ALLIANCE RIGHTS NIGERIA
#4 JABA CLOSE (CSOHOUSE),
With support from SMAAN
By The ALLIANCE FOR RIGHTS
Rectal Microbicide advocacy in Nigeria
What is it? Why do we need it? What should we do?
MICROBICIDES: Another tool for the control of HIV transmission
1. The Context of Rectal Microbicides
1.1 Role of Anal Intercourse in HIV Transmission
Overall rates of HIV transmission are still increasing, indicating that far greater attention to prevention, including new methods and technologies, is needed to decelerate the epidemic. Latest global figures show that in 2007 there were an additional 2.5 million new infections, and the number of people living with HIV hits at an estimated 33.2 million1.
A range of data suggests that a significant proportion of transmission might be attributed to anal sex. Studies show that up to 30% of the heterosexual population in many cultures engage in anal intercourse (AI) 2 3 4. Given the greater total numbers of heterosexuals than homosexuals, it is estimated that the total volume of heterosexual unprotected AI is up to fivefold that of males who have sex with males (MSM) 5. The prevalence of female AI is projected to be even greater in societies where contraception is unavailable and virginity is prized. Ultimately, it’s difficult to know the exact extent of anal intercourse because it is taboo in many societies and data are not recorded.
While transmission of HIV has shown to be 10- to 100-fold more efficient through anal than vaginal intercourse6 7, studies show that women engaging in AI seldom succeed in having their male partners use condoms8. Likewise, a recent South African study shows that among heterosexual men, anal sex was associated with being HIV-positive; those who engage in the behavior are nearly twice as likely to be infected as their male counterparts reporting only vaginal sex9.
Because women make up the majority of receptive anal partners, they, like MSM, are in need of a rectal HIV-prevention method. The same requirements for the discovery of a vaginal microbicide can be applied to the need for rectal protection: until a woman can negotiate condom use with her partners, she will need protection that she herself can control with or without her partners’ knowledge or participation.
Women are particularly vulnerable to infection. In sub-Saharan Africa, where two-thirds of HIV infections occur10, women aged 15–24 years are three times more likely to be infected than men11. The numbers underscore the need for vaginal microbicide research, to which the majority of microbicide expenditures is allocated. While some of these women are probably infected through anal sex, it is difficult to assess the role of AI in infection. Millions of women have neither the power in their sexual relationships to insist on abstinence, fidelity, or condom use, nor the social and economic resources to leave partners who put them at risk. Thus, putting a woman-controlled prevention tool into the hands of these women is the motivation driving most microbicide research.
Investments in rectal microbicides have been scant for several reasons, including the field’s perceived relevance only to MSM. As we learn more about the incidence and prevalence of heterosexual AI, this misconception will be easier to refute; however, MSM still represent a crucial population in need of interventions. Although the total incidence of unprotected AI is higher in heterosexuals, the prevalence of AI among MSM is higher. Compounding the risk to MSM are the elevated rates of HIV in this population in some regions. For example, MSM made up 44.3% of new infections in the U.S. in 200412. High rates of STIs and HIV infections testify to the fact that only one prevention tool for sexual activity—the condom—is insufficient.
Findings from a Gay Men’s Sex Survey in 2002 in the U.K. showed that 48.8% of all men who had sex with men had had unprotected anal intercourse in the past year13. More findings from the Men Study survey in 2006 in Nigeria showed that 46% of all MSM had had unprotected AI in the past 2 years. Even more concerning is that 14.6% of HIV negative (at last test) or untested men said they definitely, or probably, had unprotected anal sex with a man they thought was HIV-positive in the past year. In other countries, including Canada, Australia, and Scotland, increases in risk behaviors, STIs, and HIV incidences have been documented among MSM14 15 16.
Several surveys have measured gay men’s interest in microbicides. In a U.S. cohort, the majority of the men indicated a willingness to participate in microbicide studies17. An Internet survey of 10,000 MSM in the U.K. showed that most would use a microbicide18. According to a San Francisco study, however, only 25–35% of gay men said they would be interested in using microbicides if they weren’t as effective as condoms19.
Because of this apprehension, it should be emphasized that microbicides, when available, should be used with condoms (if possible) for additional safety; however, even a microbicide that is less effective than condoms could give people who can’t or don’t use condoms a way of reducing their risk of infection—certainly a safer option than using nothing at all.
Efforts are needed to overcome the taboo and stigma around AI, and the denial and homo-phobia that are barriers to ensuring strong efforts to address the health needs of women, gay men, and MSM.
