Paper # 34LB|
RMP-02/MTN-006: A Phase 1 Placebo-controlled Trial of Rectally Applied 1% Vaginal TFV Gel with Comparison to Oral TDF
Peter Anton*1, R Cranston2, A Carballo-Dieguez3, A Kashuba4, E Khanukhova1, J Elliott1, L Janocko5,6, W Cumberland7, C Mauck8, and I McGowan5,6
1David Geffen Sch of Med, Univ of California, Los Angeles, US; 2Univ of Pittsburgh, PA, US; 3Columbia Univ, New York, NY, US; 4Univ of North Carolina at Chapel Hill Sch of Pharmacy, Ctr for AIDS Res, US; 5Magee-Womens Res Inst, Univ of Pittsburgh, PA, US; 6Microbicides Trials Network, Pittsburgh, PA, US; 7Univ of California, Los Angeles Sch of Publ Hlth, US; and 8CONRAD, Arlington, VA, US
Background:† Both Truvada and topical 1% vaginal
tenofovir (TFV) have been shown to prevent HIV-1 infection. Here we assess the
safety, acceptability, and pharmacokinetics of oral tenofovir (TDF) and rectal
application of 1% vaginal TFV gel as well as their efficacy in suppressing ex
vivo HIV infection of rectal biopsies.
Methods:† We enrolled 18 healthy subjects at 2 sites
(14 men, 4 women; median age 44) who sequentially received:† a single dose of
TDF (300 mg) (O), a single rectal dose (R) randomized to TFV or placebo (2:1
ratio), and 7 daysí rectal dosing (R7), also randomized. General and mucosal
safety was monitored throughout. Product acceptability was assessed after R7. Ex
vivo rectal biopsy infectibility and plasma drug concentrations were
measured at 5 time points after O and R and once after R7.
Results:† All enrolled subjects completed the trial.
No differences in grade 1 or 2 adverse events were seen between treatment arms.
In 3 subjects, 8 grade 3 adverse events were reported; 6 of 8 events occurred
during R7 in 2 subjects (TFV gel arm). No significant changes were seen in
mucosal safety parameters except for decreases in tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1)
secretion post R7 (TFV gel arm). Only 25% of subjects receiving TFV liked the
gel vs 50% using placebo although 75% (TVF) and 67% (placebo) reported high
likelihood of future use. Plasma TFV Cmax and AUC were 23- and
30-fold higher during O (Cmax at 2 hours) vs R (Cmax at
0.5 hour; C24h was detectable in 50%). Plasma TFV Cmax
was 25% lower and AUC 40% higher with R7 vs R (R7 Cmax was 8 ng/mL
at 0.5 hour; C24h was detected in 50% of subjects). No significant
HIV suppression was seen following O. A non-significant decline of p24 at 0.5
hour was seen with R (p = 0.12; effect size = 0.49). R7 showed
significant suppression of infection from baseline (p = 0.02 effect size
Conclusions:† Rectal dosing with the vaginal
formulation of 1% TFV was neither entirely safe nor fully acceptable,
indicating the need for development of a rectal-specific formulation of TFV in
future rectal microbicide studies. That 7-day rectal TFV use resulted in very
significant inhibition of ex vivo HIV infection increases the likelihood
that a rectal-specific formulation of TFV might inhibit rectal acquisition of
HIV in vivo. In contrast, neither single oral (TDF) nor rectal (TFV)
dosing significantly inhibited biopsy infection, suggesting a single pericoital
use of these might not be an effective prevention strategy in reducing HIV
transmission during anal intercourse.