Microbicide
Encyclopedia
Microbicides for sexually transmitted disease
s, are pharmacologic
agents and chemical substance
s that are capable of killing or destroying certain microorganism
s that commonly cause human infection
, for example the human immunodeficiency virus
.
Microbicides are a diverse group of chemical compound
s that exert their activity by a variety of different mechanisms of action
.
Multiple compounds are currently being developed and tested for their microbicidal activity in clinical trial
s. Microbicides can be formulated in various delivery systems
, including gel
s, creams
, lotion
s, aerosol spray
s, tablet
s or films
that must be used near the time of sexual intercourse
, or as sponges, vaginal ring
s or other devices that release the active ingredient
(s) over a longer period of time. Some of these agents are being developed for vagina
l application, for rectal
use by those who engage in anal sex
.
Although there are many approaches to preventing sexually transmitted diseases in general and HIV in particular, current methods have not been sufficient to halt the spread of these diseases — particularly among women and people who live in less-developed nations
. Sexual abstinence
is not a realistic option for women who want to bear children or who are at risk of sexual violence
. In such situations, use of microbicides could offer both primary protection in the absence of condom
s and secondary protection if a condom breaks or slips off during intercourse. Microbicides may eventually prove to be safe and effective in reducing the risk of HIV transmission
during sexual activity with an infected partner.
and surfactant
microbicides, such as nonoxynol-9
, sodium dodecyl sulfate and Savvy™ (1.0% C31G), act by disrupting the viral envelope
, capsid
or lipid membrane
of microorganisms. Since detergent microbicides also tend to kill host cells and impair the barrier function of healthy mucosal
surfaces, they are less desirable than other agents. Additionally, clinical trials conducted to date have not demonstrated these agents to be effective at preventing HIV transmission. Consequently, laboratory and clinical trials testing this class of products as microbicides have largely been discontinued.
is typically quite acid
ic, with pH values of around 4. However, the alkaline
pH of semen
can effectively neutralize vaginal pH. One potential class of microbicides acts by reducing the pH of vaginal secretion
s, which might either kill or otherwise inactivate pathogenic microorganisms. One such agent is BufferGel
, a novel spermicidal
and microbicidal gel formulated to maintain the natural protective acidity of the vagina. Thus far, candidates in this category, including BufferGel, have proven to be ineffective in preventing HIV infection.
category of microbicides includes the carrageenan
s. Carrageenans are a family of linear sulfated polysaccharide
s, chemically related to heparan sulfate
, which many microbes utilize as a biochemical receptor
for initial attachment to the cell membrane
. Thus, carrageenan and other microbicides of its class act as decoy receptors for virus
binding.
Carrageenan preparations such as 0.5% PRO 2000 and 3% Carraguard® vaginal microbicide gels thus far have failed to demonstrate efficacy
in preventing HIV transmission in phase III clinical multicenter trial
s. PRO 2000 was demonstrated to be safe, but it did not reduce the risk of HIV infection in women, as explained in the MDP 301 trial results, released in December 2009. Similarly, the phase III efficacy trial of Carraguard showed that the drug was safe for use but ineffective in preventing HIV transmission in women.
Cellulose sulfate is another microbicide that was found to be ineffective in preventing the transmission of HIV. In fact, on February 1, 2007, the International AIDS Society
announced that two phase III trials of cellulose
sulfate
had been stopped because preliminary results suggested a potential increased risk of HIV in women who used the compound. At present, there is no satisfactory explanation as to why application of cellulose sulfate was associated with a higher risk of HIV infection than placebo
. According to a review of microbicide drug candidates by the World Health Organization
on March 16, 2007 a large number of compounds - more than 60 at the start of 2007 - are in the development pipeline. And at the beginning of that year, five phase III trials testing different formulations were underway.
dendrimer
ic molecule, chemicals that bind to viruses and prevent them from affecting an organism's cells. Experimental results to date using VivaGel indicate 85-100% effectiveness at blocking transmission of both HIV and genital herpes
in macaque
monkeys. It has passed through animal testing phases of the drug approval process
in Australia and the United States. Initial human safety tests are to ensue. The National Institutes of Health
and National Institute of Allergy and Infectious Diseases
have awarded grants totaling $25.7 million for VivaGel's continued development and testing. VivaGel is being developed both as a standalone microbicide gel and also as an intravaginal microbicide. VivaGel is also being evaluated for use in condoms by a leading manufacturer. VivaGel's potential benefits could in particular provide an extra resource to mitigate the current sub-Saharan AIDS pandemic
.
