Fa m i l y He a l t h RESEARCH A forum for putting knowledge into practice JuLY 2008 Volume 2, Issue 2

INSIDE

2 Clinical research update

4 Evaluating tenofovir gel in South Africa

6 Participating in microbicide trials

7 Preparing for microbicides

8 Research and advocacy partnerships sub-Saharan Africa still suffers the most from MICROBICIDES the epidemic. More than two-thirds of all HIV- FOR HIV infected people in the world live in this region. Of these, more than 60 percent are women. PREVENTION Young women are even more disproportion- ately affected. In South Africa, for example, This issue describes efforts to develop women make up 90 percent of the HIV- a safe, effective, and acceptable vaginal infected population of 15- to 24-year-olds. microbicide to prevent HIV. Women are at especially high risk of HIV Scientists around the world are working infection because of biologic susceptibility, diligently to develop new ways to prevent HIV, economic dependence on male partners, including vaccines, pre-exposure prophylaxis and inability to negotiate use within (when drugs normally used to treat HIV are all of their sexual relationships. A method of used for prevention), and topical microbicides. HIV prevention that a woman could control, Advocacy and support for prevention research such as a , could help are strong, and the availability of an effective overcome some of these inequities and save product—although likely years away—could many lives. help alleviate the HIV epidemic in sub-Saharan Africa and worldwide. An effective microbicide could be a powerful addition to current efforts to protect against The Joint United Nations Programme on HIV, including abstinence, mutual monog- HIV/AIDS recently announced that the preva- amy with uninfected partners, condom use, lence of HIV has stabilized or declined in many treatment of sexually transmitted infections, parts of sub-Saharan Africa. Nevertheless, and male circumcision. FAMILY HEALTH RESEARCH FIELD RESEARCH REPORT Eventually, a combination of different prod- ucts with more than one mechanism of action CLINICAL RESEARCH may be the most effective way to prevent a UPDATE wide range of STIs. Products with a contracep- KEYPOINTS tive ability will also be important for meeting The research pipeline is filled with diverse reproductive health needs. hopeful microbicide candidates. n An effective vaginal Research process microbicide has not Research to develop an effective vaginal After a microbicide candidate is identified, yet been identified. microbicide began nearly three decades ago. its safety and effectiveness is first assessed in test tubes and animal models. If the product n Today, more than 60 different products are in Three products are passes this stage of testing, it enters human being studied in some stage of laboratory or clinical develop- ment. Eleven of these products are in human clinical trials. large-scale effective- clinical trials, and three are in large-scale ness trials. effectiveness trials. However, no candidate In Phase I microbicide trials, scientists assess the safety of the product, determine its n The newest candi- microbicide has yet been shown to prevent HIV or other sexually transmitted infections acceptability among potential users, and dates are designed (STIs) in humans. identify its appropriate dose and formula- to stop HIV from tion. In Phase II trials, scientists again assess replicating. “The process of product development is safety and acceptability, but among more long, but the HIV-prevention community is participants and for a longer period. hopeful that an effective topical agent will be identified within the next decade,” says Dr. The final stages of microbicide trials (Phase Willard Cates, president of research at FHI. IIb and Phase III trials) are used to evaluate a product’s effectiveness in preventing HIV and other STIs. Phase IIb trials are typically smaller Types of products than Phase III trials, giving some indication of The “first generation” of microbicide candi- effectiveness and helping scientists decide dates are typically formulated as gels, which whether a larger Phase III trial is necessary. are applied to the before each act of Lasting up to four years, Phase III trials enroll sexual intercourse. These candidates employ thousands of participants who are at risk of one of three mechanisms that should theo- HIV, such as those living in communities with retically prevent HIV and other STI pathogens a relatively high incidence of HIV. from infecting cells. Some are surfactants (agents that reduce the surface tension of a Although all participants in microbicide trials liquid) that inactivate a bacterium or virus are regularly counseled on how to reduce by damaging its surface membrane. Others their risks of acquiring HIV and other STIs, enhance the vagina’s natural defenses against prior experience has shown that even with pathogens, for example by maintaining the optimal counseling and free access to con- natural acidity of the vagina in the presence doms, most women are not able to negotiate of semen, which is alkaline. Still others block condom use every time they have sex. The viruses from attaching to healthy cells. effectiveness of a candidate microbicide is tested in those sex acts in which women are The next generation of microbicide candi- not able to use . dates is based on antiretroviral drugs. These products specifically target HIV, acting later in the viral life cycle to prevent HIV from replicat- Ruling out candidates ing once it has entered the body. Although Three first-generation products—SAVVY, cellulose sulfate, and Carraguard—were ruled A counselor explains condom some are formulated as gels, others may be use to a woman participating in released through vaginal rings. And, unlike out as effective microbicides in advanced a microbicide trial. the first-generation candidates, some of the clinical trials. newer products may be delivered on a daily or monthly basis (such as through a vaginal ring) In 2005, FHI closed its Phase III trial of SAVVY regardless of the timing of intercourse. (a surfactant) in Ghana when an independent data monitoring committee determined that

