MICROBICIDES
- 1. A S E M I N A R P R E S E N T A T I O N B Y B E N J A M I N G O O D L U C K C . 1 2 / 1 0 3 1 M I C R O B I O L O G Y MICROBICIDES
- 2. INTRODUCTION HIV most often is spread through unprotected vaginal intercourse, with women twice as likely as men to become infected. (UNAIDS, 2001) Women represent more than half (52 percent) of all people living with HIV worldwide and account for nearly 60 percent of those with HIV in sub-Saharan Africa. (Rossi and Collins, 2014) Efforts to promote abstinence, monogamy and the use of male condoms have not been enough to stop the epidemic nor are these approaches practical in many settings. A vaginal microbicide could potentially give women the means to protect themselves against HIV. 2
- 3. WHAT ARE MICROBICIDES? Microbicides are products applied inside the vagina or rectum to protect against sexually transmitted infections (STIs) including human immunodeficiency virus (HIV) through sex (Lerner, 1994) Microbicides can be formulated as gels, creams, films, or suppositories (Ramjee et al., 2001) Microbicides may or may not have spermicidal activity (contraceptive effect) (Wilkinson et al., 2002) 3
- 4. Fig 1. Various Microbicide products, showing; vaginal gel, ring and film. 4
- 5. BRIEF HISTORY The idea for a microbicide-like product was first proposed about 25 years ago by reproductive health specialists and advocates who recognized the need for female-controlled HIV prevention methods. One of the first products considered was the spermicide nonoxynol-9, but clinical trials found it neither safe nor effective against HIV (Wilkinson et al., 2002) Trials of other so-called first generation microbicides also yielded disappointing results. 5
- 6. HOW DO THEY WORK? There are different ways in which microbicides act to prevent infection with genital pathogens. Some microbicides (e.g Carraguard®, Cyanoviran®, cellulose sulphate, PRO 2000®) provide a physical barrier that keeps HIV and other pathogens from reaching the target cells. Another class of microbicides (e.g. Acidform®, BufferGel®) act by enhancing the natural vaginal defence mechanisms by maintaining an acidic pH, which protects the vagina. 6
- 7. Cont. C31G and octoxynol-9 kill or disable pathogens by stripping them of their outer covering. Another class of products e.g tenofovir (PMPA) acts by preventing replication of the virus after it has entered the cell (Karim, 2010) 7
- 8. Fig.2: Mechanism of Action 8
- 9. MICROBICIDES CLINICAL TRIALS There are three phases of clinical trials that a potential mircobicide must pass through before it is judged effective and safe. 1. Phase I involves a small number of volunteers to test the safety of various doses 2. Phase II involves hundreds of volunteers to further assess safety and, in some cases, positive responses 3. Phase III involves thousands of volunteers to test safety and effectiveness 4. The Phase IIb trial, a recent innovation, is a larger variant of the Phase II trial. Phase I tends to last between twelve and eighteen months, whereas the final phase can take up to three or four years (Microbicides Trials Network, 2013) 9
- 10. Fig.3: Process of Testing 10
- 11. There are several different microbicide candidates currently being studied. As of May 2013 there were 11 phase I trials, 1 phase I/II trial, and 4 phase III trials. The current status of ongoing microbicide trials can be found here (MTN, 2013) IPM027 (The Ring Study) MTN 020 (ASPIRE) CAPRISA 008 FACTS 001 11
- 12. Product Clinical Trials Country Case Study Duration Tenofovir Vaginal gel CAPRISA 004 FACTS 001 (PhaseIII) CAPRISA 008 (PhaseIIb) South Africa South Africa South Africa 889 women 2900 women 889 women Completed 2011-2015 2011-2015 Vaginal Rings ASPIRE(MTN-020) (PhaseIII) The Ring Study (IPM 027) (PhaseIII) MTN-013/IPM 026 (PhaseI) MTN-023/IPM 30 and MTN- 024/IPM31 (PhaseI) Malawi, Uganda, South Africa and Zimbabwe South Africa and Uganda United States Malawi, Uganda, South Africa and Zimbabwe 3476 women 1650 women Unknown Adolescent girls and post- menopausal women 2012-2015 2012- 2015/2016 Completed 2012-2016 Table 1: Current Microbicides Clinical Trials 12
- 13. Which microbicide trials have recently ended? CAPRISA 004 This phase IIb trial assessed the safety and effectiveness of tenofovir gel in 900 HIV-negative, sexually active women between the ages of 18 and 40 years, living in South Africa. Results for this trial were announced in July, 2010. The statistically significant results found: 1. Tenofovir gel reduced the risk of HIV infection by 39 percent overall 2. Protective effect increased to 54 percent among women with high gel adherence The CAPRISA 004 study was the first to provide proof of concept for microbicides. The study found statistically significant results showing microbicides can prevent the sexual transmission of HIV (MTN, 2011) 13
- 14. Researchers now are evaluating microbicide products that incorporate ARV drugs, including ARVs commonly used in HIV treatment. The most studied ARV-based microbicide is tenofovir gel, which was found safe and effective in reducing HIV risk in women who used it before and after vaginal sex in a study called CAPRISA 004 but not effective in another study known as VOICE, which was designed to evaluate its daily use (as well as daily use of either the oral ARV tablet tenofovir or Truvada). TENOFOVIR/VAGINAL GELS 14
