New Oral and Long-Acting PrEP: Pills, Films, Gels, Injections and Depots
March 5, 2016
Just as the term PrEP has started to gain awareness and recognition as a generic word for a pill to prevent HIV infection, CROI 2016 included potential PrEP alternatives to daily or event-driven oral tenofovir DF plus emtricitabine (TDF/FTC).
Many of these studies are at an early stage of research but others could potentially become options within 2-3 years.
Other formulations include injectable compounds, long-acting implants, gels and a microbicide vaginal ring.
Two key issues with potential PrEP drugs were repeated concerns in these studies. Firstly, the difficulty of running efficacy studies without good models of efficacy -- whether in animal or ex vivo studies; and secondly, the lack of surrogate markers for PrEP efficacy that would help select the best compounds for future studies. Interpreting PK drug levels is complex with many studies reporting differences between levels in similar sites -- for example in vaginal or rectal fluid compared to in vaginal or rectal tissue.
The strategy for future studies is also discussed in a comment at the end of this article, driven by the need for a wider range of effective PrEP together with the increasing challenge to proove efficacy in high risk populations now that oral TDF/FTC, with good adherence, is associated with such high protection.
TAF, the New Tenofovir: First PrEP Data
Two studies on the new TAF formulation of tenofovir presented results that at first seem contradictory.
In animals studies all six monkeys receiving TAF effectively were protected from rectal exposure compared to all six monkeys receiving placebo who became quickly infected. This is exciting.1
In contrast, measuring drug levels in a small group of eight HIV negative women following a single dose of TAF (two women received placebo), showed lower active drug levels in genital and rectal tissue -- even though these were expected to be higher.2
Further studies need to determine whether these lower levels are going to affect PrEP efficacy.
LA Injections: Cabotegravir and Rilpivirine
The second PrEP compound with exciting results was the long acting (LA) slow-release formulation of cabotegravir, which is given by intramuscular injection (into the buttocks). Again there were results from both animal and human studies.
The animal studies were exciting for showing that cabotegravir LA protected against HIV transmission directly into blood -- rather than just against sexual exposure. This is remarkable because the risk of infection by blood exposure is so much higher. If similar protection it seen in human studies, this means that injections every two months might protect people vulnerable to HIV infection through shared injecting drug use.3
The human cabotegravir study mainly reported on tolerability of the injections. Although side effects were significantly higher with the active injections (compared to people who received saline) overall patient satisfaction still remained pretty high. This study also found that injections are needed every two months, rather than every three months as initially hoped. Unfortunately, one person in each of the active and placebo groups became HIV positive during this study.4
Although rilpivirine LA was also an early candidate for PrEP it seems unlikely that this compound will not now progress to larger studies. This decision is likely based on the an indication that a potential protection in rectal tissue seems unlikely to be insufficent in vaginal tissue -- based both on drug level and test tube studies.5,6
Maraviroc as PrEP: Better to Study in Combination?
Maraviroc was approved an HIV drug in 2007 but was never widely used in first-line ART because it wasn't quite as good as other options. Although it was well tolerated it needs a separate test before it can be used as treatment and has significant interactions with some other HIV meds. However, because it blocks HIV from entering CD4 cells, many researchers were interested in whether it might have a role as PrEP.
Results of a phase 2 study presented at CROI 2016 hinted that maraviroc might work as PrEP but test tube studies suggested this might be better in combination with either tenofovir or FTC.7,8
Dapivirine: First Efficacy Results of a Vaginal Ring
Another PrEP compound that was widely reported from CROI involved the use of a monthly vaginal ring that slowly released an NNRTI called dapivirine.
Two very large studies in African women reported reductions in HIV transmission that were statistically better than a placebo ring, and that protection was higher when the ring was used. As with several other large PrEP studies, low adherence complicated interpretation of the results. Most disappointing, was that the ring produced no protection for women under 21, in whom HIV risk is the highest.9,10
The need for alternative formulations for different risk groups is clear, but even in the context of good adherence, dapivirine appears to be less effective than oral tenofovir/FTC.
A more difficult question to answer is whether efficacy would be improved to a more acceptable level if the ring coformulated davipirine with a second slow release antiviral.
Tenofovir: Implants, Gels and Rings
Unlike long-acting injections that are permanent, some researchers are looking at slow release implants that would be able to be removed -- similar to a contraceptive implant.
A small silicon tube containing tenofovir alafenamide (TAF) reported good pharmacokinetic results in a dog study that modeling for human protection might only need a 50 mg dose to provide protection for a year.5
Another formulation, also using TAF, is being studied in a three-monthly biodegradable implant that would not need to be replaced if it was used for the full period.11
Use of implants might also help overcome the issue of the extremely long half-life of long-acting injections, which with rilpivirine LA have included developing NNRTI drug resistance if infections occur.
An oral presentation reported from a six-month international phase 2 study on the acceptability of a 1% tenofovir rectal gel, administered with an applicator. This was an open label cross over study with three groups: (i) daily use of the gel; (ii) event-based use with a pre- and post-sex dose; and (iii) a control group using oral TDF/FTC.12
Adherence measures included daily SMS text messaging and real-time PK evaluations. Overall, average age was 30 (though lower in the South Africa sites), with 80% of participants having some level of college education. Of 195 participants, most identified as male (71%), transgender (10%), female (2%), not stated/declined (15%).
Tolerability was similar in all three groups with approximately 30% in each arm reporting side effects that were grade 2 or higher. All interventions were acceptable (>70% said they liked each option) even though overall there was a greater preference for oral PrEP compared to gel. PK sampling showed approximately 90% use with both daily oral and daily rectal doses. Event-based gel was preferable to daily gel.
Several posters presented early results on other tenofovir formulations, including a 2" x 2" quick dissolving film (for vaginal use),13 a gel that could be used vaginally or rectally14 and a vaginal ring that identified cervical tissue as the source of infection in a macaque study.15
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