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Tenofovir Rectal Douche Provides Protective Drug Levels in
MSM Colon Tissue - on-demand, behaviorally-congruent
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HIV Research for Prevention (HIVR4P), October 21-25, 2018, Madrid
Mark Mascolini
A rectal douche delivering tenofovir proved safe and acceptable in the DREAM-01 study of 18 men who have sex with men (MSM) [1]. Median colon cell levels of tenofovir-diphosphate (TFV-DP), the active form of tenofovir, reached concentrations well above those linked to greater than 90% efficacy. But cumulative systemic tenofovir exposure lay below that seen with oral dosing.
DREAM-01 researchers suggested that a single presex dose of tenofovir as a rectal douche could (1) avoid systemic toxicities, (2) match the anatomical site of people practicing anal sex, and (3) be available as needed. They conducted this study to determine whether a tenofovir douche is safe and acceptable, achieves protective drug levels quickly, and suppresses HIV in ex vivo (outside-the-body) tests. A survey of 4751 potential users determined that 94% of those not currently douching would definitely or probably try a microbicide douche, while 98% of those currently douching would definitely or probably use the strategy.
DREAM-01 was a phase 1 single ascending dose study aiming to provide a within-person comparison of the safety, acceptability, and pharmacokinetics of 3 tenofovir rectal douche formulations. All participants gave blood, rectal tissue, and rectal fluid samples at multiple points before and during dosing. The trial enrolled 18 healthy HIV-negative MSM in Baltimore, Pittsburgh, and Los Angeles. They used single douches at 3 different tenofovir doses 1 month apart: Product A: 220 mg, 0.9 NS osmolarity (solution concentration); Product B: 660 mg, 0.9 NS osmolarity; and Product C: 660 mg, 0.45 NS osmolarity. The researchers used ex vivo explants (colorectal biopsies) to test douche ability to inhibit HIV.
Only 2 adverse events could be attributed to the tenofovir douche--blood-tinged mucous in enema effluent and rectal dryness after douche administration. Scores for colon epithelial denudation and lamina propria hemorrhage were similar before and after dosing with all 3 douche doses.
All participants stated they were likely or very likely to use Product A or B before rectal sex if it protected against HIV; 90% said they were likely or very likely to use Product C. On a scale of 0 to 5, acceptability ratings for the 3 formulations ranged from 3.92 to 4.08.
SPECT/CT imaging showed luminal distribution of radiolabeled tenofovir reaching the splenic flexure of the colon (first big bend at top of colon) 1 hour after dosing in most participants. Plasma tenofovir concentrations were significantly lower with the douche than with directly observed oral dosing in the HPTN 066 trial.
Rectal tenofovir concentrations after a single dose in DREAM-01 proved comparable to concentrations achieved after 7 consecutive dosing days with a rectal gel in previous trials. From 1 to 24 hours after dosing, median colon cell TFV-DP concentrations exceeded target inhibitory concentrations by 1.3 log10 for Product A, 2.4 log10 for Product B, and 5.0 log10 for Product C. (A 1.3-log difference is about 20-fold; a 5-log difference is 100,000-fold.) Compared with predosing measures, colon biopsies collected 1 to 24 hours after dosing reduced HIV replication 1 to 2 log10 (10- to 100-fold) in colon tissue explants. Anti-HIV activity increased with increasing TFV-DP concentrations.
DREAM-01 investigators believe their findings support further clinical development of the tenofovir rectal douche for HIV prevention.
Reference
1. Weld E, Fuchs E, Marzinke M, et al. Tenofovir douche for PrEP: on-demand, behaviorally-congruent douche rapidly achieves colon tissue concentration targets (DREAM 01 study). HIV Research for Prevention (HIVR4P), October 21-25, 2018, Madrid. Abstract OA20.03.
WEBCAST: http://webcasts.hivr4p.org/console/player/40469?mediaType=slideVideo&&crd_fl=1&ssmsrq=1541350998175&ctms=5000&csmsrq=1160
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