Future oral and long-acting formulations for PrEP: pills, films, gels, injections and depots
Simon Collins, HIV i-Base
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 prove efficacy in high-risk populations now that oral TDF/FTC (with good adherence) is associated with such high rates of 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 that became quickly infected. This is exciting. 
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. 
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. 
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. 
Although rilpivirine LA was also an early candidate for PrEP it seems unlikely that research will continue for this indication. This decision is because the protection in rectal tissue does not seem likely 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 was not 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 at CROI 2016 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 pharmacokinetics in a dog study. Modelling TAF for human protection suggests that a 50 mg dose might only be needed to provide protection for a year. 
Another formulation, also using TAF, is being studied in a three-monthly biodegradable implant that would not need to be removed if it was used for the full period. 
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 NNRTI drug resistance when 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. 
Adherence measures included daily SMS text messaging and real-time PK evaluations. Overall, average age was 30 (though lower in the South African 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) , a gel that could be used vaginally or rectally  and a vaginal ring that identified cervical tissue as the source of infection in a macaque study. 
PC-1005 is the development name for a gel formulation of the NNRTI MIV-150 and zinc acetate that is being studied as a way to provide dual protection against both HIV-1 and HSV-2. [16, 17]
Although MIV-150 has shown efficacy in macaque studies following rectal exposure, two studies at CROI 2016 on vaginal gels looked at acceptability and efficacy in test tube studies. Another slow release ring formulation has been developed that protects against HIV-1, HVS-2, HPV and pregnancy. 
MK-8591: an ARV with potential for annual dosing
Although only in early stages of development, two studies reported data on EFdA (MK-8591), a new NRTI in development by Merck that, due to a very long half-life and potency that requires very low dosing, is being studied both for treatment and prevention. 
This compound has a PK profile that with an intracellular half-life of >24 hours might allow once-weekly oral dosing with a 10 mg dose and has the potential for very extended dose parenteral formulations. In a rat study, a single dose solid state slow release formulation provided drug coverage for longer than six months, with data suggesting that this might be extended in humans to longer than one year. 
While no specific data were presented on use as PrEP it is notable that the company are already highlighting a potential interest in prevention research. If this compound does show PrEP efficacy, it would allow radically different approaches to the design for PrEP studies, for example, allowing randomised cluster approaches (similar to the PopArt study).
VRC01: using monoclonal antibodies for PrEP
Finally, in a plenary talk at the start of the conference, John Mascola from the US National Institute of Health provided an overview of using broadly neutralising monoclonal antibodies (mAbs) both for prevention and treatment. 
Animal studies using the monoclonal antibody (mAb) VRC01 have shown proof-of-concept for PrEP use and have been used to determine optimal dose, with the hope that dosing might only need to be every two months.
Two large phase 2 studies using 2-month dosing schedule are planned by HPTN to start by mid-2016. One of these aims to enrol 2400 gay men and transgender women in North and South America and the other is enrolling 1500 women in sub-Sahara Africa.
Not addressed in the talk, but a concern for all new PrEP studies, is that according to the listing on clinicaltrials.gov, both these studies plan to use an inactive placebo-control. Post publication update: free access to oral PrEP is included in the detailed protocol for these studies. 
Also, as VRC01 misses 13% of viruses, and more potent antibodies are expected shortly, this raises questions about whether it would be better to wait until two or more mAbs are combined in order to provide full coverage.
With so many new compounds and formulations with potential role for PrEP, the research and approval pathway for rapidly evaluating the most promising drugs is unclear.
Oral TDF/FTC works so well that in the context of good adherence, it is difficult for another compound to show better than near 100% efficacy. However, other drugs could easily show better tolerability, convenience and easier adherence that might show differences, especially long-lived slow release formulations.
New compounds also ideally need to be able to demonstrate efficacy in smaller studies before enrolling much larger and longer studies. Some PrEP compounds do not have non-human primate efficacy models – which with TDF/FTC supported dramatic and perhaps 100% early efficacy.
Traditional phase 3 studies enrolling thousands of participants for many years are costly, for a final intervention that needs by definition to be low cost and affordable. New approvals for PrEP are likely to depend on independent and publicly funded research that perhaps tests multiple new candidates in a single study.
Progress is only likely to be practical if efficacy studies can enrol populations with both very high incidence and a commitment to adherence. But even the designs for the recent PROUD and IPERGAY studies might not be acceptable today. PROUD included a control arm that deferred access to PrEP and IPERGAY used a placebo design that limited recruitment when participants already knew that TDF/FTC worked.
As for long-acting injectable treatment, long-acting PrEP will need to overcome issues relating to the extremely long half life that currently – in research studies – are suggesting oral dosing for a year is a requirement for people that want to stop long-acting PrEP.
CROI 2016 provided exciting tentative results but the next stages will be critical to whether and how quickly these can become real world options.
Unless stated otherwise, all references are to the Programme and Abstracts of the Conference on Retroviruses and Opportunistic Infections, 22-25 February 2016, Boston, USA. All oral presentation are online as webcasts. Abstracts are available online and most include PDF files for the full poster.
