New Oral and Long-Acting PrEP: Pills, Films, Gels, Injections and Depots
March 5, 2016
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 after rectal exposure, the two studies at CROI 2016 were on vaginal gels looking as acceptability and in test tube studies, although a slow release ring formulation has been developed that additionally protects against HPV and pregnancy.18
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.19
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.20
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 that was actually at the start of the conference, John Mascola from the U.S. National Institute of Health provided an overview of using broadly neutralising monoclonal antibodies (mAb's) both for prevention and treatment.21
Animal studies using the monoclonal antibody (mAb) VRC01 have shown proof-of-concept for working as PrEP 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 the ethical issue that both these studies plan to use an inactive placebo-control.
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. This is complicated by some PrEP compounds not having 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. This will likely need independent and publically 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 a 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 participant already knew TDF/FTC worked.
CROI provided exciting tentative results but the next stages will be critical to whether and how quickly they 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.
This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
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