In many cases, it is hoped that microbicides will block the transmission of HIV, as well as other sexually transmitted diseases, such as those caused by certain human papillomavirus
es (HPV) and herpes simplex virus
es (HSV). In 2009, StarPharma released its results for a study investigating VivaGel’s antiviral activity against HIV and HSV in humans by testing cervicovaginal samples in vitro (i.e., in a test tube). The compound displayed a high level of efficacy against HIV and HSV. However, while the results are encouraging, the study did not evaluate VivaGel’s effect in the body, so it is still unknown what the results mean for efficacy in women who would use the product in real-life settings. For example, the effect of sexual intercourse or semen on the gel, which oftentimes affects the protective properties of the drug, is still unknown. It should also be noted that the CAPRISA 004 trial demonstrated that topically applied tenofovir gel provided 51% protection against HSV-2.
of HIV reverse transcriptase
), and UC-781. These "next-generation" microbicides have received increasing attention and support because they are based on the same ARV drugs that are currently used to extend the length and improve the quality of lives of HIV-positive people. Additionally, ARVs are used to prevent vertical transmission
of HIV from mother to child during childbirth
, and are often used to prevent HIV infection from developing immediately after exposure
to the virus. Such ARV-based compounds could be formulated into topical
microbicides to be administered locally in the rectum or vagina or systemically through oral or injectable formulations, which are also known as pre-exposure prophylaxis
. ARV-based microbicides may be formulated as long-acting vaginal rings, gels and films. The results of the first efficacy trial of an ARV-based microbicide, CAPRISA 004, tested 1% tenofovir in a gel vehicle to prevent male to female HIV transmission. The trial showed that the gel, which was applied topically to the vagina, was 39% effective at preventing HIV transmission. CAPRISA 004 was the 12th microbicide efficacy study to be completed and the first to demonstrate a significant reduction in HIV transmission. The results of this trial are statistically significant
and offer proof of concept
that ARVs topically applied to the vaginal mucosa can offer protection against HIV and potentially other pathogen
s.
began the first study in Africa to test the safety and acceptability of a vaginal ring containing dapivirine. Drugs might also be administered systemically through injectable or oral formulations known as PrEP. Injectable formulations may be desirable since they could be administered infrequently, possibly once a month. It is likely, however, that such products would need to be monitored closely and would be available only through prescription. This approach also carries the risk of emergence of ARV-resistant strains of HIV.
Substantial numbers of men who have sex with men in developed countries
use lubricants containing nonoxynol-9. This suggests that they might be receptive to the concept of using topical rectal microbicides if such products were to become commercially available. However, the development of rectal microbicides is not as advanced as that of vaginal microbicides. One reason for this is that the rectum has a thinner epithelium, greater surface area and lower degree of elasticity than that of the vagina. Due to these factors, a microbicidal preparation that is effective when applied vaginally might have a different degree of effectiveness when applied rectally. In January 2010, the National Institutes of Health awarded two grants totaling $17.5 million to the University of Pittsburgh
to fund research into rectal microbicides. That research will include investigations into product acceptability of rectal microbicides with homosexual
men ages 18 to 30 years old.
Ultimately, successful topical microbicides might simultaneously employ multiple modes of action. In fact, long-acting formulations such as vaginal rings could provide the technology needed to deliver multiple active ingredients with different mechanisms of action.
trial provide statistically significant evidence that ARVs topically applied to the vaginal mucosa can offer protection against HIV and potentially other pathogens. During the course of the study, 38 of the women who used the tenofovir gel acquired HIV, whereas 60 women who used a placebo gel became HIV-infected. No tenofovir-resistant virus was detected in the women who acquired HIV infection during the study. In addition to showing efficacy against HIV, CAPRISA 004 found evidence that tenofovir gel also prevents transmission of herpes simplex virus type 2 (HSV-2). HSV-2 is a lifelong and incurable infection that can make those infected with the virus two-to-three times more likely to acquire HIV. Data collected during the CAPRISA 004 study indicate that tenofovir gel provided 51% protection against HSV-2. Tenofovir, developed by Gilead Sciences, Inc., is a well-established nucleotide reverse transcriptase inhibitor (NRTI) that interferes with the replication of HIV and is approved in tablet form for use in combination with other ARVs to treat HIV. CAPRISA 004 was a collaboration among CAPRISA, Family Health International
and CONRAD
. It was funded by the United States Agency for International Development
(USAID) and the South African Department of Science and Technology's Technology Innovation Agency
.
, Lexington, Massachusetts), a vaginal microbicide gel (0.5% dose), sparked hope that it might provide modest protection against HIV. However, the results of a larger trial released in December 2009 showed that PRO 2000 was safe as administered but was not effective at reducing the risk of HIV infection. That trial, known as MDP 301, was sponsored by the Microbicides Development Programme. MDP 301 was conducted in South Africa, Tanzania, Uganda and Zambia and included more than 9,300 women volunteers. No significant difference was found in the number of women who contracted HIV in the group given PRO 2000 compared to the group given the placebo. While this trial did not result in an effective product, it served as a model for future HIV prevention trials as it provided critical scientific information as well as important lessons from the extensive social science component and the comprehensive community engagement and preparation undertaken by the trial staff.
actually increases the risk of HIV infection. Early in the HIV/AIDS epidemic, it was discovered that nonoxynol-9 could block the replication of HIV in laboratory tests. For more than a decade, public health professionals recommended nonoxynol-9 for use as a topical microbicide, and many condom and sexual lubricant brands incorporated nonoxynol-9 for this purpose. However, subsequent clinical research showed that nonoxynol-9 can result in the formation of erosions or sores in the vagina or rectum, which are now believed to serve as points of entry for HIV and other sexually transmitted diseases. Consequently, there is now a broad consensus in the public health community that nonoxynol-9 should NOT be used as a topical microbicide.
