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Microbicides in development
| Last updated: 02.04.03 |
Formulations and devices
Formulation and delivery of a microbicide is an entirely different kind of challenge to formulating drugs or vaccines to be taken by mouth or injected. Measuring blood levels is not relevant – except, perhaps, to show that a microbicide is not absorbed! What does matter is how a substance behaves in the special environment in which it is placed.
Vaginal fluids are low in volume, which means that substances cannot easily dissolve into them. They are normally acid (pH 4 to 5) although this varies with the menstrual cycle and a woman’s age, and decreases during pregnancy. This means that a microbicide whose active ingredient won’t work in an acid environment should be avoided, since there is evidence that this acidity helps protect women from infections and should therefore be maintained. A variety of enzymes are released by the body into the vaginal fluids, although fewer than in the gut (and rectum). Again, a microbicide must be stable in the presence of these (Van den Mooter).
Absorption of a microbicide from the vagina – indeed, absorption of many drugs – varies during menstrual cycles, with changes in the thickness of the lining. It also depends on the physicochemical properties of the drug or other substance.
The physical properties of a microbicide will determine whether and how it reaches the surface it needs to cover, if it is to provide protection. The surface area of the vaginal cavity is 60 cm2, and whether a substance coats this rapidly and evenly depends on how it reacts with water, its spreadability and viscosity (and see: Burruano).
How long a substance stays in the vagina might depend on its bio-adhesive quality, which is not easy to predict and seems to depend on a range of chemical characteristics. One way to keep a substance in the vagina, despite the vagina's natural self-cleaning tendency, is to use materials that change their properties as they warm up or become more acid.
Another approach to ensuring microbicides are present when needed would be through slow-release formulations, which might however be expensive to produce. Indeed, one comment from the audience was that gels and creams are so expensive to package and deliver that tablets would be greatly preferable in practice (although there were obviously questions about how well and how fast tablets would dissolve and/or spread to where they were needed).
Ultimately, what matters most is meeting the needs of the product users for something that is very easy to apply, and is either completely unobtrusive during sex and other activities of daily life, or which actually enhances the experience of sex.
Measuring some of these properties of substances placed in the vagina is another challenge. One approach is to use magnetic resonance imaging to visualise what happens when a gel, labelled with non-toxic and non-radioactive gadolinium, is placed in a woman’s vagina. Because this method is non-invasive, and individual scans take around 30 seconds, it is possible to see how the gel is distributed inside the body before, during and after sexual intercourse. Some of the images were taken during actual intercourse, others during and after simulated intercourse using an artificial phallus. This has produced some of the most remarkable images of sex in progress ever presented at a scientific meeting! (Barnhart).
The results of these efforts were to show that while the gel was at first lodged in the upper vagina, near the cervix, it became much more evenly distributed throughout the vagina during intercourse, following a similar pattern with actual and simulated sex. If a woman stands up and walks around, this too has a big effect on the distribution of the gel. It is also clear from his work, as from other people’s, that gel is taken into the cervix where it reaches the uterus. Again, this increases greatly after actual or simulated intercourse.
An alternative and complementary approach is to use fluorescent markers, and to place a transparent phallus-shaped tube inside the vagina (or rectum) and use a scanning system to check the thickness of the gel film along and around the tube. This method shows that different gels do have different properties, and a greater or lesser likelihood of leaving patches of the vaginal wall unprotected (Katz).
Diaphragms
A major implication of research showing the microbicides – and of course semen – are taken up into the uterus is a strong suspicion that this may be where HIV infection occurs. This has led to renewed interest in preventing this using internal barrier methods, such as reusable silicone caps, which may also be turned into a means of delivering (and removing) microbicides from a woman’s vagina.
Perhaps surprisingly, there has still been no randomised controlled trial to look at the effectiveness of internal barriers in preventing either HIV or other STIs, although in 2002 a collaborative research project between the University of Nairobi in Kenya and the University of Washington in the USA began recruiting women from clinics treating STIs into a clinical trial to look at the recurrence rates of gonorrhoea and chlamydia when diaphragms are or are not used. The goal was to recruit 400 women, each to be followed up for 8 weeks at two week intervals (Cohen).