- Garcia-Lerma GJ et al. Chemoprophylaxis with oral FTC/TAF protects macaques from rectal SHIV infection
. CROI 2016, Boston. Oral abstract 107.
- Garrett KL et al. TFV and TFVdp in female mucosal tissues after a single dose of TAF. CROI 2016, Boston. Oral late breaker abstract 102LB.
- Andrews CD et al. Cabotegravir Long-acting injection protects macaques against intravenous challenge. CROI 2016, Boston. Oral abstract 105.
- Markowitz M et al. ÉCLAIR: phase 2A safety and PK study of cabotegravir LA in HIV-uninfected men. CROI 2016, Boston. Oral abstract 106.
- McGowan I. The promise and challenges of sustained delivery of PrEP. CROI 2016, Boston. Oral abstract 71.
- Dezzutti C et al. Distinct pharmacodynamic activity of rilpivirine in mucosal explant tissue. Poster abstract 874.
http://www.croiconference.org/sites/default/files/posters-2016/874.pdf (PRD poster)
- Gulick R et al. HPTN 069/ACTG 5305: phase II study of maraviroc-based regimens for HIV PrEP in MSM. CROI 2016, Boston. Oral abstract 103.
- McGowan I et al. PrEP impact on T-cell activation and explant infection: HPTN 069/ACTG 5305 substudy. Oral abstract 104.
- Baeten JM et al for the MTN-020/ASPIRE Study Team. A phase III trial of the dapivirine vaginal ring for HIV-1 prevention in women
. CROI 2016, Boston. Oral abstract 109LB.
- Nel A et al for the IPM 027/Ring study research center Teams. Safety and efficacy of dapivirine vaginal ring for HIV-1 prevention in African women
. CROI 2016, Boston. Oral abstract 110LB.
- Schlesinger EB et al. A Long-Acting Biodegradable Subcutaneous Implant for Tenofovir HIV PrEPCROI 2016, Boston. Poster abstract 879.
http://www.croiconference.org/sites/default/files/posters-2016/879.pdf (PDF poster)
- Cranston R et al. MTN-017: Rectal phase 2 extended safety and acceptability study of 1% tenofovir gel
. CROI 2016, Boston. Oral abstract 108LB.
- Bunge KE et al. Phase I trial to assess safety, PK, and PD of film and gel formulations of tenofovir. CROI 2016, Boston. Poster abstract 871.
http://www.croiconference.org/sites/default/files/posters-2016/871.pdf (PDF poster)
- Cameron M et al. Assessing formulations of tenofovir 1% gel in HIV seronegative adults via RNA-Seq. CROI 2016, Boston. Oral abstract 880.
- Ott AK et al. Transport of Drug and Virus in FRTs of Macaques 922 Treated With a TDF Intravaginal Ring. CROI 2016, Boston. Oral abstract 877.
http://www.croiconference.org/sites/default/files/posters-2016/877.pdf (PDF poster)
- Friedland BA et al. A First-in-Human Trial of PC-1005 (MIV-150 and Zinc Acetate in a Carrageenan Gel).CROI 2016, Boston. Oral abstract 875.
- Villegas G et al. CVLs From Women Vaginally Dosed With PC-1005 Inhibit Mucosal HIV-1 and HSV-2 Ex Vivo. CROI 2016, Boston. Oral abstract 876.
- Ugaonkar SR et al A novel intravaginal ring to prevent HIV-1, HSV-2, HPV, and unintended pregnancy. J Control Release. 2015 Jun 17;213:57-68. doi: 10.1016/j.jconrel.2015.06.018. [Epub ahead of print]
- Grobbler J et al. Long-acting oral and parenteral dosing of MK-8591 for HIV treatment or prophylaxis
. CROI 2016, Boston. Oral abstract 98.
- Friedman E et al. A single monotherapy dose of MK-8591, a novel NRTI, suppresses HIV for 10 days. CROI 2016, Boston. Oral late breaker abstract 437LB.
- Mascola JR. Harnessing Antibodies for HIV-1 Prevention and Treatment. Plenary talk, CROI 2106, Boston. Oral abstract 15.
Protocol for HVTN 704/HPTN 085. Version 1.0. page 22.
http://www.hptn.org/research_studies/hptn085.asp (Study website)
http://www.hptn.org/web%20documents/HPTN085/HVTN%20704%20HPTN%20085%20Protocol%20Version%201.pdf (PDF protocol)
“access to FTC/TDF PrEP at no drug cost will be offered as part of a complete HIV prevention package to every HVTN 704/HPTN 085 participant through a model initially developed with extensive, multi-stakeholder input for the HVTN 505 trial [86,87]… Availability of free FTC/TDF was indicated in the informed consent document and communicated to study participants in follow up visits. However, fewer than 15% of participants in the HVTN 505 trial have reported using PrEP at any time during the trial (in which follow-up remains ongoing).”
This article was updated on 6 April 2016 to include new information about the VRC01 studies and reference 22.