A clear highlight for HIVR4P 2016 was the unexpected volume of research into new molecules and formulations for PrEP.
This large specialised meeting has worked effectively to focus on prevention research in a meeting that is large enough to include diversity but that is still small enough to meet and talk with researchers and to get a comprehensive overview of both preclinical and clinical studies.
The diversity of the research shown by the large number of new compounds being studied for PrEP.
- Currently approved antiretrovirals (lamivudine, emtricitabine, tenfovir-DF, TAF, raltegravir, elvitegravir, rilpivirine, darunavir, rilpivirine, etravirine and maraviroc).
- New compounds from existing classes: NNRTIs (dapivirine, MIV-170, IQP-0528); integrase inhibitors (cabotegravir, MK-2048); entry inhibitors (vivriviroc, 5P12-RANTES, DS003/BMS-599793, PIE-12 trimer D-peptide, Nifviroc); and NRTIs (EFdA).
- New compounds from new classes: neutralising antibodies (VRC01, griffithsin).
It was similarly impressive to see the range of new delivery systems and formulations that are being studied.
- Single and multi-compound vaginal rings.
- Other vaginal/rectal inserts or suppositories often designed to rapidly dissolve within a minute or two.
- Vaginal and rectal gels -- sometimes developed for both or only one compartment.
- Small, thin fast-dissolving vaginal films of nanoformulations that instantly dissolve on contact with moisture (including MK-2048, vivriviroc, TDF, VRC01 and others). these films deliver similar drug levels as gels but are much less messy.
- Long-acting soft implants -- incorporating long-acting slow release formulations into something similar to a 1 mm in diameter, 2 cm long strip of cotton-like material that can be inserted under the skin, for example at the back of the neck.
- Long acting injections (cabotegravir).
- Fast absorbing small-volume rectal formulations that are designed to be rapidly absorbed into rectal tissue, similar to an enema.
Many of the new studies incorporated two, three or four compounds into new formulations, adding experimental compounds to already-approved drugs.
Together, this collective body of research suggest a huge potential for PrEP to become better and easier to use.
Other than cabotegravir LA injections and TAF which are in late-phase studies by the drug manufacturers, the majority of the research at the meeting was driven and presented by independent academic research groups, supported by either public or charitable funding. Although some pharmaceutical companies provided support in kind with drugs, many of the researchers said that this was often not the case, with some research groups having to manufacture their own versions of the active compounds of unlicensed compounds.
This pipeline also sets a challenge to regulators, funders, researchers and activists to develop approval pathways that might compare multiple investigational compounds and formulations in the same study -- both for faster proof of principal and to reduce research costs.
Many of the selected reference included below could have been categorised under several subheading -- (i.e., as new compounds and gels and multi-function combinations) but are only listed once, really to give a idea of the diversity of the PrEP pipeline.
This is an exciting period for prevention research. Even if only a few of these products in preclinical studies continue through clinical studies to approval, within 5-10 years TDF/FTC will look as archaic for PrEP as AZT monotherapy looks compared to modern ART.
Health advocates and PrEP users should be following (and driving) research into pipeline research just as treatment activists drove the development for ART.
One challenge -- and it is a significant one, will be the to develop better models and requirements for regulatory approval. PrEP studies are larger, more expensive and generally longer the ARV treatment studies with few surrogate markers of efficacy other than the impact on HIV transmission.
As PrEP becomes more effective the challenge for to match results in control arms will become increasingly difficult, given that all participants in research studies need to receive the current standard of care as minimum.
This is likely to require public investment, perhaps using multiple new compound with early promise in the same studies.