HIV Treatment Bulletin

A burgeoning PrEP pipeline: dozens of new drugs, formulations and delivery options

 HIVR4P Chicago HIV Research for Prevention 2016

Simon Collins, HIV i-Base

A clear highlight for HIV R4P 2016 was the unexpected volume of research into new molecules and formulations for PrEP.

This large specialised event 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 studies is show by the number of new compounds being studied for PrEP. See also Table 1.

  • Currently approved antiretrovirals (lamivudine, emtricitabine, tenfovir-DF, TAF, raltegravir, elvitegravir, 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 in development. See also Table 2.

  • 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, this majority of this research at the meeting was almost entirely 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 and researchers 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 references included below could have been categorised under several sub-headings – (ie as new compounds and gels and multi-function combinations) but are only listed once, just to give a idea of the diversity of the PrEP pipeline.

Table 1: PrEP investigational compounds
Currently approved antiretrovirals New compounds from existing classes New compounds from new classes
NRTIs: lamivudine, emtricitabine, tenfovir-DF, TAF.NNRTIs: rilpivirine, etravirine.
PIs: darunavir
Integrase inhibitors: raltegravir, elvitegravir.
Entry inhibitors: maraviroc
NRTIs: EFdA.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
Neutralising antibodies:
VRC01, griffithsin.
Table 2: PrEP pipeline for delivery systems and formulations
Formulation Comment
Vaginal rings Single and multiple compound.Combinations include coformulations of PrEP with contraception and STI treatment (HPV, HSV)
Vaginal and rectal inserts or suppositories Designed to rapidly dissolve within a minute or two
Vaginal and rectal gels Sometimes developed for both or only one compartment. Improved formulations – closer to lubricants.
Fast-dissolving films Nanoformulations that instantly dissolve on contact with moisture. Including MK-2048, vivriviroc, TDF, VRC01 and others. Less messy than gels.
Long-acting soft implants Long-acting slow release formulations that can be inserted under the skin similar to contraceptive implants.
Long acting injections Cabotegravir
Rectal “douche” formulations Hypo-osmotic for rapid absorption into tissue from small volumes.


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 to develop better models and requirements for regulatory approval. PrEP studies are larger, more expensive and generally longer than ARV treatment studies with few surrogate markers of efficacy other than the impact on HIV transmission.

As PrEP becomes more effective the challenge 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.

Selected references

All references are to the programme and abstracts of the 2nd HIV Research for Prevention Conference (HIVR4P), 17-21 October 2016. Abstracts are published as an open-access supplement to AIDS Research and Human Retroviruses. ( Many conference posters will be available to view and download online (

New compounds:

  • Herrera C et al. Increased activity of the entry inhibitor DS003, a BMS-378806 analogue, through binding to the CD4-induced epitope in HIV-1 gp120. Poster P08.04.
  • Kay M et al. Preclinical characterization of a potent D-peptide inhibitor of HIV entry: cholesterol-conjugated PIE12-trimer. Poster PD08.04LB.
  • Madani N et al. Prevention of vaginal transmission of simian-human immunodeficiency virus (SHIV) in rhesus monkeys by small-molecule CD4-mimetic compounds. Poster PD08.03LB.
  • Mason R et al. Next generation SIV broadly neutralizing antibodies mediate complete neutralization of SIVmac239. Poster PD08.05LB.
  • McBride J et al. Osmotically activated release of 5P12-RANTES from silicone elastomer matrices. Poster P07.23.
  • Moss J et al. Intravaginal drug delivery system with dual microbicide delivery. Poster P07.24.

Multi-function formulations: combining PrEP with other treatments (for HPV, HSV-2, STIs) or contraceptives:

  • Calenda G et al. Pharmacodynamics of griffithsin after vaginal application of a gel or intravaginal ring in macaques. Poster P07.15.
  • Calenda G et al. GRFT/carrageenan gel Inhibits HIV and HSV-2 in human cervical mucosa. Poster P07.19.
  • Holt J et al. Pharmacokinetics of dapivirine and levonorgestrel in sheep when administered vaginally in a silicone matrix ring. Poster abstract PD04.01.
  • Kleinbeck K et al. Preclinical safety and stability assessment of a dual compartment microbicide gel targeting multiple viral sexually transmitted infections. Poster P07.34.
  • Levendosky K et al. Preclinical evaluation of a griffithsin/carrageenan formulation to prevent HIV infection. Poster P08.17LB.
  • Murphy D et al. Manufacture, release testing and content assay of dapivirine and dapivirine + levonorgestrel vaginal rings for testing of pharmacokinetics in sheep. Poster P07.11.
  • Shankar G et al. Development and evaluation of release profile of innovative two-polymer (SR-2P) bioadhesive vaginal microbicide gels to prevent HIV. Poster P07.47LB.
  • Srinivasan P et al. Pharmacokinetics of a multipurpose prevention technology pod-intravaginal ring for HIV-1, HSV, and contraception. Poster PD03.04.
  • Tyo KM et al. Electrospun Polymer Nanofibers for Long- term Protection against HIV and HSV-2. Poster P07.32.

