Current State of Rectally-applied PrEP
Rectal microbicides have the potential to be an exciting development and useful resource for HIV prevention during anal sex. As one type of topically-applied pre-exposure prophylaxis (PrEP), rectal microbicides are self-administered in the rectal cavity prior to anal sex. An advantage of rectal microbicides is that they can deliver the drug, in a relatively high concentration, to the part of the body where it’s needed prior to sex.
Rectal microbicides are gaining recognition for their potential to complement or enhance other HIV prevention strategies. A recent article published in the Journal of Controlled Release by Rute Nunes, Bruno Sarmento and José das Neves reviewed the challenges and successes in developing rectal microbicides, including the state of the current field, which we summarize here.
The active ingredients
Initial investigations into rectal microbicides first focused on non-specific microbicides such as nonoxynol-9 (typically used in products meant for vaginal use), then moved on to antiretrovirals similar to those used in HIV treatment. Tenofovir (marketed under the trade name Viread) has been the most widely used active ingredient in current microbicide research after a landmark 2010 clinical trial demonstrated its efficacy in preventing HIV. The study—known as CAPRISA 004—confirmed the potential microbicides have to be an important HIV prevention tool.
“CAPRISA 004 was the first study to show that a microbicide can prevent HIV infection in women. It was also the first microbicide to be tested that was antiretroviral-based. There has not been a lot of investment in microbicide development and earlier products that were tested were based on what products were available. The CAPRISA 004 results have helped to stimulate and catalyze more investment in microbicide research and development,” explained Quarraisha Abdool Karim, PhD, Principal Investigator for CAPRISA 004.
Other antiretroviral drugs are also currently being tested to determine if they are able to protect rectal tissue from HIV infection, such as fusion inhibitors (L’644), reverse transcriptase inhibitors (e.g., dapivirine), and protease inhibitors (e.g., saquinavir). Microbicide development may also benefit from combinations of antiretroviral drugs, which may increase drug potency and decrease the likelihood of developing a drug resistance. Currently, the Combination HIV Antiretroviral Rectal Microbicide (CHARM) program based at the University of Pittsburgh is set to develop and test a product composed of both tenofovir and maraviroc (Selzentry).
Out from the shadow of vaginal microbicide development
Research and development of rectally-applied microbicides only recently has diverged as a separate line of inquiry from vaginal microbicides.
Gels that were originally designed for vaginal use were first tested for safety and acceptability when applied rectally, with minimal success. A 1% tenofovir gel previously tested as a vaginal microbicide in the RMP-02/MTN-006 study caused gastrointestinal adverse events and was disliked by study participants. Another gel formulated for vaginal use (containing UC-781, a reverse transcriptase inhibitor) was planned for testing in a study on rectal use, but clinical development of this product was halted due to drug formulation problems. Clinicaltrials.gov, on a page describing a clinical trial sponsored by CDC to test two concentrations of the UC-781 gel on men and women, indicates that the trial has been withdrawn and that the product is no longer being considered for further development.
With evidence that vaginal formulations must be re-developed for rectal use, safety and acceptability studies [MTN-007; MTN-014; MTN-017; Project Gel; CHARM 01/CHARM 02] have since used reduced-glycerin 1% tenofovir gels, which are better-tolerated when applied rectally. Future research will likely test microbicide formulations developed specifically for rectal, as opposed to vaginal, application.
Maximizing acceptability, accessibility, and ease of use
The importance of testing different forms of microbicides with potential end users cannot be overstated since an undesirable product may be under-utilized—even if it’s entirely effective. Nunes and colleagues describe the various microbicide dosage forms (e.g., gel, liquid, or suppository) and volumes (e.g, how much liquid or gel is delivered in one use), in addition to taste, smell, color, and in-use feel that have been investigated in clinical trials.