s are a highly effective method for blocking the transmission of most sexually transmitted diseases (with HPV being a notable exception). However a variety of social factors, including, but not limited to, the sexual disempowerment of women in many cultures, tend to limit the feasibility of condom use. Thus, topical microbicides might provide a useful woman-initiated alternative to condoms. Some sub-Saharan African cultures view vaginal lubrication as undesirable. Since some topical microbicide formulations currently under development function as lubricants, such dry sex traditions may pose a barrier to the implementation of topical microbicide programs. Recent data on product acceptability, however, show that many men and women enjoy using gels that would contain the microbicide drug during sex.
Sexually transmitted disease
Sexually transmitted disease , also known as a sexually transmitted infection or venereal disease , is an illness that has a significant probability of transmission between humans by means of human sexual behavior, including vaginal intercourse, oral sex, and anal sex...
s, are pharmacologic
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
agents and chemical substance
Chemical substance
In chemistry, a chemical substance is a form of matter that has constant chemical composition and characteristic properties. It cannot be separated into components by physical separation methods, i.e. without breaking chemical bonds. They can be solids, liquids or gases.Chemical substances are...
s that are capable of killing or destroying certain microorganism
Microorganism
A microorganism or microbe is a microscopic organism that comprises either a single cell , cell clusters, or no cell at all...
s that commonly cause human infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
, for example the human immunodeficiency virus
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
.
Microbicides are a diverse group of chemical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
s that exert their activity by a variety of different mechanisms of action
Pharmacodynamics
Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect...
.
Multiple compounds are currently being developed and tested for their microbicidal activity in clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s. Microbicides can be formulated in various delivery systems
Drug delivery
Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. Drug delivery technologies modify drug release profile, absorption, distribution and elimination for the benefit of improving product efficacy and safety, as well...
, including gel
Gel
A gel is a solid, jelly-like material that can have properties ranging from soft and weak to hard and tough. Gels are defined as a substantially dilute cross-linked system, which exhibits no flow when in the steady-state...
s, creams
Cream (pharmaceutical)
A cream is a topical preparation usually for application to the skin. Creams for application to mucus membranes such as those of the rectum or vagina are also used. Creams may be considered pharmaceutical products as even cosmetic creams are based on techniques developed by pharmacy and...
, lotion
Lotion
A lotion is a low- to medium-viscosity, topical preparation intended for application to unbroken skin. By contrast, creams and gels have higher viscosity.Lotions are usually applied to external skin with bare hands, a clean cloth, cotton wool or gauze...
s, aerosol spray
Aerosol spray
Aerosol spray is a type of dispensing system which creates an aerosol mist of liquid particles. This is used with a can or bottle that contains a liquid under pressure. When the container's valve is opened, the liquid is forced out of a small hole and emerges as an aerosol or mist...
s, tablet
Tablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose...
s or films
Coating
Coating is a covering that is applied to the surface of an object, usually referred to as the substrate. In many cases coatings are applied to improve surface properties of the substrate, such as appearance, adhesion, wetability, corrosion resistance, wear resistance, and scratch resistance...
that must be used near the time of sexual intercourse
Sexual intercourse
Sexual intercourse, also known as copulation or coitus, commonly refers to the act in which a male's penis enters a female's vagina for the purposes of sexual pleasure or reproduction. The entities may be of opposite sexes, or they may be hermaphroditic, as is the case with snails...
, or as sponges, vaginal ring
Vaginal ring
Vaginal rings are polymeric drug delivery devices designed to provide controlled release of drugs for intravaginal administration over extended periods of time. The ring is inserted into the vagina and provides contraception protection...
s or other devices that release the active ingredient
Active ingredient
An active ingredient is the substance of a pharmaceutical drug or a pharmaceutical ingredient and bulk active in medicine; in pesticide formulations active substance may be used. Some medications and pesticide products may contain more than one active ingredient...
(s) over a longer period of time. Some of these agents are being developed for vagina
Vagina
The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...
l application, for rectal
Rectum
The rectum is the final straight portion of the large intestine in some mammals, and the gut in others, terminating in the anus. The human rectum is about 12 cm long...
use by those who engage in anal sex
Anal sex
Anal sex is the sex act in which the penis is inserted into the anus of a sexual partner. The term can also include other sexual acts involving the anus, including pegging, anilingus , fingering, and object insertion.Common misconception describes anal sex as practiced almost exclusively by gay men...
.
Although there are many approaches to preventing sexually transmitted diseases in general and HIV in particular, current methods have not been sufficient to halt the spread of these diseases — particularly among women and people who live in less-developed nations
Developing country
A developing country, also known as a less-developed country, is a nation with a low level of material well-being. Since no single definition of the term developing country is recognized internationally, the levels of development may vary widely within so-called developing countries...