In Zimbabwe, women have been enrolled in a two month programme to help them use condoms more effectively. Those who remain inconsistent in their use of condoms are then recruited into a diaphragm acceptability study, in which they are taught how to apply a diaphragm to protect the cervix, and encouraged to use it with KY jelly. Preliminary results, from the first 156 women enrolled, are that almost all used the diaphragms, and more than half used them more than half the time while having sex (van der Straten).
The pipeline
Where microbicide research is concerned, it can be useful to distinguish between studies of potentially active ingredients and studies of potential products, formulated for use by people. This section is mainly about the ingredients.
There is no shortage of ideas. By 2002, according to the Alliance for Microbicide Development, about 52 product leads were being actively developed, with at least five in Phase II or III clinical trials. Interestingly, this was about the same number as two years before. Several leads - mostly related to nonoxynol-9 - were no longer in active development, while others had been added to the list.
The list which follows sets out some of the categories of active products, and the rationale for their use. Most of these have shown some activity in laboratory studies but, as will be apparent from the previous sections, this is no guarantee that they will be of value in real life.
A more complete list, complete with progress reports on individual products, is maintained and published online by the Alliance for Microbicide Development (www.microbicide.org).
The rationale for these has been explained earlier, and is also discussed in relation to lemon juice (Do we already have a microbicide?). BufferGel is proceeding towards trials as a microbicide; Acidform, developed by TOPCAD, is active against some vaginal infections (Tevi-Benissan). There were disappointing results in a trial where it was combined with N-9 and led to increased adverse effects from the N-9. It may be evaluated as a spermicide in populations at low risk of HIV.
Naturally occurring antibiotics that are poorly absorbed into the body and could be effective against a range of bacteria. Those which act against bacterial membranes can also damage the HIV viral envelope without harming mammalian cells. Gramicidin would be dangerous if it did enter the blood stream and also suffers from the disadvantage that it is not directly soluble in water. An alcohol-based formulation would be incompatible with condoms.
Chlorhexidine has been studied in childbirth, with the idea that a microbicide rinse in the birth canal might protect a baby from exposure to the mother's virus during birth.
Cyanovirin was originally isolated from blue-green algae; it binds very specifically to HIV gp120. Work on cyanovirin is now focussed on engineering lactobacilli to produce it, harmless bacteria which could live in the vagina and provide enhanced protection for long periods
It is also possible to grow large quantities of human anti-HIV antibodies very cheaply in plants. A mixture of several antibodies may be more effective than a single one; there are already animal studies which have shown that SHIV infection can be prevented using such a mixture when administered by injection. It has also been shown that antibodies produced in this way will retain their activity for many hours in vaginal conditions. Unfortunately, female monkeys were not protected from vaginal challenge with an SHIV using an external application of the same monoclonal antibodies that had protected when given by injection, even when those antibodies were directly mixed with the culture used to challenge the monkeys (Lewis).
Lactobacilli are a natural part of the vaginal flora: they produce hydrogen peroxide, which inhibits HIV. They also maintain vaginal acidity through the production of lactic acid. Incidentally, N9 is known to interfere with these bacteria.
These include the three products that are most advanced towards testing in the next round of Phase III trials, as previously mentioned. Cellulose sulphate has also been identified by WHO as a priority for research. Preliminary evidence has been reported that a bacterial polysaccharide related to heparin (but without its anticoagulant properties) is effective against HIV (Vicenzi).
A chemically modified relative of carrageenan (PC-710) has been identified by Population Council researchers and appears more effective than Carraguard in protecting mice against HSV, even when administered after the mice have been exposed to the virus (Maguire).
SAMMA, a polymer of mandelic acid produced by treating it with sulfuric acid, is in pre-clinical evaluation and shows strong inhibition of HIV and HSV without damaging living cells (Herold).
These products all work on the same principle as N9 and may suffer from the same problems. For example, a study of menfegol foaming tablets showed that women who used them experienced a high incidence of internal lesions.