1.2 The Potential Impact of a Rectal Microbicide
Utilizing mathematical modeling, a team from the University of California–Los Angeles (UCLA) recently evaluated the potential impact of rectal microbicides on reducing HIV transmission. Using the MSM bathhouse setting for analysis, it found that even if microbicide use was fairly modest (30–50%), microbicide efficacy would only need to exceed 30% in order to have a significant impact in spreading secondary infections. A 50% effective microbicide, used in 50% of sex acts would reduce the number of new infections at disease invasion in the bathhouse by 13%20. More importantly, this model suggested that a microbicide with greater than 30% efficacy would significantly reduce the number of secondary HIV infections in the bathhouse.
UCLA researchers believe that even a moderately effective rectal microbicide would be of benefit in MSM bathhouse scenarios as well as in other high-risk environments that include heterosexual AI.
The cost savings to the global health system of averting HIV infections with rectal microbicides has yet to be mathematically modeled; however, it can be inferred through vaginal microbicide cost modeling that the savings would be in the billions when rectal microbicide use reduces the burden of care and treatment required of health systems21. The prevention of HIV infection through rectal microbicides will also reduce workplace illness and loss of productivity, resulting in indirect financial savings.
1.3 Socio-cultural Challenges
Microbicide research is a new field with less than 15 years of study. In relation to its potential, the field is underfunded. Large pharmaceutical companies that usually fund new drug development have shied away from microbicide research, as they have with vaccines, because they see it as too much financial risk for too little profit. As a result, the task of microbicide development has fallen to scientists at nonprofit organizations, universities, and small biotech companies— all of which rely on government grants and foundation contributions to keep their research going. Progress has been slow due to inadequate funding from donor governments and from traditional multilateral institutions.
Homophobia and stigma have slowed down the progress of necessary research on the prevention of rectally acquired infections. In Nigeria and elsewhere, investment in rectal microbicides is difficult because civil society and policy makers are hesitant to talk about AI.
1.4 Scientific Challenges
Formulating a microbicide for rectal use is, for two reasons, more scientifically challenging than producing one for vaginal use. First, rectal tissue is far more fragile than most of the tissue lining the vagina. The vaginal epithelium is up to 40 cell layers thick. Rectal epithelium is composed of a single cell layer and is vulnerable to infection and trauma. The cells in the mucosa below the epithelium also contain many CD4 T cells with lots of necessary co-receptors, rendering them especially susceptible to HIV.
Second, the colon is a tube that extends from the anus to the appendix, whereas the vagina is a closed pouch. The inside of the vagina can be completely coated with only about 3–5 ml of product. Since the rectal cavity isn’t closed, it could require significantly more product to cover the rectal walls where they need protection. One of the key questions scientists are trying to answer now is exactly how much product it will take and what areas have to be covered to achieve the desired protective effect.
1.5 Research: Current and Past
To date, published rectal microbicide research has been limited. The only human trials for a specific product were for the spermicide nonoxynol-9 (N-9) in three separate studies in MSM22 23 24. The studies by Phillips et al. demonstrated the potential for significant mucosal toxicity.
Since then, a promising study showed that cyanovirin, an HIV-cell fusion blocker derived from blue-green algae, prevents rectal transmission in the SHIV-infected macaque model25.
A more recent study showed that an oral tenofovir/FTC combination also prevents rectal SHIV transmission in macaques26; however, there is still little known about the basics of HIV transmission in the rectum. Researchers are currently trying to determine which elements of the intestinal mucosa are the initial targets of infection, and which region of the colon needs safeguarding with a microbicide.
In a sobering discovery presented in 2004, scientists found that a semen simulate can travel two to three feet up the colon27, which means a microbicide may be required to travel the same long distance to provide adequate protection. Although this represents a significant challenge, gastroenterologists routinely prescribe topical products to treat colitis associated with inflammatory bowel disease. These products usually formed as foams, enemas, or suppositories, may provide a useful model for developing rectal microbicide formulations.
They are designed to deliver drugs to the same region of the colon that might be most vulnerable to HIV infection. Preclinical rectal microbicide development research includes the use of cell lines, intestinal explants (biopsies), and macaque studies of microbicide safety and efficacy. These investigations will enable the advancement of microbicide studies into exploratory human trials. These studies will optimize microbicide safety evaluation in humans; provide initial ex vivo/in vitro efficacy data; and yield information about distribution and bioavailability of rectal microbicides. The goal will be to assess the most cost-effective and predictive assays for use in future microbicide development.
Other preclinical research will target the behavioral correlates of AI as well as acceptability studies of candidate formulations. These studies are crucial to developing a product that people will find acceptable and actually use. The findings will help guide the selection of the formulation used in final human trials and will provide a rational basis for the development of other classes of rectal microbicides28.
Microbicide compounds that are currently under study for rectal use (in addition to vaginal use) include topical formulations of antiretroviral drugs, including the nucleotide analogue reverse transcriptase inhibitor PMPA, a form of tenofovir, as well as TMC 120 (dapivirine), a second-generation non-nucleoside reverse transcriptase inhibitor. Another non-nucleoside reverse transcriptase inhibitor, UC-781, is poised for phase 1 clinical trials this year.