. Sexual abstinence
Sexual abstinence
Sexual abstinence is the practice of refraining from some or all aspects of sexual activity for medical, psychological, legal, social, philosophical or religious reasons.Common reasons for practicing sexual abstinence include:*poor health - medical celibacy...
is not a realistic option for women who want to bear children or who are at risk of sexual violence
Sexual violence
Sexual violence occurs throughout the world, although in most countries there has been little research conducted on the problem. Due to the private nature of sexual violence, estimating the extent of the problem is difficult...
. In such situations, use of microbicides could offer both primary protection in the absence of condom
Condom
A condom is a barrier device most commonly used during sexual intercourse to reduce the probability of pregnancy and spreading sexually transmitted diseases . It is put on a man's erect penis and physically blocks ejaculated semen from entering the body of a sexual partner...
s and secondary protection if a condom breaks or slips off during intercourse. Microbicides may eventually prove to be safe and effective in reducing the risk of HIV transmission
Transmission (medicine)
In medicine and biology, transmission is the passing of a communicable disease from an infected host individual or group to a conspecific individual or group, regardless of whether the other individual was previously infected...
during sexual activity with an infected partner.
Detergents
DetergentDetergent
A detergent is a surfactant or a mixture of surfactants with "cleaning properties in dilute solutions." In common usage, "detergent" refers to alkylbenzenesulfonates, a family of compounds that are similar to soap but are less affected by hard water...
and surfactant
Surfactant
Surfactants are compounds that lower the surface tension of a liquid, the interfacial tension between two liquids, or that between a liquid and a solid...
microbicides, such as nonoxynol-9
Nonoxynol-9
Nonoxynol-9, sometimes abbreviated as N-9, is an organic compound that is used as a surfactant. It is a member of the nonoxynol family of nonionic surfactants. N-9 and related compounds are ingredients in various cleaning and cosmetic products. It is widely used in contraceptives for its...
, sodium dodecyl sulfate and Savvy™ (1.0% C31G), act by disrupting the viral envelope
Viral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...
, capsid
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
or lipid membrane
Lipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
of microorganisms. Since detergent microbicides also tend to kill host cells and impair the barrier function of healthy mucosal
Mucous membrane
The mucous membranes are linings of mostly endodermal origin, covered in epithelium, which are involved in absorption and secretion. They line cavities that are exposed to the external environment and internal organs...
surfaces, they are less desirable than other agents. Additionally, clinical trials conducted to date have not demonstrated these agents to be effective at preventing HIV transmission. Consequently, laboratory and clinical trials testing this class of products as microbicides have largely been discontinued.
Vaginal defense enhancers
Healthy vaginal pHPH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
is typically quite acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
ic, with pH values of around 4. However, the alkaline
Alkalinity
Alkalinity or AT measures the ability of a solution to neutralize acids to the equivalence point of carbonate or bicarbonate. The alkalinity is equal to the stoichiometric sum of the bases in solution...
pH of semen
Semen
Semen is an organic fluid, also known as seminal fluid, that may contain spermatozoa. It is secreted by the gonads and other sexual organs of male or hermaphroditic animals and can fertilize female ova...
can effectively neutralize vaginal pH. One potential class of microbicides acts by reducing the pH of vaginal secretion
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
s, which might either kill or otherwise inactivate pathogenic microorganisms. One such agent is BufferGel
BufferGel
BufferGel is the brand name of a spermicide and microbicide gel which is being tested for its potential development into a preventative medicine to stop the transmission of HIV.-Testing:...
, a novel spermicidal
Spermicide
Spermicide is a contraceptive substance that eradicates sperm, inserted vaginally prior to intercourse to prevent pregnancy. As a contraceptive, spermicide may be used alone. However, the pregnancy rate experienced by couples using only spermicide is higher than that of couples using other methods...
and microbicidal gel formulated to maintain the natural protective acidity of the vagina. Thus far, candidates in this category, including BufferGel, have proven to be ineffective in preventing HIV infection.
Polyanions
The polyanionPolyelectrolyte
Polyelectrolytes are polymers whose repeating units bear an electrolyte group. These groups will dissociate in aqueous solutions , making the polymers charged. Polyelectrolyte properties are thus similar to both electrolytes and polymers , and are sometimes called polysalts. Like salts, their...
category of microbicides includes the carrageenan
Carrageenan
Carrageenans or carrageenins are a family of linear sulfated polysaccharides that are extracted from red seaweeds. There are several varieties of carrageen used in cooking and baking. Kappa-carrageenan is used mostly in breading and batter due to its gelling nature...
s. Carrageenans are a family of linear sulfated polysaccharide
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
s, chemically related to heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
, which many microbes utilize as a biochemical receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
for initial attachment to the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. Thus, carrageenan and other microbicides of its class act as decoy receptors for virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
binding.
