Cervical barrier delivery systems
Cups or diaphragms that are used in contraception protect the cervix (potentially preventing cervicitis) and could be adapted for use with different microbicides, concentrating the formulation on target cells in the cervix.
A few of these are in development including the Duet Cup (a one size, disposable cervical barrier, prefilled with BufferGel microbicide) and the SILCS diaphragms, one size but reusable barriers that can also hold microbicides.
Use of such cervical barriers is more common in industrialised nations and there is some question as to how well they will be as accepted in other cultures. According to one study from Brazil, diaphragms were the least popular of three delivery devices (comparing to plastic applicators and intravaginal rings). Some women complained of difficulty inserting them and of local or mechanical irritation. Many woman also don’t like keeping the reusable diaphragms in for more than one use, but if every women starting using the single use devices, their disposal could create environmental problems (too much waste).
At US $0.25 per unit, they are also more expensive than standard plastic applicators. However, since they may be more closely associated with contraception than HIV prevention, they may not create a crisis of trust between men and women in long-term relationships as is possible when a microbicide is only for HIV or other sexually transmitted diseases (STIs) (to be discussed in a later article).
SILCS is moving to a contraceptive effectiveness study with N-9 scheduled to begin July 2006.
Most of the leading microbicides have been formulated as gels. To make certain that enough microbicide is delivered, plastic applicators have been developed prefilled with a set volume of gel that a woman must insert into her vagina. A number of studies at the Microbicides 2006 conference addressed the acceptance of these devices and the uptake of this process (to be discussed in a later article). However, Professor Sharon Hillier of the University of Pittsburgh reviewed a number of other ways to deliver microbicides in earlier stages of development.
Genetically modified live organism vectors
Several teams have shown that organisms that make up part of the normal vaginal or intestinal flora, such as Lactobacillus and Escherichia coli, can be genetically modified to continuously produce and release molecules with anti-HIV activity, such as soluble CD4, cyanovirin or gp41.
Such vectors could also be delivered long before sexual activity, but it would be nearly impossible to ensure delivery of an effective dose. For one thing, the genetically modified organisms may not be as adaptable as the native flora, and it would be difficult to know whether successful and sustained colonisation had indeed occurred within an individual. Finally, the immune system may react against the organism or the protein which it is secreting.
And would such vectors be accepted by people who are afraid to eat or grow genetically modified grain — would people consent to having such organisms seeded into their own vaginas or rectums?
Nevertheless, a number of products have already been formulated including MucoCept HIV, a vaginal Lactobacillus which can secrete cyanovirin that is now being studied in pig-tailed macaques. Also at the conference, Dr Dean Hamer of the US National Cancer Institute gave a presentation on a strain of E. coli genetically engineered to secrete gp41 (which stably binds gp120) in the gut. Studies have demonstrated that it can colonise the rectum in mice following ampicillin treatment, and Dr Hamer presented new data showing that it effectively colonised the intestinal tract of rhesus macaques, protecting about half of them from rectal challenge with SIV.
Intravaginal rings
Intravaginal rings are another commonly used device for contraception in industrialised countries that are relatively unknown in resource-limited settings. However, rings are a sustained release mechanism that could potentially deliver a variety of microbicides (with contraceptive, antibiotic, anti-STI or anti-HIV activity) over a long period of time. Rings increase compliance and acceptability because they can be inserted weeks before sex — and are usually undetectable to the male partner.
The downside to this is that the woman is exposed to more drug so there is a greater potential for side-effects. Also, if a woman should seroconvert while using rings containing ARVs, this would be the optimal method for inducing ARV resistance.
IPM has conducted phase I trials - with reservoir type rings containing dapivirine - that have demonstrated good safety and tissue levels of drug. IPM is also looking at a variety of other new ring technologies which can deliver multiple drugs.
Semen activated microbicides
Perhaps the most innovative microbicide delivery research is being conducted by Dr. Patrick Kiser and colleagues in Utah (of all places), who are looking at a number of technologies to optimise microbicide delivery in the vagina in the presence of semen.
Essentially, polymers containing ARVs could be delivered in a long lasting gel that stays inert in the normal pH of the vagina. However, with exposure to semen, the gel turns into a liquid. Semen contains high levels of natural proteases that then free the ARVs (bound to a molecule which looks like the proteases' natural substrate or target). The ARVs are then immediately available to combat HIV present within the semen. This gets the drug exactly where it needs to go, when it is needed, and protects the woman from systemic effects of the drug when not having sex. Somewhat different gels could also be formulated for rectal deployment.
Primary reference
Hillier SL. Microbicides: State of the Art and Its Evolution. Microbicides 2006 Conference, Cape Town, Monday oral plenary, 2006.
Other references
Ballagh SA. BufferGel® Duet: safety and acceptability study of a novel product combining a mechanical and chemical barrier in the vagina. Microbicides 2006 Conference, Cape Town, abstract OB23, 2006.
Barnhart K T. BufferGel® with diaphragm found to be an effective contraceptive in two Phase II/III trials. Microbicides 2006 Conference, Cape Town, abstract OB22, 2006.
Patton D, Cosgrove-Sweeney Y, Rohan L. 0.5% Octylglycerol gel: vaginal safety evaluation in the macaque model. Microbicides 2006 Conference, Cape Town, abstract PA54, 2006.
Patton D, Cosgrove-Sweeney Y, Hillier S. Rectal safety studies conducted in the pigtailed macaque. Microbicides 2006 Conference, Cape Town, abstract PA59, 2006.
Trifonova R, Pasicznyk J-M, Fichorova R. Biocompatibility of solid dosage anti-HIV-1microbicides and vaginal products with the mucosal cytokine network.
Kilbourne-Brook M. SILCS diaphragm: acceptability of a single-size, reusable cervical barrier by couples in three countries. Microbicides 2006 Conference, Cape Town, abstract PC33, 2006.
Hardy E. Devices for the administration of a vaginal microbicide: use difficulties, adherence to use and preferred device. Microbicides 2006 Conference, Cape Town, abstract PC23, 2006.
Lagenaur L. Vaginal lactobaccil for mucosal delivery of the anti-HIV microbicide, cyanovirin-N. Microbicides 2006 Conference, Cape Town, abstract OA33, 2006.
Hamer D, Henry K. Live microbial microbicides for HIV. Microbicides 2006 Conference, Cape Town, abstract OA30, 2006.
Kiser P. Novel delivery systems for microbicides: semen triggered release and in situ gelling polymer carrier. Microbicides 2006 Conference, Cape Town, abstract OA32, 2006.