- 15. Fig.4: Tenofovir Vaginal gel 15
- 16. Fig.5: Picture showing the oral ARV tablet and the tenovovir vaginal gel L-R: Left: Oral ARV tablet (tenofovir) Right: Tenofovir Vaginal gel 16
- 17. As an alternative to vaginal gels, researchers are evaluating other formulations, including paper-thin quickdissolve vaginal films that after insertion would melt away and disperse active drug to protect cells in the vagina. Films are in the early phases of clinical testing. VAGINAL FILMS 17
- 18. Fig.6: A paper-thin quick dissolving vaginal film 18
- 19. VAGINAL RINGS Vaginal rings, flexible products that fit comfortably inside the vagina and provide sustained delivery of drugs over a period of time, are being tested in both early phase studies and Phase III trials. Vaginal ring products are already used in many countries to deliver hormonal contraception. For HIV prevention, the dapivirine ring is the first vaginal ring – and the first HIV-prevention product intended for monthly use – to enter efficacy testing. 19
- 20. Cont. Vaginal rings containing both an ARV and a contraceptive are also being developed that would potentially provide women both HIV protection and contraception in a single product. Phase I trials began in 2014. 20
- 22. RECTAL MICROBICIDES Although the majority of microbicide research has focused on products to prevent HIV through vaginal sex, anal sex is common among men who have sex with men (MSM) and practiced by women around the world. According to some estimates, the risk of infection through anal sex is 20 times greater than vaginal sex because the rectal lining, the mucosa, is thinner and much more fragile than the lining of the vagina. 22
- 23. CONT. An important first step to the development of rectal microbicides has been evaluating the rectal safety of microbicides originally formulated as vaginal gels, in particular, tenofovir gel. An early study found that the vaginal formulation of tenofovir gel caused gastrointestinal side effects when used in the rectum, so researchers tested a reformulated version of the gel with less glycerin in a follow-up study called MTN-007. That study found the reduced glycerin gel safe, acceptable and better tolerated than the vaginal gel when used in the rectum. 23
- 24. HOW IS IT FUNDED? In 2011 around $186 million was invested in microbicide research and development (a 25 percent decrease on the previous year). This decline has been associated with the cycle of funding disbursement, rather than a decline in investment. About 95 percent of this money came from the public sector, 5 percent came from the philanthropic sector, and <1 percent was accounted for by commercial companies (only $1 million). To ensure microbicides a re available to women in low- and middle-income countries, profit margins would need to be low (UNAIDS, 2008) 24
- 25. CONCLUSION A safe and effective microbicide has potential to become a key method of HIV prevention. As the trials above demonstrate, microbicide research and development brings us ever closer to having a successful candidate. Any successful product would have to undergo review and licensing by regulatory agencies before becoming available to the public. It would take time to work out the best formulation and dosage; find a suitable delivery method; and distribute the product. 25
- 26. REFERENCES HIV Vaccines and Microbicides Resource Tracking Working Group (2012) Investing to End the AIDS Epidemic: A New Era for HIV Prevention Research & Development Karim, Q.A. (2010) ' Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women', Science 329(5996) Lerner S., (1994). Microbicides: a woman-controlled HIV prevention method in the making. SIECUS : 22:10-3. Lisa Rossi and Clare Collins. 2014. “ Fact sheet about microbicides”. Microbicides Trials Network, www.mtnstopshiv.org Microbicide Trials Network, (2011). MTN Statement on Decision to Discontinue Use of Tenofovir Gel in VOICE, a Major HIV Prevention Study in Women Microbicide Trials Network, (2013). Fact Sheet: Understanding the results of VOICE 26
- 27. Cont. UNAIDS, (1996). International Working Group on Vaginal Microbicides, Recommendations for the development of microbicides. AIDS, 10:1-6. Ramjee G, Gouws E, Andrews A, Myer L, Weber A.E., (2001). The acceptability of a vaginal microbicides among South African men. International Family planning Perspectives, 27:164-170. UNAIDS, (2001). AIDS epidemic update: Joint United Nations Programme on HIV/AIDS and the World Health Organization. UNAIDS, (2008). Microbicides: challenges to development and distribution. Wilkinson D, Tholandi M, Ramjee G, Rutherford GW., (2002). Nonoxynol- 9 spermicide for prevention of vaginally acquired HIV and other sexually transmitted infections: systematic review and meta-analysis of randomised controlled trials including more than 5000 women. Lancet Infectious Diseases; 2:613-617 World Health Organization, (2009). Regulatory issues in microbicide development. 27