A phase I trial has been carried out on a microbicide containing sodium lauryl sulfate, a detergent widely used as a foaming agent in shampoos and toothpaste. After application twice daily for 14 days by 47 women and 23 male partners, 'minor symptoms (mild or moderate) possibly related to the product use were observed in about one third of subjects. The most common events were erythema, itching, burning sensation, vaginal discharge and vaginal dryness. No genital ulceration or lesions were seen during gel use.' Whether this will be sufficiently reassuring to justify further research remains to be seen; as a detergent, SLS is in the same broad category as nonoxynol-9 (Trottier).
A class of natural and synthetic proteins of which the most famous are haemoglobin and chlorophyll. 75 different compounds have been evaluated in cell culture systems at Emory University, USA, and several have been shown to interact strongly with the HIV-1 envelope molecule, preventing cell entry (Vzorov).
Antiviral drugs as microbicides
A number of antiretroviral drugs are being investigated as potential HIV-specific microbicides. In practice, they would probably be added to other broader spectrum products, to give extra protection against HIV. For example, Loviride has been tested in combination with chlorhexidine, delivered as a vaginal suppository. However, there are some special problems associated with using antiretrovirals in this way.
The list of drugs which have been considered includes;
On the positive side, some of these drugs are highly active against HIV at low concentrations.
NNRTIs such as TMC 210 and UC-781 are interesting because they bind very strongly to the reverse transcriptase enzyme, even within the HIV-1 viral particle, which means they could inactivate the virus before it enters a cell.
Dapivirine (TMC120) from Tibotec-Virco, is the first antiretroviral drug to show protection against HIV as a microbicide in an animal model, in a combined formulation with another potential microbicide. The company is now a part of Johnson and Johnson which means, in effect, that this may be the first microbicide to be developed by a major pharmaceutical company (perhaps more by accident than as part of their corporate strategy).
Similarly, the fusion inhibitor T-20 acts on the virus before it enters the cell and could be particularly effective in preventing infection. However, this drug is currently very costly to manufacture, which rules it out as a practical microbicide. SPL7013 is an experimental product being developed as a microbicide by Star Pharma in Australia, which may be close to clinical trials.
One problem with most of these candidates is that they may be absorbed into the body and, if used regularly by someone with HIV, might select for drug-resistant virus. Drug-resistant virus in the genital tract, if it were then transmitted to a partner or a baby, would be particularly undesirable.
The prime use and need for an HIV-specific microbicide such as one based on these drugs might seem to be, in finding a microbicide that is not also a contraceptive. However, such a microbicide would have especially stringent safety requirements attached to it, on account of the risk to any children that might be born to its users.
The balance of risks and benefits for a drug used at the very earliest stages of pregnancy by an HIV-negative woman could be very different to the balance for the same drug used in the final stages of pregnancy to prevent transmission of HIV from a woman who is known to be HIV-positive.
The likelihood of unexpected side-effects would argue against making antiviral-based microbicides available 'over the counter' from the outset, and a prescription-only microbicide would not be much use as a public health tool.
References
Barnhart KT. Noninvasive in vivo imaging of microbicides. Microbicides 2002, Antwerp (www.itg.be/micro2002), 2002.
Burruano BT et al. Method for the assessment and evaluation of HIV microbicide formulations. XIV International AIDS Conference, Barcelona, abstract MoPeD3663, 2002.
Cohen CR. The diaphragm: a female controlled method to prevent HIV and other sexually transmitted infections? Microbicides 2002, Antwerp (www.itg.be/micro2002), Antwerp.
Di Fabio S et al. Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by a microbicide containing an NNRTI - Dapivirine (TMC120). XIV International AIDS Conference, Barcelona, abstract WeOrD1315, 2002.
Herold B et al. SAMMA is a novel microbicide which inhibits human immunodeficiency virus and herpes simplex virus entry. XIV International AIDS Conference, Barcelona, abstract WeOrD1314, 2002.
Katz DF. Measurement, analysis and interpretation of vagina gel coating distributions in women. Microbicides 2002, Antwerp (www.itg.be/micro2002), 2002.
Lewis MG et al. Neutralizing antibodies applied to the mucosal surface, or preincubated with challenge virus ex vivo fail to protect macaques against SHIV challenge. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 77, 2002.