Carrageenan preparations such as 0.5% PRO 2000 and 3% Carraguard® vaginal microbicide gels thus far have failed to demonstrate efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
in preventing HIV transmission in phase III clinical multicenter trial
Multicenter trial
A multicenter research trial is a clinical trial conducted at more than one medical center or clinic. Most large clinical trials, particularly Phase III trials, are conducted at several clinical research centers...
s. PRO 2000 was demonstrated to be safe, but it did not reduce the risk of HIV infection in women, as explained in the MDP 301 trial results, released in December 2009. Similarly, the phase III efficacy trial of Carraguard showed that the drug was safe for use but ineffective in preventing HIV transmission in women.
Cellulose sulfate is another microbicide that was found to be ineffective in preventing the transmission of HIV. In fact, on February 1, 2007, the International AIDS Society
International AIDS Society
The International AIDS Society is an independent association of HIV professionals, with 14,000 members from 190 countries working at all levels of the global response to AIDS. IAS members include researchers from all disciplines, clinicians, public health and community practitioners on the...
announced that two phase III trials of cellulose
Cellulose
Cellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to over ten thousand β linked D-glucose units....
sulfate
Sulfate
In inorganic chemistry, a sulfate is a salt of sulfuric acid.-Chemical properties:...
had been stopped because preliminary results suggested a potential increased risk of HIV in women who used the compound. At present, there is no satisfactory explanation as to why application of cellulose sulfate was associated with a higher risk of HIV infection than placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
. According to a review of microbicide drug candidates by the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
on March 16, 2007 a large number of compounds - more than 60 at the start of 2007 - are in the development pipeline. And at the beginning of that year, five phase III trials testing different formulations were underway.
Nanoscale dendrimers
VivaGel® is a sexual lubricant with antiviral properties manufactured by Australian pharmaceutical company Starpharma. The active ingredient is a nanoscaleNanoscopic scale
The nanoscopic scale usually refers to structures with a length scale applicable to nanotechnology, usually cited as 1-100 nanometers. The nanoscopic scale is a lower bound to the mesoscopic scale for most solids....
dendrimer
Dendrimer
Dendrimers are repetitively branched molecules. The name comes from the Greek word "δένδρον" , which translates to "tree". Synonymous terms for dendrimer include arborols and cascade molecules. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric...
ic molecule, chemicals that bind to viruses and prevent them from affecting an organism's cells. Experimental results to date using VivaGel indicate 85-100% effectiveness at blocking transmission of both HIV and genital herpes
Herpes genitalis
Herpes genitalis refers to a genital infection by Herpes simplex virus.Following the classification HSV into two distinct categories of HSV-1 and HSV-2 in the 1960s, it was established that "HSV-2 was below the waist, HSV-1 was above the waist"...
in macaque
Macaque
The macaques constitute a genus of Old World monkeys of the subfamily Cercopithecinae. - Description :Aside from humans , the macaques are the most widespread primate genus, ranging from Japan to Afghanistan and, in the case of the barbary macaque, to North Africa...
monkeys. It has passed through animal testing phases of the drug approval process
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
in Australia and the United States. Initial human safety tests are to ensue. The National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
and National Institute of Allergy and Infectious Diseases
National Institute of Allergy and Infectious Diseases
The National Institute of Allergy and Infectious Diseases is one of the 27 institutes and centers that make up the National Institutes of Health , an agency of the United States Department of Health and Human Services...
have awarded grants totaling $25.7 million for VivaGel's continued development and testing. VivaGel is being developed both as a standalone microbicide gel and also as an intravaginal microbicide. VivaGel is also being evaluated for use in condoms by a leading manufacturer. VivaGel's potential benefits could in particular provide an extra resource to mitigate the current sub-Saharan AIDS pandemic
HIV/AIDS in Africa
HIV/AIDS is a major public health concern and cause of death in Africa. Although Africa is home to about 14.5% of the world's population, it is estimated to be home to 67% of all people living with HIV and to 72% of all AIDS deaths in 2009.-Overview:...
.
In many cases, it is hoped that microbicides will block the transmission of HIV, as well as other sexually transmitted diseases, such as those caused by certain human papillomavirus
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
es (HPV) and herpes simplex virus
Herpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
es (HSV). In 2009, StarPharma released its results for a study investigating VivaGel’s antiviral activity against HIV and HSV in humans by testing cervicovaginal samples in vitro (i.e., in a test tube). The compound displayed a high level of efficacy against HIV and HSV. However, while the results are encouraging, the study did not evaluate VivaGel’s effect in the body, so it is still unknown what the results mean for efficacy in women who would use the product in real-life settings. For example, the effect of sexual intercourse or semen on the gel, which oftentimes affects the protective properties of the drug, is still unknown. It should also be noted that the CAPRISA 004 trial demonstrated that topically applied tenofovir gel provided 51% protection against HSV-2.
