Microbicides 2006: what products are in the pipeline?

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Although scientists have identified a great number of ways to disrupt HIV transmission, “the near term pipeline of microbicides ready to enter [early clinical studies] is fairly modest and... needs to be expanded rapidly,” Professor Sharon Hillier of the University of Pittsburgh and Magee-Women’s Hospital said at the start of the Microbicides 2006 conference held in Cape Town last week.

Prof. Hillier gave a plenary talk on the evolving microbicide product pipeline and novel mechanisms to deliver microbicidal compounds, preparing the audience for some of the new developments which would be presented later in the week.

The need for new strategies is great, because the handful of microbicides that have advanced into large scale human trials have relatively low potency against HIV (compared to antiretroviral drugs) — and there is no guarantee that they will actually work in practice. “We need to have a lot of different approaches in the race,” Prof. Hillier said.



A product (such as a gel or cream) that is being tested in HIV prevention research. It could be applied topically to genital surfaces to prevent or reduce the transmission of HIV during sexual intercourse. Microbicides might also take other forms, including films, suppositories, and slow-releasing sponges or vaginal rings.


The physical form in which a drug is manufactured or administered. Examples of formulations include tablets, capsules, powders, and oral and injectable solutions. A drug may be available in multiple formulations.


How well something works (in a research study). See also ‘effectiveness’.


A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.


Applied directly to the affected area, as opposed to systemic. For example, a cream or lotion, applied to body surfaces such as the skin or mucous membranes inside the vagina or rectum.


Fortunately, many ways to prevent HIV and other sexually transmitted diseases (STIs) in the vagina or rectum have been identified — each with its own set of strengths and challenges for development.

Surface active agents

Surface active agents (or membrane disruptive agents) could prevent HIV and STI transmission and pregnancy by forming a protective barrier in the vagina or rectum. Surface active agents are also cheap to make.

Nonoxynol-9 (N-9) was an early surface active microbicide that has been abandoned because it was abrasive to mucosal tissue and actually increasing transmission risks. Newer surface active products have been shown to have very low toxicity. However, such compounds are not specific for HIV and their effectiveness will depend on how thoroughly they coat the vagina or rectum (even with the best gel formulations, bare spots are likely), as well as how consistently they are used.

Furthermore, these products need to be applied shortly before coitus (and may not be on hand when intercourse has not been planned). If too closely linked to sex, products could be stigmatised in some cultures in the same way that condoms have been — although a study of 200 people in Nigeria presented at the conference suggested that this may not be a problem for the leading product, Savvy, and that acceptance of this microbicide was very high (90%). Even so, there were complaints about excessive wetness, and in other cultures where dry sex is the norm (such as parts of Southern Africa), men may insist that women not use such products.

USAID-sponsored efficacy trials of Savvy are ongoing — however, a major Savvy study in Ghana had to be discontinued when observed rates of HIV transmission were determined to be too low in both the Savvy and placebo-controlled arm for the study to reach a statistically significant conclusion. A related study in Nigeria is still continuing, however, while a study comparing Savvy and tenofovir (Viread) gel vs. placebo is being planned.

Two other new surface active agents in development include cellulose acetate 1,2-benzenedicarboxylate (CAP), a polymer mixture, with a long history of safe use in humans as enteric coating for capsules and tablets, and octylglycerol (a naturally occurring antimicrobial lipid found in human breast milk). Preclinical studies in tissue models and macaques presented at the conference demonstrated that these products should be safe in the rectum (for octylglycerol) and vagina (for both products).

Fusion/entry inhibitors

Most of the products in advanced clinical trials are simple entry or fusion inhibitors such as cellulose sulfate, PRO 2000 and Carraguard. In test tube studies, the negatively charged active molecules in these gels have been shown to interfere with the binding of HIV, HSV-2 and other enveloped viruses to CD4 and other receptors on macrophages and dendritic cells.

Though these compounds are more directly microbicidal than surface active agents, they are fairly non-specific for HIV and may have a relatively low potency in the presence of seminal fluid and vaginal flora. While they may persist in the vagina longer than surface active agents, they are still generally formulated in gels which have to be applied (with plastic applicators) prior to sex.

But thus far they appear to be quite safe and have moved into large clinical efficacy studies which will be discussed in more detail in a future article.

The buzz at the conference was that if any of these products are shown to work in clinical trials, they are likely to only be “mildly” effective (reducing transmission by 30-40%). Prof. Hillier said that they may wind up being “considered as secondary actives for combination products.”