Maguire R. PC-710, an exceptionally effective carrageenan-based microbicide. XIV International AIDS Conference, Barcelona, abstract TuPeF5302, 2002.
Tevi-Benissan C et al. ACIDFORM: an acid-buffering and bio-adhesive gel with activity against bacterial vaginosis and Trichomonas vaginalis in vitro. XIV International AIDS Conference, Barcelona, abstract MoPeD3659, 2002.
Trottier S et al. Phase I clinical trial to evaluate the safety, tolerance and acceptability of the invisible condom™ when applied intravaginally to healthy female subjects. XIV International AIDS Conference, Barcelona, abstract LbPp2212, 2002 [sodium lauryl sulfate].
Van den Mooter G. Formulation aspects of vaginal microbicides. Microbicides 2002, Antwerp (www.itg.be/micro2002), 2002.
van der Straten A et al. Diaphragms are well accepted in sexually active Zimbabwean women. XIV International AIDS Conference, Barcelona, abstract TuOrD1236, 2002.
Vicenzi E et al. Sulfated Escherichia coli K5 polysaccharide derivatives inhibit human immunodeficiency type -1 (HIV-1) replication. XIV International AIDS Conference, Barcelona, abstract MoPeA3029, 2002.
Vzorov AN et al. Porphyrins with high virucidal activity for HIV-1. XIV International AIDS Conference, Barcelona, abstract MoPeA3023, 2002.
Formulation and delivery of a microbicide is an entirely different kind of challenge to formulating drugs or vaccines to be taken by mouth or injected. Measuring blood levels is not relevant – except, perhaps, to show that a microbicide is not absorbed! What does matter is how a substance behaves in the special environment in which it is placed.
Vaginal fluids are low in volume, which means that substances cannot easily dissolve into them. They are normally acid (pH 4 to 5) although this varies with the menstrual cycle and a woman’s age, and decreases during pregnancy. This means that a microbicide whose active ingredient won’t work in an acid environment should be avoided, since there is evidence that this acidity helps protect women from infections and should therefore be maintained. A variety of enzymes are released by the body into the vaginal fluids, although fewer than in the gut (and rectum). Again, a microbicide must be stable in the presence of these (Van den Mooter).
Absorption of a microbicide from the vagina – indeed, absorption of many drugs – varies during menstrual cycles, with changes in the thickness of the lining. It also depends on the physicochemical properties of the drug or other substance.
The physical properties of a microbicide will determine whether and how it reaches the surface it needs to cover, if it is to provide protection. The surface area of the vaginal cavity is 60 cm2, and whether a substance coats this rapidly and evenly depends on how it reacts with water, its spreadability and viscosity (and see: Burruano).
How long a substance stays in the vagina might depend on its bio-adhesive quality, which is not easy to predict and seems to depend on a range of chemical characteristics. One way to keep a substance in the vagina, despite the vagina's natural self-cleaning tendency, is to use materials that change their properties as they warm up or become more acid.
Another approach to ensuring microbicides are present when needed would be through slow-release formulations, which might however be expensive to produce. Indeed, one comment from the audience was that gels and creams are so expensive to package and deliver that tablets would be greatly preferable in practice (although there were obviously questions about how well and how fast tablets would dissolve and/or spread to where they were needed).
Ultimately, what matters most is meeting the needs of the product users for something that is very easy to apply, and is either completely unobtrusive during sex and other activities of daily life, or which actually enhances the experience of sex.
Measuring some of these properties of substances placed in the vagina is another challenge. One approach is to use magnetic resonance imaging to visualise what happens when a gel, labelled with non-toxic and non-radioactive gadolinium, is placed in a woman’s vagina. Because this method is non-invasive, and individual scans take around 30 seconds, it is possible to see how the gel is distributed inside the body before, during and after sexual intercourse. Some of the images were taken during actual intercourse, others during and after simulated intercourse using an artificial phallus. This has produced some of the most remarkable images of sex in progress ever presented at a scientific meeting! (Barnhart).