Rectal microbicide research is underfunded and impeding scientific inquiry. We must advocate for more research, but questions remain as to the most effective strategy: should the rectal microbicide community of advocates, policy makers and scientists in the world continue to ride the status quo, applying for piecemeal Health Research grants and continuing in the shadow of vaginal microbicide research and development?
Or, should the rectal microbicide community take a more directed approach and openly advocate for its own specially funded programs? Will scientists then be more willing to come forward and ask for what they need? “Greater strides in the development of rectal microbicides can be achieved by targeted grant funding,” says Osmond D’Cruz, a researcher at Parker Hughes Institute. “At present, this area is just a side project of vaginal microbicides.”
Others, however, caution that community advocacy efforts on behalf of rectal microbicides may wake a sleeping giant and thus threaten to create a backlash against all microbicide funding. After all, the U.S. funds 74% of global vaginal microbicide public investment29.
Advocates are looking to the governments of Europe and Canada to accelerate their support for rectal microbicide research and development. Although it is possible for advocates and scientists to overtly talk about the need for rectal products without fear of political reprisals in certain countries like Nigeria, many advocates aren’t convinced that setting up a separate program for rectal microbicides is realistic, even in progressive settings.
“We’ve made progress in focusing policy maker attention on the need for microbicides,” says Anna Forbes, coordinator of the Global Campaign’s efforts in North American and Europe. “When people think of new prevention technologies, they tend to think of vaccines first, and we’ve had to do a lot of awareness raising to expand that view,” she adds. “The next move would be to get these governments to recognize the need for parallel rectal and vaginal tracks within the broad topical microbicide funding. That would be a huge step forward.” Specifically, advocates would like to see the European Commission (EC) begin to support
rectal microbicides explicitly within basic science and clinical trial budget lines so that scientists could apply for funding; however, the EC needs to rethink the way it supports microbicides altogether and focus on taking the product all the way through development, instead of only supporting various stages separately. Whatever the strategy, the securing of public funding for every stage of rectal microbicide R&D must be a priority.
Private sector investment will be easier to secure once proof of concept is achieved.
The public and private sectors, donors and investors, international agencies, policy makers, health providers, advocates, and activists all have critical roles to play in ensuring the development of a rectal microbicide for those who need them most—women and their partners, as well males who have sex with males—a large cross-section of the world’s population.
The AIDS Alliance Initiative recommends the following urgent actions in order to discover a rectal microbicide within a time frame proportionate to the urgency of its need.
• Provide a minimum of $350 million for targeted rectal microbicide research funding over the next 10 to 15 years, or an average of at least $35 million per year to build a comprehensive rectal microbicide research program.
• Provide transparency and an increase in institutional commitment to explicitly fund rectal microbicide development.
• Commit to supporting phase 1 rectal safety studies for all vaginal microbicide candidates being evaluated in phase 2B/3 efficacy trials.
International nongovernmental organizations must:
• Form a body to specifically track rectal microbicide development, to ensure funding, and to coordinate research, regulatory approval, and advocacy.
• Recruit new scientists to the field and promote rectal microbicide research within the scientific community.
• Initiate ideas for grant proposals to create demand for funding.
• Reach out to affected communities to educate and to promote rectal microbicide trial preparedness.
• Promote global, national, and regional surveillance efforts to determine percentage of
HIV infections attributed to AI in order to better assess the need for rectal microbicide development.
• Raise awareness, educate, and mobilize communities to foment a stronger, more visible demand for rectal microbicides and to elevate the profile of microbicides among policy makers.
• Ensure linkages to the broader microbicide movement and to advocates working on other prevention technologies.
Regulatory agencies must:
• Create support and development guidelines to accelerate the study and licensure of rectal microbicides.
• Request that all New Drug Applications for vaginal microbicides include at least one rectal safety study as part of the submission package.
1. Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO). UNAIDS/WHO AIDS epidemic update. 2007.
2. Mosher WD, Chandra A, Jones J. Sexual behavior and selected health measures: men and women 15–44 years of age, United States, 2002. Adv Data. September 2005; (362): 1-55.
3. Caceres C, Oss V, Marin B, Hudes E, al e. Young people and the structure of sexual risks in Lima. AIDS. 1997; 11((suppl. 1)): S67–77.
4. Ramjee G GE. Prevalence of HIV among truck drivers visiting sex workers in KwaZulu-Natal, South Africa. Sex Transm Dis. 2002; 29: 44–9.
5. Rohr B, Gross M, Mayer K. Rectal microbicides that protect against HIV infection, report from the Workshop Creating a Research and Development Agenda. Baltimore, Maryland, June 7–8, 2001.