Acid/buffering agents

The environment of the vagina is on the acidic side, but semen contains strong alkalinizing properties to protect sperm from the vagina’s natural defenses. Unfortunately, increasing the pH in the vagina also protects microbes such as HIV and increases the likelihood of their transmission. Acid or buffering agents, such as leading products, BufferGel (which has a pH of 3.9), and Acidform are sometimes called vaginal defence enhancers because they restore the vagina to its naturally acidic state. Buffering agents may also protect against both pregnancy and sexually transmitted infections by killing sperm and by inactivating acid-sensitive pathogens.

Many women try to restore their PH by using acidic washes (such as vinegar or juice). But “lemon and lime juice are toxic and do not buffer effectively,” Prof. Hillier said.

But the buffering agents in commercial development have low local toxicity and no systemic activity. They are active, in vitro, against bacterial vaginosis (BV) and several sexually transmitted infections. However, their potency is rather low, although it could be improved by combining them with other products such as cervical barrier delivery devices (see below).

A clinical efficacy study comparing BufferGel to PRO 2000 (see below) and placebo is underway in Zimbabwe, Zambia, Malawi and South Africa.


One solution to the low potency potential of the previous microbicides would be to use antiretrovirals (ARVs), which already have proven efficacy as therapeutics. Drugs such as oral tenofovir are being tested in advanced studies worldwide as pre-exposure prophylaxis (PREP) to prevent HIV transmission, but tenofovir and many other ARVs can also be formulated as topical microbicides. For example, there was a conference presentation on a gel formulation of tenofovir (1%) that demonstrated protection in four out of six monkeys who were challenged with SIV rectally. Tenofovir gel is already moving forward into expanded phase 2 testing (HPTN 059).

One drawback of formulating ARVs into microbicides is that they only work against HIV — with no activity against other STIs or other benefits for vaginal health or contraception. Thus, unless it is combined with products that offer such attributes, a man who discovers that a woman is using an ARV-only microbicide may conclude that she doesn’t trust him — and this could spell trouble for the product’s use once it is marketed.

Another potential weakness for ARV microbicides, at least for those containing only a single ARV compound, is drug resistance. For example, if a woman’s partner has HIV which is resistant to the ARV in her microbicide, she may not be as protected as she thinks. Also, if a woman who is unaware that she is HIV-infected takes a single drug like tenofovir for PREP, she could develop resistance to the drug and possibly limit her future treatment options. It is unclear, however, whether that would happen with a microbicide containing a single ARV that is not systemically absorbed. Drug levels would probably be too low to select for drug resistant virus, but no one knows for certain yet.

Another issue is that the barrier to ARV resistance development may be lower for some subtypes of HIV. For example, in a presentation later during in the conference, Professor Mark Wainberg, of Toronto, Canada, noted that the K65R mutation that confers resistance to tenofovir may be more common in people with HIV-1C. Prof. Wainberg conducted a laboratory study with HIV-1C isolates showing that resistance developed after only twelve weeks exposure to the drug (compared to more than a year for HIV-1B). If tenofovir becomes commonly used for treatment in southern Africa (and at present it is too expensive), its potential for microbicide use could be limited here.

One possible solution to the resistance problem would be to use combination ARVs in the microbicide.

Fortunately, there is a host of ARV compounds to choose from, including many whose clinical development as oral drugs was halted when they were found to have poor systemic absorption. For example, previous animal and human studies have shown that one compound being considered for development, MIV-150, is non-toxic, and although the compound is well tolerated, it was found to be poorly absorbed orally. Another conference presentation was on zinc-finger inhibitors, which never worked out in clinical development as oral compounds, but still look promising as topical microbicides.

Many of the ARVs have been licensed to the International Partnership for Microbicides (IPM). IPM is a non-profit public-private partnership established to accelerate the development of microbicides for resource-limited countries, with funding from the Bill and Melinda Gates Foundation, the Rockefeller Foundation, and from various international governments and multilateral organisations.

IPM identifies the most promising ARV candidates for microbicidal development, licenses them from the big pharmaceutical companies and handles their clinical development. If the microbicides are shown to be effective, IPM has the right to distribute the microbicides at affordable prices in the developing world while the originator pharmaceutical company retains the right to market the products in the western industrialised countries.

IPM’s first product dapirivine (TMC 120) was licensed from Tibotec/Johnson & Johnson only two years ago, and now a gel formulation of the non-nucleoside reverse transcriptase inhibitor (NNRTI) is slated to enter a very large (10,000+ participants) efficacy study next year. IPM is also studying a sustained release formulation of drug (see below). A benefit of such delivery forms is that ARV-containing microbicides can be effective even when applied or delivered long before (or even shortly) coitus.