page 2 JULY 2008 FAMILY HEALTH RESEARCH the incidence of HIV was so low that the study South Africa. Results, released in 2008, showed would not be able to determine whether that the Carraguard gel was safe and accept- SAVVY could prevent HIV. FHI closed its paral- able. However, it did not reduce the risk of lel Phase III trial of SAVVY in Nigeria in 2006, acquiring HIV. Although these results were after a similar committee concluded that the disappointing, the Carraguard trial was the first trial was unlikely to find a protective effect if effectiveness trial to be completed as planned it continued. Earlier studies had shown that for a product that was developed specifically spermicides containing another surfactant, as a microbicide—an historic accomplishment nonoxynol-9, may actually increase the risk in the eyes of many microbicide advocates. of HIV infection when women at high risk of infection use them frequently. More effectiveness trials Three microbicide candidates—BufferGel, In 2007, CONRAD closed its Phase III trial PRO 2000, and tenofovir—are currently in of cellulose sulfate (an inhibitor of viral large-scale effectiveness trials. Three additional attachment and entry) in South Africa, products—ACIDFORM, the invisible condom, Benin, Uganda, and India after a planned and dapivirine—will enter the advanced interim analysis suggested that the product stages of clinical trials soon (see table). might contribute to an increased risk of HIV. Because of these safety concerns, FHI simul- “As with all other HIV-prevention taneously closed its Phase III trial of cellulose approaches, no vaginal product is expected sulfate in Nigeria. However, the final data to offer 100 percent protection against HIV from both trials showed that cellulose sulfate or other STIs,” says Dr. Cates. “At best, an had not significantly affected the risk of HIV effective product would prevent infection infection either positively or negatively. perhaps half the time. But even a partially effective microbicide could help women Most recently, the Population Council com- who might otherwise not be able to protect pleted a Phase III trial of Carraguard (another themselves at all.” inhibitor of viral attachment and entry) in

Microbicide Effectiveness Trials

Mechanism of action Microbicide Trial status Enhances vaginal defenses BufferGel* The Microbicide Trials Network is conducting a Phase II/IIb trial of BufferGel vs. 0 5% against pathogens PRO 2000 gel vs. a placebo vs. no intervention (condoms only) in Malawi, South Africa, Zambia, Zimbabwe, and the United States. Results of the trial, begun under the HIV Prevention Trials Network, are expected in 2009. ACIDFORM* CONRAD and partners are planning a Phase III trial of a diaphragm with ACIDFORM gel in Madagascar (for the prevention of STIs other than HIV). Inhibits viral attachment PRO 2000* The Microbicides Development Programme is conducting a Phase III trial of 0.5% PRO and entry 2000 gel vs. a placebo in Zambia, Tanzania, and South Africa. Results are expected in 2009. See “BufferGel” above for information on a second trial involving PRO 2000. Invisible condom* Scientists at Laval University and partners are planning a Phase III trial of the invisible condom (a gel containing sodium lauryl sulfate, a common ingredient in soap). Sites are to be determined. Inhibits viral replication Tenofovir The Centre for the AIDS Programme of Research in South Africa (CAPRISA) and part- ners are conducting a Phase IIb trial of 1 percent tenofovir gel vs. a placebo in South Africa. Results are expected in 2010. The Microbicide Trials Network is planning a Phase IIb study of tenofovir gel vs. oral tenofovir vs. oral Truvada (a combination of tenofovir and a second antiretroviral drug, emtricitabine) vs. a placebo gel vs. an oral placebo in South Africa, Malawi, Uganda, Zambia, and Zimbabwe. Dapivirine The International Partnership for Microbicides is planning a Phase III trial of dapivirine gel. Sites are to be determined.

