Disappointing tenofovir PrEP trials: maybe “adherence” is not to blame

Reports of modest success from two trials (2010) of tenofovir as pre-exposure prophylaxis against HIV (PrEP)– CAPRISA 004 (1) (topical gel/women) relative risk reduction (RRR) 39%; iPrEX (2) (oral tablet/MSM) RRR 44% – have inspired recent contributions to STI journal.  In particular, there have been attempts to model the possible impact on the epidemic of incorporating PrEP in the toolbox of interventions (STI 2011; 87: suppl. 1, see especially: http://sti.bmj.com/content/87/Suppl_1/A36.1.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9; http://sti.bmj.com/content/87/Suppl_1/A350.2.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9): also studies evaluating the potential acceptability of PrEP in various settings (see: http://sti.bmj.com/content/early/2012/09/25/sextrans-2012-050648.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9; http://sti.bmj.com/content/88/4/258.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9).

Further tenofovir PrEP trials have produced results that are puzzlingly varied, and, given the hopes placed in PrEP as a preventative tool, somewhat disappointing:  CDC TDF2 (3) (oral tablet/heterosexual partners of men/women of indeterminate HIV status) RRR 62%; Partner’s PrEP (4) (oral tablet/heterosexual partners of HIV+ men/women) RRR 75%FEM-PrEP (5) (oral tablet/women) discontinued for futility; VOICE (topical gel/women) discontinued for futility. This has prompted some reflection on the efficacy of large RCT of the kind, with the discussion focussing on the difficulties around adherence (http://sti.bmj.com/content/87/Suppl_1/A196.3.abstract?sid=778e710d-42a6-4de3-a7e3-b9cd3f22a57e).  Crucially, Hendrix discusses the problem of disentangling the drug-related factors from issues of adherence (http://sti.bmj.com/content/87/Suppl_1/A1.4.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9).

One complicating factor in assessing tenofovir PrEP trial results is the use of two “routes” – oral tablet and topical gel – likely to produce concentrations of the drug at different anatomical sites.  This issue has now been taken up in an important recent paper (Hendrix & Bumpus) reporting the results of Microbicide Trials Network (MTN) study 001 (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0055013).  In discussing pharmacokinetic issues, this paper also deals with the role of adherence as an explanatory variable in a way that casts an altogether fresh light on the issues Hendrix tackles in the above-cited paper (http://sti.bmj.com/content/87/Suppl_1/A1.4.abstract?sid=dc8129a6-8215-4699-a8f5-050cd87a8ff9).

MTN-001 is a crossover study in which all participants were assigned to a randomized sequence of daily tenofovir orally vaginally, or both orally and vaginally in three 6-week periods.  The key finding is that the concentration of the drug in its active form tenofovir disphosphate in vaginal mucosa achieved by the gel is 130-173 times greater than that achieved by the tablet; whereas the concentration in the serum and peripheral blood mononuclear cells (PMBC) achieved by the gel is respectively 58 and 56 times less.

It has generally been assumed that it is vaginal tissue concentration of the drug which gives protection.  One possible conclusion we might draw from these findings is that vaginal tissue is not, in fact, the critical site of ARV action.  The problem is that CAPRISA 004 (1) demonstrates that vaginal gel is having some effect through the vaginal compartment; yet that effect – given that it exists – is not at the level that might have been anticipated given 1. the increased HIV protection, and, especially, 2. increased toleration of missed doses, that we would expect from such a concentration. The second point is particularly important given the weight attached in this discussion to adherence as an explanatory variable.  With the half-life of elimination of tenofir diphosphate an estimated 90 hours, women having dosed once with gel could stop all dosing for more than 2 weeks before their vaginal tissue concentration fell to the vaginal concentrations achieved in oral dosing!  Hence, non-adherence appears not to be a plausible as a sole explanatory variable.  Something else must be going on.  But what?  The authors suggest, first, the possibility of tissue toxicity either from the tenofovir or the gel vehicle; second, some other factor that we are as yet unable to determine.

The authors conclude, naturally, that identification of the unknown variable is essential to improving future PrEP development…

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