Vaginal and rectal gels:

  • Calenda G et al. Pharmacodynamics of griffithsin after vaginal application of a gel or intravaginal ring in macaques. P07.17.
  • Carballo-Diéguez A et al. High levels of adherence to a rectal microbicide gel and to oral PrEP achieved in MTN-017. Oral abstract OA20.01.
  • Shetler C et al. Tenofovir/IQP-0528 combination gel effectively inhibits HIV and Is not affected by semen. Poster P08.06.
  • Ham A et al. IQP-0528: the pharmacokinetics of an anti-HIV NNRTI in non-human primates from various dosage forms. Poster PD03.05.
  • McBride J et al. Sheep pharmacokinetics of a topical aqueous gel containing the anti-HIV CCR5 receptor inhibitor 5P12-RANTES. Poster P07.22.
  • Russo J et al. Preclinical evaluation of prototype rectal griffithsin gels for HIV prevention. Poster P08.08.

Fast-dissolving vaginal and rectal tablets, implants and suppositories:

  • Clark MR et al. Long-acting intrauterine system delivers integrase inhibitor throughout the reproductive tract of rabbits and macaques. Poster P07.40.
  • Dobard C et al. Pharmacokinetic evaluation of rectal tenofovir suppositories in macaques. Poster P07.07.
  • Lal M et al. A convenient, self-administered microbicide fast-dissolving insert as pre-exposure prophylaxis for HIV prevention. Late breaker poster P07.46LB.
  • Littlefield S et al. Clinical performance, acceptability, and optimization of fast-dissolve vaginal inserts designed for HIV-prevention: results from two clinical studies. Oral abstract OA06.05.
  • Swarner S et al. A biodegradable, subcutaneous implant for delivery of antiretroviral (ARV) drugs. Poster P07.44.
  • Zhang W et al. Development and proof-of-concept clinical evaluation of a freeze-dried topical microbicide insert for on-demand HIV prevention. Oral abstract OA12.02.

Fast-dissolving films (vaginal):

  • das Neves J et al. Pharmacokinetics and safety of vaginal tenofovir/efavirenz-loaded nanoparticles-in-film in Mice. Abstract P07.25.
  • Grab S et al. Extended release of a combination dapivirine/MK-2048 film for HIV prevention. Poster P07.43.
  • Ham A et al. IQP-0528: the pharmacokinetics of an anti-HIV NNRTI in non-human primates from various dosage forms. Poster PD03.05.
  • Jiang Y et al. Vaginal safety evaluation of a triple antiretroviral drug-loaded electrospun fiber microbicide in nonhuman primates. Poster abstract PD03.03.
  • Regev G et al. Novel application of hot melt extrusion for the manufacture of vaginal microbicide films. Poster P07.16.
  • Vaca GB et al. Safety and efficacy assessment of VRCO1-N and MB66 microbicide film in an in vitro vaginal environment. Poster P07.15.

Intravaginal rings (IVR):

  • Calenda G et al. Pharmacodynamics of griffithsin after vaginal application of a gel or intravaginal ring in macaques. P07.17.
  • Dezzutt C et al. Evaluation of MK-2048 and vicriviroc MK-2048A formulated as single or combination intravaginal rings for development as a vaginal microbicide. OA12.05. – data for CROI 2017)
  • Evanoff A et al. A single-reservoir microbicide intravaginal ring for dual delivery of tenofovir and elvitegravir. Oral abstract OA12.04.
  • Marshall LJ et al. Impact of vaginal ring geometry and drug loading on pharmacokinetics of dapivirine and darunavir in macaques. Poster abstract P07.13.
  • Marshall LJ et al. Utility of the sheep model for testing the 28-day MK-2048A intravaginal ring and determining the correlates of exposure for vicriviroc and MK-2048. Poster P06.07.
  • Murphy D et al. Visualising maraviroc release from silicone elastomers using magnetic resonance imaging. Poster abstract P07.10.
  • Wilson M et al. Formulation development of DS003 ethylene vinyl acetate vaginal rings. Poster P07.39.

Douche applications:

  • Date A et al. Optimizing enema vehicle osmolality for improved colorectal microbicide delivery. Poster abstract PD03.02.

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