Antiretrovirals
In recent years, researchers have begun to focus on another class of microbicides, the antiretroviral (ARV) agents. ARVs work either by preventing the HIV virus from entering a human host cell, or by preventing its replication after its has already entered. Examples of ARV drugs being tested for prevention include tenofovir, dapivirine (a diarylpyrimidine inhibitorReverse transcriptase inhibitor
Reverse-transcriptase inhibitors are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.-Mechanism:...
of HIV reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
), and UC-781. These "next-generation" microbicides have received increasing attention and support because they are based on the same ARV drugs that are currently used to extend the length and improve the quality of lives of HIV-positive people. Additionally, ARVs are used to prevent vertical transmission
Vertical transmission
Vertical transmission, also known as mother-to-child transmission, is the transmission of an infection or other disease from mother to child immediately before and after birth during the perinatal period. A pathogen's transmissibility refers to its capacity for vertical transmission...
of HIV from mother to child during childbirth
Childbirth
Childbirth is the culmination of a human pregnancy or gestation period with the birth of one or more newborn infants from a woman's uterus...
, and are often used to prevent HIV infection from developing immediately after exposure
Post-exposure prophylaxis
Post-exposure prophylaxis is any prophylactic treatment started immediately after exposure to a pathogen , in order to prevent infection by the pathogen and the development of disease.-Rabies:...
to the virus. Such ARV-based compounds could be formulated into topical
Topical
In medicine, a topical medication is applied to body surfaces such as the skin or mucous membranes such as the vagina, anus, throat, eyes and ears.Many topical medications are epicutaneous, meaning that they are applied directly to the skin...
microbicides to be administered locally in the rectum or vagina or systemically through oral or injectable formulations, which are also known as pre-exposure prophylaxis
Pre-exposure prophylaxis
Pre-exposure prophylaxis is any medical or public health procedure used before exposure to the disease causing agent, its purpose is to prevent, rather than treat or cure a disease. An example would be if a doctor gave a medication used to treat a disease to a healthy person who is not thought to...
. ARV-based microbicides may be formulated as long-acting vaginal rings, gels and films. The results of the first efficacy trial of an ARV-based microbicide, CAPRISA 004, tested 1% tenofovir in a gel vehicle to prevent male to female HIV transmission. The trial showed that the gel, which was applied topically to the vagina, was 39% effective at preventing HIV transmission. CAPRISA 004 was the 12th microbicide efficacy study to be completed and the first to demonstrate a significant reduction in HIV transmission. The results of this trial are statistically significant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
and offer proof of concept
Proof of concept
A proof of concept or a proof of principle is a realization of a certain method or idea to demonstrate its feasibility, or a demonstration in principle, whose purpose is to verify that some concept or theory that has the potential of being used...
that ARVs topically applied to the vaginal mucosa can offer protection against HIV and potentially other pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s.
Formulations
Most of the first generation microbicides were formulated as semi-solid systems, such as gels, tablets, films, or creams, and were designed to be applied to the vagina before every act of intercourse. However, vaginal rings have the potential to provide long-term controlled release of microbicide drugs. Long-acting formulations, like vaginal rings, are potentially advantageous since they could be easy to use, requiring replacement only once a month. This ease of use could prove very important to make sure that products are used properly. In 2010, the International Partnership for MicrobicidesInternational Partnership for Microbicides
The International Partnership for Microbicides or IPM is a non-profit product development partnership founded by Dr. Zeda Rosenberg in 2002 to prevent HIV transmission by accelerating the development and availability of a safe and effective microbicide for use by women in developing...
began the first study in Africa to test the safety and acceptability of a vaginal ring containing dapivirine. Drugs might also be administered systemically through injectable or oral formulations known as PrEP. Injectable formulations may be desirable since they could be administered infrequently, possibly once a month. It is likely, however, that such products would need to be monitored closely and would be available only through prescription. This approach also carries the risk of emergence of ARV-resistant strains of HIV.
Substantial numbers of men who have sex with men in developed countries
Developed country
A developed country is a country that has a high level of development according to some criteria. Which criteria, and which countries are classified as being developed, is a contentious issue...
use lubricants containing nonoxynol-9. This suggests that they might be receptive to the concept of using topical rectal microbicides if such products were to become commercially available. However, the development of rectal microbicides is not as advanced as that of vaginal microbicides. One reason for this is that the rectum has a thinner epithelium, greater surface area and lower degree of elasticity than that of the vagina. Due to these factors, a microbicidal preparation that is effective when applied vaginally might have a different degree of effectiveness when applied rectally. In January 2010, the National Institutes of Health awarded two grants totaling $17.5 million to the University of Pittsburgh
University of Pittsburgh
The University of Pittsburgh, commonly referred to as Pitt, is a state-related research university located in Pittsburgh, Pennsylvania, United States. Founded as Pittsburgh Academy in 1787 on what was then the American frontier, Pitt is one of the oldest continuously chartered institutions of...
to fund research into rectal microbicides. That research will include investigations into product acceptability of rectal microbicides with homosexual
Homosexuality
Homosexuality is romantic or sexual attraction or behavior between members of the same sex or gender. As a sexual orientation, homosexuality refers to "an enduring pattern of or disposition to experience sexual, affectional, or romantic attractions" primarily or exclusively to people of the same...
men ages 18 to 30 years old.
Ultimately, successful topical microbicides might simultaneously employ multiple modes of action. In fact, long-acting formulations such as vaginal rings could provide the technology needed to deliver multiple active ingredients with different mechanisms of action.