* Also being evaluated for contraceptive ability.

page 3 A FORUM FOR PUTTING KNOWLEDGE INTO PRACTICE FAMILY HEALTH RESEARCH FIELD RESEARCH REPORT A semi-rural district outside of Durban, Vulindlela is home to almost half a million EVALUATING people. For years, the residents of Vulindlela TENOFOVIR GEL had experienced the effects of AIDS on their community, watching as family graveyards IN SOUTH AFRICA filled up at an astonishing pace. Finally, the traditional village chief, or Inkosi, was com- Community members play important pelled to take an unusual step: He contacted role in trial. a group of local scientists.

The Centre for the AIDS Programme of Dr. Abdool Karim was one of the scientists Research in South Africa (CAPRISA) and its who met with the traditional leaders of partners are testing the effectiveness of teno- Vulindlela one Saturday morning in 2001. fovir gel—a promising antiretroviral-based After welcoming the visitors, the Inkosi microbicide—in two South African com- apologized that he could not spend the munities. The intense collaboration between entire day with the group, as planned. “He CAPRISA and the community of Vulindlela had several funerals to attend,” recalls Dr. demonstrates just how vital community Abdool Karim. involvement can be in the preparation and conduct of a microbicide trial. In response to the concerns of the tradi- tional leaders, CAPRISA conducted extensive “Vulindlela is one of many communities we research on the nature of the HIV epidemic have worked in,” says Dr. Quarraisha Abdool in the community. For two years, scientists Karim, CAPRISA’s associate scientific direc- hosted focus group discussions with local tor and one of the principal investigators of stakeholders, studied the HIV cases from The semi-rural district of Vulindlela, the tenofovir gel trial. “But our experience in local clinics, and conducted “verbal” autop- shown here, is one of two communities Vulindlela has been unique.” sies to establish the main causes of death participating in the trial. in the community. Armed with these data,

THE TRIAL ...... AND WHY IT IS UNIQUE n Phase IIb study evaluating the safety and n First effectiveness trial of an antiretroviral- effectiveness of tenofovir gel in preventing based microbicide HIV infection n First microbicide trial that an institution in n Enrolling 980 sexually active, HIV- the developing world is leading uninfected women, ages 18 to 40, who are n First microbicide trial that a South African at high risk of acquiring HIV government agency is co-funding n Being conducted at clinical research sites n First time that South Africa has secured an in Vulindlela and Durban up-front voluntary license to manufacture n Study participants randomized to use either and distribute a microbicide if it is proven 1 percent tenofovir gel or a placebo gel effective n Participants counseled to apply the gel via single-use, prefilled applicators before and after intercourse n Participants given free condoms and coun- seled on reducing the risks of infection n Participants and their partners provided with free screening and treatment for sexually transmitted infections n Results expected in 2010

page 4 JULY 2008 FAMILY HEALTH RESEARCH they were able to secure funding to estab- community, study participants, and research lish an AIDS treatment program. Today, the team. The group is a mixture of commu- program cares for more than 5,000 patients, nity leaders, representatives from religious including 1,300 who are receiving antiretro­ and women’s organizations, young people, viral treatment. As part of a community government health care providers, and other fellowship program, CAPRISA also trained 32 stakeholders who review study materials and CAPRISA community members as HIV/AIDS educators. provide advice on recruitment and reten- tion. They also function as a conduit through CAPRISA is a nonprofit organiza- Despite these accomplishments, the preva- which community members can voice any tion dedicated to researching new lence of HIV remained high in Vulindlela. At concerns about the trial or other research ways to prevent and treat HIV last measure, about 55 percent of women ages that CAPRISA is conducting. and tuberculosis, and to building 20 to 24 were infected. This alarming statistic local research infrastructure and highlighted the importance of finding an So far, more than 3,000 women in Vulindlela capacity. CAPRISA is collaborating effective HIV-prevention method that women have received general information about with CONRAD, FHI, and the South could control. Ultimately, CAPRISA selected the tenofovir gel trial. Among these women, African Ministry of Science and Vulindlela as one of the study sites for its teno- 800 volunteers have been screened, and Technology (through LIFElab) on its fovir gel trial, which began in May 2007. 454 have been enrolled in the study. As a effectiveness trial of tenofovir gel. testament to CAPRISA’s dedication to build- More information about the trial is available at: http://www.caprisa. Together, the researchers and local tradi- ing research capacity in the region, all of org/Projects/microbicides.html#5. tional leaders established the Vulindlela the study staff—including the recruitment Community Research Support Group teams, community educators, and project to function as a liaison between the managers—are South African.

