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


BACKGROUND
ClinicalTrials.gov NCT01575405.
University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Magee-Womens Research Institute, Pittsburgh, Pennsylvania, United States of America.
Ian
I
Mcgowan
University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Ross D
RD
Cranston
Magee-Womens Research Institute, Pittsburgh, Pennsylvania, United States of America.
Kathryn
K
Duffill
Magee-Womens Research Institute, Pittsburgh, Pennsylvania, United States of America.
Aaron
A
Siegel
Magee-Womens Research Institute, Pittsburgh, Pennsylvania, United States of America.
Jarret C
JC
Engstrom
Magee-Womens Research Institute, Pittsburgh, Pennsylvania, United States of America.
Alexyi
A
Nikiforov
Magee-Womens Research Institute, Pittsburgh, Pennsylvania, United States of America.
Cindy
C
Jacobson
Magee-Womens Research Institute, Pittsburgh, Pennsylvania, United States of America.
Khaja K
KK
Rehman
David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States of America.
Julie
J
Elliott
David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States of America.
Elena
E
Khanukhova
University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Kaleab
K
Abebe
CONRAD, Arlington, Virginia, United States of America.
Christine
C
Mauck
HJF-DAIDS, a Division of The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Contractor to National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, United States of America.
Hans M L
HM
Spiegel
University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Magee-Womens Research Institute, Pittsburgh, Pennsylvania, United States of America.
Charlene S
CS
Dezzutti
University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Magee-Womens Research Institute, Pittsburgh, Pennsylvania, United States of America.
Lisa C
LC
Rohan
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
Mark A
MA
Marzinke
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
Hiwot
H
Hiruy
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
Craig W
CW
Hendrix
Alpha StatConsult LLC, Damascus, Maryland, United States of America.
Nicola
N
Richardson-Harman
David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, United States of America.
Peter A
PA
Anton
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D005260:Female; D005782:Gels; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D006801:Humans; D016130:Immunophenotyping; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008297:Male; D055118:Medication Adherence; D064307:Microbiota; D008875:Middle Aged; D010641:Phenotype; D012007:Rectum / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000068698:Tenofovir / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D016896:Treatment Outcome; D055815:Young Adult
D019380:Anti-HIV Agents; D000891:Anti-Infective Agents, Local; D005782:Gels; D000068698:Tenofovir