A Phase 1 Randomized, Open Label, Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Three Formulations of Tenofovir 1% Gel (the CHARM-01 Study)

Ian Mcgowan, Ross D Cranston, Kathryn Duffill, Aaron Siegel, Jarret C Engstrom, Alexyi Nikiforov, Cindy Jacobson, Khaja K Rehman, Julie Elliott, Elena Khanukhova, Kaleab Abebe, Christine Mauck, Hans M L Spiegel, Charlene S Dezzutti, Lisa C Rohan, Mark A Marzinke, Hiwot Hiruy, Craig W Hendrix, Nicola Richardson-Harman, Peter A Anton, Ian Mcgowan, Ross D Cranston, Kathryn Duffill, Aaron Siegel, Jarret C Engstrom, Alexyi Nikiforov, Cindy Jacobson, Khaja K Rehman, Julie Elliott, Elena Khanukhova, Kaleab Abebe, Christine Mauck, Hans M L Spiegel, Charlene S Dezzutti, Lisa C Rohan, Mark A Marzinke, Hiwot Hiruy, Craig W Hendrix, Nicola Richardson-Harman, Peter A Anton

Abstract

Objectives: The CHARM-01 study characterized the safety, acceptability, pharmacokinetics (PK), and pharmacodynamics (PD) of three tenofovir (TFV) gels for rectal application. The vaginal formulation (VF) gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials and the RMP-02/MTN-006 Phase 1 rectal safety study. The reduced glycerin VF (RGVF) gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. A third rectal specific formulation (RF) gel was also evaluated in the CHARM-01 study.

Methods: Participants received 4 mL of the three TFV gels in a blinded, crossover design: seven daily doses of RGVF, seven daily doses of RF, and six daily doses of placebo followed by one dose of VF, in a randomized sequence. Safety, acceptability, compartmental PK, and explant PD were monitored throughout the trial.

Results: All three gels were found to be safe and acceptable. RF and RGVF PK were not significantly different. Median mucosal mononuclear cell (MMC) TFV-DP trended toward higher values for RF compared to RGVF (1136 and 320 fmol/106 cells respectively). Use of each gel in vivo was associated with significant inhibition of ex vivo colorectal tissue HIV infection. There was also a significant negative correlation between the tissue levels of TFV, tissue TFV-DP, MMC TFV-DP, rectal fluid TFV, and explant HIV-1 infection.

Conclusions: All three formulations were found to be safe and acceptable. However, the safety profile of the VF gel was only based on exposure to one dose whereas participants received seven doses of the RGVF and RF gels. There was a trend towards higher tissue MMC levels of TFV-DP associated with use of the RF gel. Use of all gels was associated with significant inhibition of ex vivo tissue HIV infection.

Trial registration: ClinicalTrials.gov NCT01575405.

Conflict of interest statement

Competing Interests: This analysis was supported by a subcontract with Advanced BioScience Laboratories, Inc., Rockville, MD, and its subcontractor, Alpha StatConsult, LLC, through an NIH/NIAID/DAIDS contract: ''Comprehensive Resources for HIV Microbicides and Biomedical Prevention'' (#HHSN272201000001C). Co-author Nicola Richardson-Harman is employed by Alpha StatConsult, LLC. Co-author C. Hendrix has had research support from Gilead Sciences from 05/01/09-04/30/10. The contract was managed by the Johns Hopkins School of Medicine. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Fig 1. CHARM-01 study design.
Fig 1. CHARM-01 study design.
Fig 2. Flow diagram of participant progress…
Fig 2. Flow diagram of participant progress through the CHARM-01 study.
Fig 3. PK/PD relationship between rectal tissue…
Fig 3. PK/PD relationship between rectal tissue TFV and colorectal tissue supernatant HIV-1 p24 after use of the VF TFV gel, the RGVF TFV gel, and the RF TFV gel.
The black line represents PK/PD relationship for the entire data set across all three formulations.