Completed clinical trials
A major breakthrough in microbicide research, announced in July 2010, proved that an ARV-based microbicide does work. A trial led by the Centre for the AIDS Programme of Research in South Africa (CAPRISA), conducted in South Africa, demonstrated that the ARV tenofovir, when used in a vaginal gel, was 39% effective at preventing HIV transmission from men to women during sex.Tenofovir gel,CAPRISA 004
In July 2010, the Centre for the AIDS Programme of Research in South Africa (CAPRISA) released results of a study that established "proof of concept" that an ARV-based topical microbicide can reduce the likelihood of HIV transmission. The trial, CAPRISA 004, was conducted in South Africa among 889 women to evaluate the ability of 1% tenofovir gel to prevent male-to-female HIV transmission. In an important milestone for HIV prevention, the CAPRISA 004 study found a 39% lower HIV infection rate in women using 1% tenofovir gel as compared to those women using a placebo gel. In addition, tenofovir gel was shown to be safe as tested. The results of the CAPRISA 004CAPRISA 004
CAPRISA 004 is the name of a clinical trial conducted by CAPRISA. This particular study was the first to show that a topical gel could reduce a person's risk of contracting HIV. The gel used in the study contained a microbicide.-Background:...
trial provide statistically significant evidence that ARVs topically applied to the vaginal mucosa can offer protection against HIV and potentially other pathogens. During the course of the study, 38 of the women who used the tenofovir gel acquired HIV, whereas 60 women who used a placebo gel became HIV-infected. No tenofovir-resistant virus was detected in the women who acquired HIV infection during the study. In addition to showing efficacy against HIV, CAPRISA 004 found evidence that tenofovir gel also prevents transmission of herpes simplex virus type 2 (HSV-2). HSV-2 is a lifelong and incurable infection that can make those infected with the virus two-to-three times more likely to acquire HIV. Data collected during the CAPRISA 004 study indicate that tenofovir gel provided 51% protection against HSV-2. Tenofovir, developed by Gilead Sciences, Inc., is a well-established nucleotide reverse transcriptase inhibitor (NRTI) that interferes with the replication of HIV and is approved in tablet form for use in combination with other ARVs to treat HIV. CAPRISA 004 was a collaboration among CAPRISA, Family Health International
Family Health International
Family Health International is a public health and development organization dedicated to improving living standards of the world's most vulnerable people. Family Health International has 2,500 staff conducting research and implementing programs in fifty-five countries...
and CONRAD
CONRAD (organization)
CONRAD is a non-profit organization which seeks to improve reproductive health, especially in developing countries. It does this by promoting clinical research, particularly that research which involves microbicides for sexually transmitted diseases....
. It was funded by the United States Agency for International Development
United States Agency for International Development
The United States Agency for International Development is the United States federal government agency primarily responsible for administering civilian foreign aid. President John F. Kennedy created USAID in 1961 by executive order to implement development assistance programs in the areas...
(USAID) and the South African Department of Science and Technology's Technology Innovation Agency
Technology Innovation Agency
The Technology Innovation Agency is an organization which reviews and promotes government-funded science projects in South Africa.-Projects:The TIA was a coordinating agency in the following projects:...
.
PRO 2000
Results released in February 2009 from a clinical trial of PRO 2000 (Indevus PharmaceuticalsEndo Pharmaceuticals
Endo Pharmaceuticals Inc. is an American pharmaceutical company. It was created as a result of a management buyout from DuPont Merck in 1997. Three DuPont Merck executives Endo Pharmaceuticals Inc. is an American pharmaceutical company. It was created as a result of a management buyout from...
, Lexington, Massachusetts), a vaginal microbicide gel (0.5% dose), sparked hope that it might provide modest protection against HIV. However, the results of a larger trial released in December 2009 showed that PRO 2000 was safe as administered but was not effective at reducing the risk of HIV infection. That trial, known as MDP 301, was sponsored by the Microbicides Development Programme. MDP 301 was conducted in South Africa, Tanzania, Uganda and Zambia and included more than 9,300 women volunteers. No significant difference was found in the number of women who contracted HIV in the group given PRO 2000 compared to the group given the placebo. While this trial did not result in an effective product, it served as a model for future HIV prevention trials as it provided critical scientific information as well as important lessons from the extensive social science component and the comprehensive community engagement and preparation undertaken by the trial staff.
Carrageenan
The phase III clinical trial for carrageenan-based Carraguard showed that it had no statistical effect on HIV infection, according to results released in 2008. The study did show that the gel was safe, with no side effects or increased risks. The trial also provided valuable information about usage patterns in trial participants.Nonoxynol-9
Substantial clinical evidence suggests that regular use of a commonly used spermicide called nonoxynol-9Nonoxynol-9
Nonoxynol-9, sometimes abbreviated as N-9, is an organic compound that is used as a surfactant. It is a member of the nonoxynol family of nonionic surfactants. N-9 and related compounds are ingredients in various cleaning and cosmetic products. It is widely used in contraceptives for its...
actually increases the risk of HIV infection. Early in the HIV/AIDS epidemic, it was discovered that nonoxynol-9 could block the replication of HIV in laboratory tests. For more than a decade, public health professionals recommended nonoxynol-9 for use as a topical microbicide, and many condom and sexual lubricant brands incorporated nonoxynol-9 for this purpose. However, subsequent clinical research showed that nonoxynol-9 can result in the formation of erosions or sores in the vagina or rectum, which are now believed to serve as points of entry for HIV and other sexually transmitted diseases. Consequently, there is now a broad consensus in the public health community that nonoxynol-9 should NOT be used as a topical microbicide.