The results of these efforts were to show that while the gel was at first lodged in the upper vagina, near the cervix, it became much more evenly distributed throughout the vagina during intercourse, following a similar pattern with actual and simulated sex. If a woman stands up and walks around, this too has a big effect on the distribution of the gel. It is also clear from his work, as from other people’s, that gel is taken into the cervix where it reaches the uterus. Again, this increases greatly after actual or simulated intercourse.
An alternative and complementary approach is to use fluorescent markers, and to place a transparent phallus-shaped tube inside the vagina (or rectum) and use a scanning system to check the thickness of the gel film along and around the tube. This method shows that different gels do have different properties, and a greater or lesser likelihood of leaving patches of the vaginal wall unprotected (Katz).
Diaphragms
A major implication of research showing the microbicides – and of course semen – are taken up into the uterus is a strong suspicion that this may be where HIV infection occurs. This has led to renewed interest in preventing this using internal barrier methods, such as reusable silicone caps, which may also be turned into a means of delivering (and removing) microbicides from a woman’s vagina.
Perhaps surprisingly, there has still been no randomised controlled trial to look at the effectiveness of internal barriers in preventing either HIV or other STIs, although in 2002 a collaborative research project between the University of Nairobi in Kenya and the University of Washington in the USA began recruiting women from clinics treating STIs into a clinical trial to look at the recurrence rates of gonorrhoea and chlamydia when diaphragms are or are not used. The goal was to recruit 400 women, each to be followed up for 8 weeks at two week intervals (Cohen).
In Zimbabwe, women have been enrolled in a two month programme to help them use condoms more effectively. Those who remain inconsistent in their use of condoms are then recruited into a diaphragm acceptability study, in which they are taught how to apply a diaphragm to protect the cervix, and encouraged to use it with KY jelly. Preliminary results, from the first 156 women enrolled, are that almost all used the diaphragms, and more than half used them more than half the time while having sex (van der Straten).
The pipeline
Where microbicide research is concerned, it can be useful to distinguish between studies of potentially active ingredients and studies of potential products, formulated for use by people. This section is mainly about the ingredients.
There is no shortage of ideas. By 2002, according to the Alliance for Microbicide Development, about 52 product leads were being actively developed, with at least five in Phase II or III clinical trials. Interestingly, this was about the same number as two years before. Several leads - mostly related to nonoxynol-9 - were no longer in active development, while others had been added to the list.
The list which follows sets out some of the categories of active products, and the rationale for their use. Most of these have shown some activity in laboratory studies but, as will be apparent from the previous sections, this is no guarantee that they will be of value in real life.
A more complete list, complete with progress reports on individual products, is maintained and published online by the Alliance for Microbicide Development (www.microbicide.org).
- Acid buffers (Acidform, BufferGel)
The rationale for these has been explained earlier, and is also discussed in relation to lemon juice (Do we already have a microbicide?). BufferGel is proceeding towards trials as a microbicide; Acidform, developed by TOPCAD, is active against some vaginal infections (Tevi-Benissan). There were disappointing results in a trial where it was combined with N-9 and led to increased adverse effects from the N-9. It may be evaluated as a spermicide in populations at low risk of HIV.
- Antibiotics (gramicidin, squalamine, defensins - including protegrins)
Naturally occurring antibiotics that are poorly absorbed into the body and could be effective against a range of bacteria. Those which act against bacterial membranes can also damage the HIV viral envelope without harming mammalian cells. Gramicidin would be dangerous if it did enter the blood stream and also suffers from the disadvantage that it is not directly soluble in water. An alcohol-based formulation would be incompatible with condoms.
- Antiseptics (chlorhexidine, undecylinic acid)
Chlorhexidine has been studied in childbirth, with the idea that a microbicide rinse in the birth canal might protect a baby from exposure to the mother's virus during birth.
- HIV-specific binding agents (cyanovirin, monoclonal antibodies/plantibodies)
Cyanovirin was originally isolated from blue-green algae; it binds very specifically to HIV gp120. Work on cyanovirin is now focussed on engineering lactobacilli to produce it, harmless bacteria which could live in the vagina and provide enhanced protection for long periods
It is also possible to grow large quantities of human anti-HIV antibodies very cheaply in plants. A mixture of several antibodies may be more effective than a single one; there are already animal studies which have shown that SHIV infection can be prevented using such a mixture when administered by injection. It has also been shown that antibodies produced in this way will retain their activity for many hours in vaginal conditions. Unfortunately, female monkeys were not protected from vaginal challenge with an SHIV using an external application of the same monoclonal antibodies that had protected when given by injection, even when those antibodies were directly mixed with the culture used to challenge the monkeys (Lewis).