CCR5 antagonists

CCR5 antagonists, including PSC-RANTES, aplaviroc, maraviroc and Merck-167, are a new class of highly potent ARVs that could be effective even when applied as a topical microbicides days before coitus. CCR5 antagonists bind to CCR5 receptors and specifically block HIV fusion to cells for up to five days — and the virus finds it difficult to develop resistance to them.

Some CCR5 antagonists have had toxicity problems when used as therapeutic agents, however Prof Hillier believes that, since there are a number of these compounds to choose from, with careful preclinical selection, there is a good chance that a safe and effective product can be identified for further development as a topical microbicide.

None of these compounds are in human trials as topical microbicides yet. Howecer, PSC-RANTES has been shown to protect against transmission in the macaque model and is being developed specifically for vaginal application. However, the formulation challenges are considerable because it is a rather large molecule and could be expensive to manufacture. Meanwhile, Merck 167 and two related molecules have recently been licensed for development by IPM.

gp120 binders

Although some microbicides in clinical development may block fusion by binding to gp120, a number of more sophisticated and potent HIV fusion inhibitors have been identified including Cyanovirin-N, dendrimers (SPL, VivaGel), and a couple of BMS compounds that have now been licensed to IPM.

Cyanovirin, which is derived from blue-green algae may be difficult and expensive to formulate. However, it can be expressed in a number of different genetically altered organisms such as tobacco and potentially even in intestinal and vaginal flora (see below).

Dendrimers (SPL, VivaGel), which have also shown activity against herpes virus 2, are in phase 1 clinical trials and beginning studies for STI prevention.

Current gp120 binder formulations (gels) must be used shortly before sex, but in the future these may be formulated for once-daily use or in rings which will allow for non-coital use (see below).

Primary reference

Hillier SL. Microbicides: State of the Art and Its Evolution. Microbicides 2006 Conference, Cape Town, Monday oral plenary, 2006.

Conclusion: Towards combination and multi-purpose products

“There isn’t really a single approach, it's really a family of approaches... and combinations are probably the way that we need to go,” said Prof. Hiller.

She stressed that combinations have a lower risk of breakthrough infections and have a proven therapeutic approach in a number of diseases. There are some challenges though because the complexity of formulating such products can be great. Furthermore, the regulatory approval process of combination products can be tedious. For example, in the United States, the current Food and Drug Administration (FDA) regulatory pathway requires that combination products to be evaluated in “A vs. B vs. A+B” clinical trials. And clinical trials that are trying to measure small improvements (20 to 30%) in an infrequent clinical marker (HIV seroconversion) can wind up being enormous and exhorbitantly expensive. Licensing issues can also be complex — the great hope here, though is IPM, which controls the rights to combine the products that they have licensed any way they like.

Despite these difficulties, Prof. Hillier maintains that “many of us believe that combinations are the long term future.” In the nearer term future, if proven efficacious, combinations of cervical barriers and non-specific microbicides will be the first available. Then she believes that combinations based on acid buffer gels plus a high potency active may be developed because they have lower regulatory barriers.

She also stressed that given the difficulty in moving combination products through clinical trials and towards regulatory approval, it becomes all the more important to give early consideration of formulation and pharmacology challenges. “And researchers need to better define the target for each active microbicide and how best to deliver the microbicide to that target,” she said.

Finally, these products still have to be accepted and used regularly by people once on the market. Prof. Hillier believes that ultimately hybrid combination products that not only work against HIV but serve other purposes such as contraception, preventing other infections or improving vaginal hygiene are the most likely to be accepted and used by women once they reach the market.

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.

Cosgrove-Sweeney Y, Patton D. Cellulose Acetate Phthalate (CAP): Vaginal Safety Evaluation in the Macaque Model. Microbicides 2006 Conference, Cape Town, abstract PA57, 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. Microbicides 2006 Conference, Cape Town, abstract OA35, 2006.

Mosier D. Lack of resistance to a candidate topical microbicide targeting CCR5. Microbicides 2006 Conference, Cape Town, abstract OA8, 2006.

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.

Oladele D et al. Acceptability of savvy (C31G) gel in phase III randomised clinical trial in Lagos, Nigeria. Microbicides 2006 Conference, Cape Town, abstract PC57, 2006.

Hamer D, Henry K. Live Microbial Microbicides for HIV. Microbicides 2006 Conference, Cape Town, abstract OA30, 2006.

Shattock M. Protection of macaques against rectal SIV challenge by mucosally-applied PMPA. Microbicides 2006 Conference, Cape Town, abstract OA15, 2006.

Wallace G. HIV-1 nucleocapsid zinc finger inhibitors (zfi’s) impede HIV-1 trans infection in cellular and explant models. Microbicides 2006 Conference, Cape Town, abstract OA25, 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.