-11 21525346

28. Kuklenyik Z, Martin A, Pau C, Holder A, Youngpairoj AS, Zheng Q, et al. On-line coupling of anion exchange and ion pair chromatography for measurement of intracellular triphosphate metabolites of reverse transcriptase inhibitors. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877:3659–66. doi: 10.1016/j.jchromb.2009.09.007

29. Del Prete GQ, Smedley J, Macallister R, Jones GS, Li B, Hattersley J, et al. Short Communication: Comparative Evaluation of Coformulated Injectable Combination Antiretroviral Therapy Regimens in Simian Immunodeficiency Virus-Infected Rhesus Macaques. AIDS Res Hum Retroviruses. 2016;32(2):163–8. Epub 2015/09/09. doi: 10.1089/AID.2015.0130 26150024.

30. Emtriva [package insert], Gilead Sciences Inc., Foster City CA. 2012.

31. Reinhardt V. Working with rather than against macaques during blood collection. J Appl Anim Welf Sci. 2003;6(3):189–97. doi: 10.1207/S15327604JAWS0603_04 14612267.