- Hydrogen peroxide ( Lactobacillus suppositories, H202 gel)
Lactobacilli are a natural part of the vaginal flora: they produce hydrogen peroxide, which inhibits HIV. They also maintain vaginal acidity through the production of lactic acid. Incidentally, N9 is known to interfere with these bacteria.
- Sulphated and other charged polymers: dextrin-2-sulphate, dextrans, naphthalene sulphonate polymer (PRO 2000), carrageenans (e.g. CarraGuard = PC-515), sulphonated polysaccharides, polystyrene sulphonate, cellulose sulphate, cellulose acetate phthalate, hydroxyphthalyl-beta-lactoglobulin, heparins.
These include the three products that are most advanced towards testing in the next round of Phase III trials, as previously mentioned. Cellulose sulphate has also been identified by WHO as a priority for research. Preliminary evidence has been reported that a bacterial polysaccharide related to heparin (but without its anticoagulant properties) is effective against HIV (Vicenzi).
A chemically modified relative of carrageenan (PC-710) has been identified by Population Council researchers and appears more effective than Carraguard in protecting mice against HSV, even when administered after the mice have been exposed to the virus (Maguire).
SAMMA, a polymer of mandelic acid produced by treating it with sulfuric acid, is in pre-clinical evaluation and shows strong inhibition of HIV and HSV without damaging living cells (Herold).
- Surface Active Agents (surfactants): N9 in new formulations, N9/octoxynol-9 /benzalkonium chloride (BZK)/sodium cholate (NaCh) combinations, amphoteric surfactants (e.g. C31G), menfegol, N-docasanol, 2-octylglycerol, polybiguanides, sodium dodecyl sulfate (SDS).
These products all work on the same principle as N9 and may suffer from the same problems. For example, a study of menfegol foaming tablets showed that women who used them experienced a high incidence of internal lesions.
A phase I trial has been carried out on a microbicide containing sodium lauryl sulfate, a detergent widely used as a foaming agent in shampoos and toothpaste. After application twice daily for 14 days by 47 women and 23 male partners, 'minor symptoms (mild or moderate) possibly related to the product use were observed in about one third of subjects. The most common events were erythema, itching, burning sensation, vaginal discharge and vaginal dryness. No genital ulceration or lesions were seen during gel use.' Whether this will be sufficiently reassuring to justify further research remains to be seen; as a detergent, SLS is in the same broad category as nonoxynol-9 (Trottier).
- Porphyrins
A class of natural and synthetic proteins of which the most famous are haemoglobin and chlorophyll. 75 different compounds have been evaluated in cell culture systems at Emory University, USA, and several have been shown to interact strongly with the HIV-1 envelope molecule, preventing cell entry (Vzorov).
Antiviral drugs as microbicides
A number of antiretroviral drugs are being investigated as potential HIV-specific microbicides. In practice, they would probably be added to other broader spectrum products, to give extra protection against HIV. For example, Loviride has been tested in combination with chlorhexidine, delivered as a vaginal suppository. However, there are some special problems associated with using antiretrovirals in this way.
The list of drugs which have been considered includes;
- NNRTIs: TMC 210 (dapivirine), UC-781 (thiocarboxanilide), nevirapine (NVP), loviride (loviridine)
- nucleotide analogues: tenofovir
- nucleoside analogues: AZT derivatives, lamivudine (3TC), didanosine (ddI)
- receptor blockers: bicyclams
- entry/fusion inhibitors: T-20, SPL7013
On the positive side, some of these drugs are highly active against HIV at low concentrations.
NNRTIs such as TMC 210 and UC-781 are interesting because they bind very strongly to the reverse transcriptase enzyme, even within the HIV-1 viral particle, which means they could inactivate the virus before it enters a cell.
