Microbicides for sexually transmitted diseases


Microbicides for sexually transmitted diseases
Tenofovir
Tenofovir disoproxil fumarate
Systematic (IUPAC) name
{(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphonic acid
Clinical data
Pregnancy cat. B ( U.S. )
Legal status ℞-only (U.S.) , POM ( UK )
Identifiers
CAS number 147127-20-6 YesY
ATC code J05AF07
Chemical data
Formula C9H14N5O4P 
 N(what is this?)  for sexually transmitted diseases (verify)

Microbicides for sexually transmitted diseases, are pharmacologic agents and chemical substances that are capable of killing or destroying certain microorganisms that commonly cause human infection, for example the human immunodeficiency virus.

Microbicides are a diverse group of chemical compounds 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 trials. Microbicides can be formulated in various delivery systems, including gels, creams, lotions, aerosol sprays, tablets or films that must be used near the time of sexual intercourse, or as sponges, vaginal rings or other devices that release the active ingredient(s) over a longer period of time. Some of these agents are being developed for vaginal 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.[1] In such situations, use of microbicides could offer both primary protection in the absence of condoms 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.[2][3]

Contents

Mechanisms of action

Detergents

Detergent 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.[citation needed] Consequently, laboratory and clinical trials testing this class of products as microbicides have largely been discontinued.[citation needed]

Vaginal defense enhancers

Healthy vaginal pH is typically quite acidic, 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 secretions, 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.[4]

Polyanions

chemical structure of cellulose sulfate
cellulose sulfate, also known as sulfate cellulose or sulfocellulose

The polyanion category of microbicides includes the carrageenans. Carrageenans are a family of linear sulfated polysaccharides, 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 trials. 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.[5] Similarly, the phase III efficacy trial of Carraguard showed that the drug was safe for use but ineffective in preventing HIV transmission in women.[6]

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.[7] 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.[8] And at the beginning of that year, five phase III trials testing different formulations were underway.

Nanoscale dendrimers

Example of dendrimers - their chemical structure is typically symmetric around the core, and often adopts a spherical three-dimensional morphology as the IPA[clarification needed] dendrimers

VivaGel® is a sexual lubricant with antiviral properties manufactured by Australian pharmaceutical company Starpharma. The active ingredient is a nanoscale dendrimeric molecule, chemicals that bind to viruses and prevent them from affecting an organism's cells.[9] 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.[10] 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 papillomaviruses (HPV) and herpes simplex viruses (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.[11]

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.[12] Examples of ARV drugs being tested for prevention include tenofovir, dapivirine (a diarylpyrimidine inhibitor of HIV reverse transcriptase), and UC-781.[13] 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.[14] 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.[15] 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 pathogens.[15]

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 Microbicides began the first study in Africa to test the safety and acceptability of a vaginal ring containing dapivirine.[16] 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.[17]

Substantial numbers of men who have sex with men in developed countries use lubricants containing nonoxynol-9.[citation needed] This suggests that they might be receptive to the concept of using topical rectal microbicides if such products were to become commercially available.[18] 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.[19] 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.[20] 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.

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.[21]

Tenofovir gel,CAPRISA 004

chemical structure of Tenofovir,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.[21] The results of the CAPRISA 004 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.

PRO 2000

MDP1 - chemical structure of molecule

Results released in February 2009 from a clinical trial of PRO 2000 (Indevus Pharmaceuticals, Lexington, Massachusetts), a vaginal microbicide gel (0.5% dose), sparked hope that it might provide modest protection against HIV.[22] 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.[23] 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.[24]

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.[25][26]

Nonoxynol-9

chemical structure of nonoxynol-9

Substantial clinical evidence suggests that regular use of a commonly used spermicide called nonoxynol-9 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.[27]

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.[28][29] 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.[30] 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.[31] 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.[32] 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.[33] 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.[34] One potential risk of the PrEP approach is that drugs present in the systemic circulation might, over time, create ARV-resistant HIV strains.[34]

Social factors

Condoms are a highly effective method for blocking the transmission of most sexually transmitted diseases (with HPV being a notable exception).[citation needed] 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.[35] Thus, topical microbicides might provide a useful woman-initiated alternative to condoms. Some sub-Saharan African cultures view vaginal lubrication as undesirable.[36] 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.[34]

See also

References

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  2. ^ global-campaign. "Research: microbicides". http://www.global-campaign.org/about_microbicides.htm. Retrieved october 2010. 
  3. ^ rectalmicrobicide. "Research: rectalmicrobicides". http://www.rectalmicrobicides.org/. Retrieved october 2010. 
  4. ^ HIV infection. "Research: HIV infection". http://www.hptn.org/web%20documents/HPTN035/NIAID%20HPTN%20035%20Final%20Press%20Release.pdf. Retrieved october 2010. 
  5. ^ HIV infection in women. "Research: HIV infection in women". http://www.avac.org/ht/d/sp/i/3426/pid/3426f. Retrieved october 2010. 
  6. ^ HIV trasmission. "Research: HIV trasmission". http://www.popcouncil.org/mediacenter/newsreleases/Carraguard_Findings.html. Retrieved october 2010. 
  7. ^ Cellulose sulfate microbicide trial stopped. "Research: Cellulose sulfate microbicide trial stopped". http://www.who.int/mediacentre/news/statements/2007/s01/en/index.html. Retrieved october 2010. , World Health Organization
  8. ^ Cellulose sulfate microbicide trial stopped. "Research: Cellulose sulfate microbicide trial stopped". http://www.who.int/mediacentre/news/statements/2007/s01/en/index.html. Retrieved october 2010. 
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  12. ^ http://www.caprisa.org/joomla/index.php/component/content/article/1/225
  13. ^ UC-781. "Research: UC-781". http://www.avac.org/ht/a/GetDocumentAction/i/3109. Retrieved october 2010. 9
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  15. ^ a b BasedMicrobicides. "Research:BasedMicrobicides". http://www.global-campaign.org/clientfiles/FS-ARV-BasedMicrobicides. Retrieved october 2010. 
  16. ^ control to fight AIDS. AFP: "Research:New vaginal ring borrows from birth control to fight AIDS". http://www.google.com/hostednews/afp/article/ALeqM5iZIqphwxvTmJxxhCRibhNPEtsL2Q AFP:. Retrieved october 2010. 
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  19. ^ global-campaign. "global-campaign". http://www.global-campaign.org/rectal.htm#vaginal. Retrieved october 2010. 
  20. ^ Templeton, David (2010-01-09). "$17 million grant to help Pitt researcher develop anti-HIV gel". Pittsburgh Post-Gazette. http://www.post-gazette.com/pg/10009/1027004-114.stm#ixzz0cFx8ZcNr. 
  21. ^ a b caprisa. "caprisa". http://www.caprisa.org/joomla/index.php/component/content/article/1/225. Retrieved october 2010. 
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