Peter Anton from the University of California presented late breaker results from a phase 1 study of rectal use of the tenofovir gel used in the Caprisa 004 study.1
HIV-negative participants (14 men and four women) received sequentially a single oral dose of tenofovir, single rectal dose of tenofovir gel or placebo, and seven days rectal dosing, also randomised, each separated by a two week wash out and sampling period. The study measured efficacy by ex vivo infectibility of in vivo exposed cells from rectal biopsies, and monitored plasma drug concentrations in multiple compartments and general product acceptability.
Primary endpoint was safety defined by grade >/= 2 events and secondary safety by a large panel tests relating to mucosal injury that were developed for an earlier HPTN 056 rectal microbicide study.
Most side effects were grade 1 and occurred during the seven-day rectal use, more frequently with the active gel (12 vs 2 people, p=0.001; 37 vs 6 events, p=0.002) were gastrointestinal (GI). However, two people reported five grade 3 GI events. The only differences seen between groups in the panel of mucosal indices were decrease in two cytokines (IL1-beta and TNF-alpha) only seen at 30 minutes post dosing after the seven-day exposure.
Neither gel was particularly liked (25% tenofovir, 50% placebo) but approximately 75% in each group said they would use it if it proved to be effective.
As expected, plasma dosing achieved significantly higher levels (approximately 2 logs higher) in plasma compared to tissue, with rectal dosing not accumulating tenofovir levels in plasma.
Importantly, active drug levels of tenofovir diphosphate, 30 minutes post dosing with single rectal dose were >100-fold higher in rectal tissue compared to oral dose, achieved in 80% of samples, and were five times higher following the 7 day dosing.
Rectal biopies taken 30 minutes post dose were infectible at baseline. Single oral dose showed no effect and single rectal dose showed a trend to an effect but after 7 day rectal dosing the tenofovir exposed cells showed significantly greater resistance to infection.
This allows the first analysis to show a strong positive correlation between tenofovir DP drug level following in vivo exposure and HIV inhibition (r2=0.33, p=0.0011).
While the study concluded that although the acceptability of the gel was lower, the gel was safe in terms of tissue exposure, and topical application achieved tissue concentrations of tenofovir diphosphate that demonstrated ex vivo protection from infection.
Oral Tenofovir vs. Daily Gel vs. Both
Craig Hendrix from Johns Hopkins University, Baltimore, and colleagues presented results from an open-label phase 2 study of daily oral tenofovir, daily gel and dual oral/gel in 144 sexually active HIV-negative women (aged 18-45) at four US and three African sites. This was a three-stage cross over study with each stage lasting six weeks separated by one week washout.2
The study looked at safety, adherence, acceptability and pharmacokinetics.
The gel resulted in levels of tenofovir diphosphate that were 100-fold higher in vaginal tissues compared to oral dosing, and dual dosing made no additional impact on tissue concentrations.
Although excellent adherence was reported (>90% all doses reported as taken; and >80% people taking >90% of doses) the drugs levels observed at any time point in the pharmacokinetic study showed that 35-65% of the people in all groups had drug levels below the 99% confidence interval from historical reference cohorts.
No differences in side effects overall were seen between the three regimens, though nausea, diarrhoea and headache were more common during the oral and dual stages (all <15%). Vaginal symptoms and reduced phosphates (general transient) were similar between stages. Nine cases of grade 3/4 hypophosphatemia occurred in 4 oral, 2 gel and 3 dual participants.
The presentation noted that although active concentration in the target site were good from the gel, and not increased by additional oral dosing, the optimum dose required for efficacy is not known and this is an important point.