Dapivirine (TMC120) from Tibotec-Virco, is the first antiretroviral drug to show protection against HIV as a microbicide in an animal model, in a combined formulation with another potential microbicide. The company is now a part of Johnson and Johnson which means, in effect, that this may be the first microbicide to be developed by a major pharmaceutical company (perhaps more by accident than as part of their corporate strategy).
Similarly, the fusion inhibitor T-20 acts on the virus before it enters the cell and could be particularly effective in preventing infection. However, this drug is currently very costly to manufacture, which rules it out as a practical microbicide. SPL7013 is an experimental product being developed as a microbicide by Star Pharma in Australia, which may be close to clinical trials.
One problem with most of these candidates is that they may be absorbed into the body and, if used regularly by someone with HIV, might select for drug-resistant virus. Drug-resistant virus in the genital tract, if it were then transmitted to a partner or a baby, would be particularly undesirable.
The prime use and need for an HIV-specific microbicide such as one based on these drugs might seem to be, in finding a microbicide that is not also a contraceptive. However, such a microbicide would have especially stringent safety requirements attached to it, on account of the risk to any children that might be born to its users.
The balance of risks and benefits for a drug used at the very earliest stages of pregnancy by an HIV-negative woman could be very different to the balance for the same drug used in the final stages of pregnancy to prevent transmission of HIV from a woman who is known to be HIV-positive.
The likelihood of unexpected side-effects would argue against making antiviral-based microbicides available 'over the counter' from the outset, and a prescription-only microbicide would not be much use as a public health tool.
References
Burruano BT et al. Method for the assessment and evaluation of HIV microbicide formulations. XIV International AIDS Conference, Barcelona, abstract MoPeD3663, 2002.
Cohen CR. The diaphragm: a female controlled method to prevent HIV and other sexually transmitted infections? Microbicides 2002, Antwerp (www.itg.be/micro2002), Antwerp.
Di Fabio S et al. Inhibition of vaginal transmission of HIV-1 in hu-SCID mice by a microbicide containing an NNRTI - Dapivirine (TMC120). XIV International AIDS Conference, Barcelona, abstract WeOrD1315, 2002.
Herold B et al. SAMMA is a novel microbicide which inhibits human immunodeficiency virus and herpes simplex virus entry. XIV International AIDS Conference, Barcelona, abstract WeOrD1314, 2002.
Katz DF. Measurement, analysis and interpretation of vagina gel coating distributions in women. Microbicides 2002, Antwerp (www.itg.be/micro2002), 2002.
Lewis MG et al. Neutralizing antibodies applied to the mucosal surface, or preincubated with challenge virus ex vivo fail to protect macaques against SHIV challenge. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 77, 2002.
Maguire R. PC-710, an exceptionally effective carrageenan-based microbicide. XIV International AIDS Conference, Barcelona, abstract TuPeF5302, 2002.
Tevi-Benissan C et al. ACIDFORM: an acid-buffering and bio-adhesive gel with activity against bacterial vaginosis and Trichomonas vaginalis in vitro. XIV International AIDS Conference, Barcelona, abstract MoPeD3659, 2002.
Trottier S et al. Phase I clinical trial to evaluate the safety, tolerance and acceptability of the invisible condom™ when applied intravaginally to healthy female subjects. XIV International AIDS Conference, Barcelona, abstract LbPp2212, 2002 [sodium lauryl sulfate].
Van den Mooter G. Formulation aspects of vaginal microbicides. Microbicides 2002, Antwerp (www.itg.be/micro2002), 2002.
van der Straten A et al. Diaphragms are well accepted in sexually active Zimbabwean women. XIV International AIDS Conference, Barcelona, abstract TuOrD1236, 2002.
Vicenzi E et al. Sulfated Escherichia coli K5 polysaccharide derivatives inhibit human immunodeficiency type -1 (HIV-1) replication. XIV International AIDS Conference, Barcelona, abstract MoPeA3029, 2002.
Vzorov AN et al. Porphyrins with high virucidal activity for HIV-1. XIV International AIDS Conference, Barcelona, abstract MoPeA3023, 2002.