Current research
Significant efforts are under way to develop safe and effective topical microbicides. Several different gel formulations are currently undergoing testing in phase III clinical efficacy trials, and about two dozen other products are in various phases of development. Results from CAPRISA 004, while promising, may need to be confirmed by other clinical trials before the microbicide tenofovir gel is made available to the public. This decision rests with regulators, particularly in South Africa. In 2013, the VOICE study (MTN 003), another large-scale trial, is scheduled to release results. VOICE is evaluating three different strategies to prevent HIV in women: one ARV-based microbicide and two different regimens that consist of taking oral ARVs on a daily basis. The VOICE trial is testing 1% tenofovir vaginal gel in a once-daily formulation. It is not known at this time if VOICE will be considered a confirmatory trial for CAPRISA 004, which used a different dosing strategy. Products known as Pre-Exposure Prophylaxis, or PrEP, are also being tested at various stages of the development process. These products, administered orally or via injection, would contain ARVs to protect HIV-negative people from becoming infected. In this strategy, individuals would receive ARVs before they were exposed to HIV, with the goal of lowering their risk or preventing of infection. One of the potential advantages of PrEP is that an individual could use it autonomously, without the need to negotiate with a partner, and it is not dependent on the time of sex. It is hoped that those unable to negotiate condom use with their sex partners would still be able to reduce their risk of HIV infection with the use of an oral or injectable prevention drug. Current PrEP candidates in development include tenofovir and Truvada, which is a combination of two ARV compounds — tenofovir and emtricitabine. One potential risk of the PrEP approach is that drugs present in the systemic circulation might, over time, create ARV-resistant HIV strains.Social factors
CondomCondom
A condom is a barrier device most commonly used during sexual intercourse to reduce the probability of pregnancy and spreading sexually transmitted diseases . It is put on a man's erect penis and physically blocks ejaculated semen from entering the body of a sexual partner...
s are a highly effective method for blocking the transmission of most sexually transmitted diseases (with HPV being a notable exception). However a variety of social factors, including, but not limited to, the sexual disempowerment of women in many cultures, tend to limit the feasibility of condom use. Thus, topical microbicides might provide a useful woman-initiated alternative to condoms. Some sub-Saharan African cultures view vaginal lubrication as undesirable. Since some topical microbicide formulations currently under development function as lubricants, such dry sex traditions may pose a barrier to the implementation of topical microbicide programs. Recent data on product acceptability, however, show that many men and women enjoy using gels that would contain the microbicide drug during sex.
See also
- Rectal microbicideRectal microbicideA rectal microbicide is a microbicide for rectal use. Most commonly such a product would be a topical gel inserted into the anus so that it make act as protection against the contract of a sexually transmitted infection during anal sex....
- sexually transmitted diseaseSexually transmitted diseaseSexually transmitted disease , also known as a sexually transmitted infection or venereal disease , is an illness that has a significant probability of transmission between humans by means of human sexual behavior, including vaginal intercourse, oral sex, and anal sex...
- Tenofovir
- Cellulose sulfate
- Antiseptics
- CondomCondomA condom is a barrier device most commonly used during sexual intercourse to reduce the probability of pregnancy and spreading sexually transmitted diseases . It is put on a man's erect penis and physically blocks ejaculated semen from entering the body of a sexual partner...
- CarrageenanCarrageenanCarrageenans or carrageenins are a family of linear sulfated polysaccharides that are extracted from red seaweeds. There are several varieties of carrageen used in cooking and baking. Kappa-carrageenan is used mostly in breading and batter due to its gelling nature...
- DendrimerDendrimerDendrimers are repetitively branched molecules. The name comes from the Greek word "δένδρον" , which translates to "tree". Synonymous terms for dendrimer include arborols and cascade molecules. However, dendrimer is currently the internationally accepted term. A dendrimer is typically symmetric...
s - supramolecular chemistrySupramolecular chemistrySupramolecular chemistry refers to the area of chemistry beyond the molecules and focuses on the chemical systems made up of a discrete number of assembled molecular subunits or components...
External links
- AVAC
- Information on microbicides
- International Partnership for Microbicides
- Microbicides Development Programme
- Rectal Microbicides
- International Rectal Microbicide
- European Microbicides Project
- AIDSPortal page on microbicides
- Starpharma's VivaGel Product Homepage
- HIV Microbicides and Female-Controlled
- Global Campaign for Microbides
- homepage and IRMA
- CHAARM project:Combined Highly Active Anti-Retroviral Microbicides