References

    1. McGowan I, Dezzutti C. Rectal Microbicide Development. Curr Top Microbiol Immunol 2013. April 24.
    1. Beyrer C, Abdool KQ. The changing epidemiology of HIV in 2013. Curr Opin HIV AIDS 2013. July;8(4):306–10. 10.1097/COH.0b013e328361f53a
    1. Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med 2015. February 5;372(6):509–18. 10.1056/NEJMoa1402269
    1. Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med 2012. August 2;367(5):411–22. 10.1056/NEJMoa1202614
    1. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010. December 30;363(27):2587–99. 10.1056/NEJMoa1011205
    1. Abdool KQ, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010. September 3;329(5996):1168–74. 10.1126/science.1193748
    1. Anton PA, Cranston RD, Kashuba A, Hendrix C, Bumpus NN, Richardson-Harman N, et al. RMP-02/MTN-006: A Phase 1 rectal safety, acceptability, pharmacokinetic and pharmacodynamic study of tenofovir 1% gel compared to oral tenofovir disoproxil fumarate. AIDS Res Hum Retroviruses 2012. September 3;11:1412–21. 10.1089/AID.2012.0262
    1. Rohan LC, Moncla BJ, Kunjara Na Ayudhya RP, Cost M, Huang Y, Gai F, et al. In vitro and ex vivo testing of tenofovir shows it is effective as an HIV-1 microbicide. PLoS ONE 2010;5(2):e9310 10.1371/journal.pone.0009310
    1. Dezzutti CS, Rohan LC, Wang L, Uranker K, Shetler C, Cost M, et al. Reformulated tenofovir gel for use as a dual compartment microbicide. J Antimicrob Chemother 2012. May 11;67(9):2139–42. 10.1093/jac/dks173
    1. McGowan I, Hoesley C, Cranston RD, Andrew P, Janocko L, Dai JY, et al. A Phase 1 Randomized, Double Blind, Placebo Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel (MTN-007). PLoS ONE 2013;8(4):e60147 10.1371/journal.pone.0060147
    1. Dezzutti CS, Russo J, Wang L, Abebe KZ, Li J, Friend DR, et al. Development of HIV-1 rectal-specific microbicides and colonic tissue evaluation. PLoS ONE 2014;9(7):e102585 10.1371/journal.pone.0102585
    1. Anton PA, Saunders T, Elliott J, Khanukhova E, Dennis R, Adler A, et al. First Phase 1 double-blind, placebo-controlled, randomized rectal microbicide trial using UC781 gel with a novel index of ex vivo efficacy. PLoS ONE 2011;6(9):e23243 10.1371/journal.pone.0023243
    1. Moher D, Schulz KF, Altman D. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 2001. April 18;285(15):1987–91.
    1. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. PLoS Med 2010. March;7(3):e1000251 10.1371/journal.pmed.1000251
    1. Schwartz JL, Ballagh SA, Kwok C, Mauck CK, Weiner DH, Rencher WF, et al. Fourteen-day safety and acceptability study of the universal placebo gel. Contraception 2007. February;75(2):136–41.
    1. van der Straten A, Montgomery E, Pillay D, Cheng H, Naidoo A, Cele Z, et al. Feasibility, performance, and acceptability of the Wisebag for potential monitoring of daily gel applicator use in Durban, South Africa. AIDS Behav 2013. February;17(2):640–8. 10.1007/s10461-012-0330-y
    1. Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Lofberg R. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut 2000. September;47(3):404–9.
    1. McGowan I, Elliott J, Cortina G, Tanner K, Siboliban C, Adler A, et al. Characterization of baseline intestinal mucosal indices of injury and inflammation in men for use in rectal microbicide trials (HIV Prevention Trials Network-056). J Acquir Immune Defic Syndr 2007. December 1;46(4):417–25.
    1. Stoner KA, Rabe LK, Austin MN, Meyn LA, Hillier SL. Quantitative survival of aerobic and anaerobic microorganisms in Port-A-Cul and Copan transport systems. J Clin Microbiol 2008. August;46(8):2739–44. 10.1128/JCM.00161-08
    1. Rabe LK, Hillier SL. Optimization of media for detection of hydrogen peroxide production by Lactobacillus species. J Clin Microbiol 2003. July;41(7):3260–4.
    1. Hendrix CW, Chen BA, Guddera V, Hoesley C, Justman J, Nakabiito C, et al. MTN-001: randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments. PLoS ONE 2013;8(1):e55013 10.1371/journal.pone.0055013
    1. Bland JM, Altman DG. Calculating correlation coefficients with repeated observations: Part 1—Correlation within subjects. BMJ 1995. February 18;310(6977):446
    1. Nuttall J, Kashuba A, Wang R, White N, Allen P, Roberts J, et al. Pharmacokinetics of tenofovir following intravaginal and intrarectal administration of tenofovir gel to rhesus macaques. Antimicrob Agents Chemother 2012. January;56(1):103–9. 10.1128/AAC.00597-11
    1. Severy L, Newcomer S. Critical issues in contraceptive and STI acceptability research. Journal of Social Issues 2005;61(1):45–65.
    1. Hunt PW, Shulman N, Hayes TL, Dahl V, Somsouk M, Funderburg NT, et al. The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T cell recovery: a randomized trial. Blood 2013. April 15;121(23):4635–46. 10.1182/blood-2012-06-436345
    1. Doleans-Jordheim A, Bergeron E, Bereyziat F, Ben-Larbi S, Dumitrescu O, Mazoyer MA, et al. Zidovudine (AZT) has a bactericidal effect on enterobacteria and induces genetic modifications in resistant strains. Eur J Clin Microbiol Infect Dis 2011. October;30(10):1249–56. 10.1007/s10096-011-1220-3
    1. Faith JJ, Guruge JL, Charbonneau M, Subramanian S, Seedorf H, Goodman AL, et al. The long-term stability of the human gut microbiota. Science 2013. July 5;341(6141):1237439 10.1126/science.1237439
    1. Richardson-Harman N, Hendrix CW, Bumpus NN, Mauck C, Cranston RD, Yang K, et al. Correlation between Compartmental Tenofovir Concentrations and an Ex Vivo Rectal Biopsy Model of Tissue Infectibility in the RMP-02/MTN-006 Phase 1 Study. PLoS ONE 2014;9(10):e111507 10.1371/journal.pone.0111507
    1. Louissaint NA, Cao YJ, Skipper PL, Liberman RG, Tannenbaum SR, Nimmagadda S, et al. Single Dose Pharmacokinetics of Oral Tenofovir in Plasma, Peripheral Blood Mononuclear Cells, Colonic Tissue, and Vaginal Tissue. AIDS Res Hum Retroviruses 2013. May 29;29(11):1443–50. 10.1089/AID.2013.0044
    1. Dezzutti CS, Hladik F. Use of human mucosal tissue to study HIV-1 pathogenesis and evaluate HIV-1 prevention modalities. Curr HIV/AIDS Rep 2013. March;10(1):12–20. 10.1007/s11904-012-0148-2
    1. Richardson-Harman N, Mauck C, McGowan I, Anton P. Dose response relationship between tissue concentrations of UC781 and explant infectibility with HIV-1 in the RMP-01 rectal safety study. AIDS Res Hum Retroviruses 2012. August 18;28(11):1422–33. 10.1089/AID.2012.0073
    1. Herbst JH, Jacobs ED, Finlayson TJ, McKleroy VS, Neumann MS, Crepaz N. Estimating HIV prevalence and risk behaviors of transgender persons in the United States: a systematic review. AIDS Behav 2008. January;12(1):1–17.

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