6. Vittinghoff E, Douglas J, Judon F, McKiman D, MacQueen K, Buchinder SP. Per-contact risk of human immunodeficiency virus between male sexual partners. American Journal of Epidemiology. 1999; 150(3): 306–11.
7. Kalichman SC, Rompa D, Luke W, Austin J. HIV transmission risk behaviours among HIV-positive persons in serodiscordant relationships. Int J STD AIDS. October 2002; 13(10): 677–82.
8. Rohr B, et al.
9. Lane T, Pettifor A, Pascoe S, Fiamma A, Rees H. Heterosexual anal intercourse increases risk of HIV infection among young South African men. AIDS. 2006; 20(1): 123–25.
10. Joint United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO). UNAIDS/WHO AIDS epidemic update. 2005.
11. Kim J, Watts CH. Gaining a foothold: tackling poverty, gender, inequality and HIV in Africa. BMJ. 2005; 331: 769–72.
12. Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention-Surveillance and Epidemiology, Special Data Request. November 2005.
13. Hickson F, Weatherburn P, Reid D, Stephens M. Out and about. Findings from the United Kingdom, gay men’s sex survey 2002. Sigma Research, 2003. http://www.sigmaresearch.org.uk/reports.html.
14. HIV/AIDS Epi Updates, May 2005; Surveillance and Risk Assessment Division, Centre for Infectious Disease Prevention and Control, Public Health Agency of Canada, 2005.
15. Van De Ven P, Prestage G, French J, et al. Increase in unprotected anal intercourse with casual partners among Sydney gay men in 1996–98. Aust NZ J Publ Heal. 1998; 22: 814–18.
16. Hart GJ, Williamson LM. Increase in HIV sexual risk behaviour in homosexual men in Scotland, 1996–2002: prevention failure? Sex Transm Infect. October 2005; 81(5): 367–72.
17. Gross M, Buchbinder SP, Celum C, Heagerty P, Seage GR 3rd, Rectal Microbicides for U.S. Gay Men. Are clinical trials needed? Are they necessary? Sex Transm Dis. 1998; 25(6): 296–302.
18. Reid D, Weatherburn P, Hickson F, Stephens M, Hammond G. On the move, findings from the United Kingdom, gay men’s sex survey. Sigma Research. 2003. http://www.sigmaresearch.org.uk/reports.html. Accessed April 3, 2006.
19. The study by Carballo-Diéguez was based on a secondary analysis of data from the third phase of the Urban Men’s Health Study (UMHS-3). Catania J, Paul J, Pollack L, Fisher L, Folkman S, Osmond D. UMHS III Sexual trauma and HIV risk behavior of Gay Men. http://www.caps.ucsf.edu/pdfs/2004portfolio/UMHS3.pdf. Accessed April 7, 2006
20. Breban R, McGowan I, Topaz C, Schwartz E, Anton P, Bowler S. Modeling the potential impact of rectal microbicides to reduce HIV transmission in bathhouses. Mathematical Biosciences and Engineering. In press.
21. The Economics of Microbicide Development: A Case for Investment. Rockefeller Foundation.
22. Tabet SR, Surawicz C, Horton S, et al. Safety and toxicity of nonoxynol-9 gel as a rectal microbicide. Sex Transm Dis. Infect. 1999; 26: 564–71.
23. Phillips DM, Taylor CL, Zacharopoulous VR, Maguire RA. Nonoxynol-9 causes rapid exfoliation of sheets of rectal epithelium. Contraception. 2000;62: 149–54.
24. Phillips DM, Sudol KM, Taylor CL, Guichard L, Elsen R, Maguire RA. Lubricants containing n-9 may enhance rectal transmission of HIV and other STDs. Contraception. 2004; 70: 107–10.
25. Tsai CC, Emau P, Jiang Y, Tian B, Morton WR, Gustafson KR, et al. Cyanovirin-n gel as a topical microbicide prevents rectal transmission of SHIV89.6p in macaques. AIDS Res Hum Retroviruses. 2003; 19: 535–41.
26. Garcia-Lerma J, Otten R, Qari S, Jackson E, Luo W, Monsour M, et al. Prevention of rectal SHIV transmission in macaques by tenofovir/FTC combination [abstract].
Paper presented at: 12th Conference on Retroviruses and Opportunistic Infections. February 5–8, 2005. Boston, MA
27. Hendrix CW, et al. Imaging the distribution of a rectal microbicide gel and semen surrogate in the lower GI tract [abstract]. Paper presented at: International Conference on Microbicides. March 28–31, 2004. London.
28. Global Campaign for Microbicides. Rectal microbicide presentation, November 2005. http://www.global-campaign.org/download.htm. Accessed January 7, 2006
29. http://www.avac.org/#2 Ibid.