Gels consistently are rated as more preferential than liquid enemas and suppositories—although Nunes and colleagues note that the large size of suppositories used in past trials may have contributed to their significantly lower ratings. Product developers contend with reaching a balance between the volume of gel or liquid microbicide needed to protect the entire area vulnerable to HIV transmission (the rectosigmoid and descending colon) and users’ preferences for smaller volumes that minimize leakage and messiness.
Unfortunately, Nunes and colleages conclude that, based on user acceptability studies conducted thus far, an ideal, universal product has not yet been tested and that “further work in the field is required.”
Product packaging and applicators have also been investigated, with the expectation that a discreet, easy-to-carry, and easy-to-use product will lead to better uptake and use. Clinical trials with MSM have commonly relied on pre-filled applicators designed for vaginal administration. Complaints by men using these applicators with regard to their size, appearance, and effects point to a need for continued efforts to design a rectal-specific applicator that will be acceptable to a wide variety of users.
Users seem to prefer pre-filled, one-time-use microbicide applicators. This design ensures that a standard dose is given at each use, reducing the risk of user error introduced if applicators must be filled before each use. Multi-use applicators, on the other hand, could defray manufacturing costs and increase the end product’s affordability.
Not enough known about excipients
When formulating microbicide gels to carry an active drug, developers use substances—called excipients—know to be pharmacologically inactive. The toxicity evaluations of these excipients are often neglected during development, although many have not been tested for long-term usage.
A binding agent called Edetic Acid (EDTA), commonly used in microbicides, has potential to cause problems. Nunes and colleages note that “in the case of rectal use, EDTA allows increasing drug permeability” and that while the effect of this on HIV transmission is not yet known, “such potential epithelial barrier disruption may be deleterious.”
Since some compounds have been shown to increase absorption of viral particles, Nunes and colleagues call for “toxicological evaluation of excipients intended for microbicide use and, ideally, the establishment of a specific database of safe (and hazardous) ingredients.”
Encouragingly, early cost projections of microbicides have suggested their potential for affordability.
Manufacturers prefer gel-based formulations, in particular, because they can be produced in large-scale batches and are thus easy and cheap to manufacture. A vaginal gel used in the RMP-02/MTN-006 trial has been estimated to cost $0.13 per dose, if a reusable applicator is employed. This cost rises to $0.20/dose with a paper applicator, and $0.66 with a pre-filled plastic applicator.
Citing evidence that South American men who have sex with men would be willing to pay up to $0.30 per dose for rectal microbicides, the Nunes and colleagues conclude that single-use paper applications “may be considered reasonable in order to assure cost-effectiveness” in low-resource areas.
Where we are now
The first Phase II clinical trial [MTN-017] of a rectally-applied microbicide launched in late 2013 for MSM and trans women. Results from this study, which is currently still underway, will determine whether the formulation of a reduced-glycerin 1% tenofovir gel has potential to be an effective rectal microbicide. Results from the trial are expected in early 2015.
While it’s clear that strides have been made, Nunes and colleagues note that “the development of rectal microbicides is still in its infancy.” And with many issues related to user adoption dictated by personal preference, they note that it may be that a “one-size-fits-all” product may not be warranted.
Quarraisha Abdool Karim, PhD, Associate Scientific Director for the Center for the AIDS Programme of Research in South Africa and expert on microbicide-based HIV prevention, envisions a time a few years down the line when topical microbicides will be part of an array of safe and effective HIV prevention resources that are available.
“The landscape might be similar to what we have now for contraceptives—people can choose what suits them depending on what they might need at different times in their life. It’s about ensuring that we have safe and effective products to meet different needs of different niche populations. To me, that’s the ideal situation. It doesn’t matter what’s driving your risk—what matters is that we have enough options that everybody can be protected.”
Nunes and colleagues conclude that, “Presently, a standard, safe, effective, and highly acceptable rectal microbicide seems elusive, but, as explored in this work, may be achievable.”
Nunes, R. and others. Formulation and delivery of anti-HIV rectal microbicides: Advances and challenges. Journal of Controlled Release. September 16, 2014.