ADHERENCE within 12 hours before sex and again up A participant’s adherence to the study regi- to 12 hours after sex, no matter how many men is absolutely vital for valid results in times a woman has sex within that period. a trial. Yet, unstable living conditions and This core message is summarized as BAT-24: other stressors sometimes make it difficult a dose Before sex, a dose After sex, and not for women to follow the directions for using more than Two applications within 24 hours. the study products. When a woman reports problems with The CAPRISA team has implemented an adherence, the nurse helps her develop a innovative Adherence Support Program to plan to address them. The counselor also help increase adherence rates. The program writes “adherence support prescriptions” that is based on the intention-motivation- spell out practical, customized suggestions behavioral skills model of HIV prevention, for each individual’s situation. which reduces the risk of infection through behavioral change.

Before enrolling in the trial, potential partici- pants learn about using the gel applicators, possible side effects of the gel, the time Explicit instructions on using required to participate in the trial, and the the gel applicators, combined benefits and risks of participating. Once with tailored counseling dur- enrolled, each woman receives tailored ing the trial, help participants adhere to the study regimen. counseling provided by a nurse using an approach called “motivational interviewing.” Counselors use various teaching techniques to emphasize that the gel has to be inserted

page 5 A FORUM FOR PUTTING KNOWLEDGE INTO PRACTICE FAMILY HEALTH RESEARCH FIELD RESEARCH REPORT also use a questionnaire to assess a woman’s understanding of a study before she signs an PARTICIPATING IN informed consent form agreeing to participate MICROBICIDE TRIALS in the study. KEYPOINTS Researchers use multiple strategies to However, researchers also recognize that protect participants. informed consent should be a continuing n The informed con- process rather than a one-time event. In the sent process aims to two Phase III cellulose sulfate trials that have Since 1996, more than 20,000 women have give participants a been conducted, for instance, the study staff participated in clinical trials to help identify a complete, continuing administered this type of questionnaire both safe and effective vaginal microbicide. understanding of a before and during the trials. trial. All of the women volunteered for the trials, knowing they were going to help answer Involving communities n Community repre- a question about the safety, acceptability, Researchers also have an increasing appre- sentatives can help and in some cases effectiveness of a study ciation for the value of involving communi- researchers design product. They agreed to return to their study ties in decisions about how the trials are trials that are accept- sites every three months, or even monthly, designed and implemented. Most trials have able, relevant, and to receive counseling, supplies of gel and community liaison officers, and many have ethical. condoms, and an HIV test. community advisory boards that serve as a link between researchers and the communi- n Ensuring continuity of Study staff also made a commitment to the ties where the research is conducted. Some care for women who women. In their study protocols, counseling trials also train participants to educate their become infected with messages, and educational materials, the fellow participants and other community HIV during a trial is staff outlined how they would protect the members about the study. challenging. safety, confidentiality, and human rights of each study participant. Their experiences have These community representatives help ensure shown just how complex—and critical—that that the trials are designed and implemented commitment can be. in an acceptable, relevant, and ethical way. The representatives review study protocols and informed consent forms, evaluate draft Truly informing women educational materials, relay community First, researchers have an ethical responsibil- concerns to the study staff, refute rumors, and ity to ensure that participation in a clinical help disseminate study results. Such commu- trial is voluntary and that the women who nity involvement generates support for micro- enroll in a trial understand exactly what their bicide research and reduces the likelihood participation means. that a woman will be stigmatized because of her participation in a trial. The women must understand that the researchers do not know whether the study product works, that a portion of the partici- Ensuring access to care pants may be randomly assigned to use a One of the most complex issues facing micro- placebo that contains no microbicide, and bicide researchers is how to provide access to that all participants need to continue using treatment for the relatively small number of condoms and other HIV-prevention mea- women who seroconvert (become infected sures throughout the study. with HIV) during a trial, as well as for the many more volunteers who are ineligible to partici- Explaining technical terms and research pate because pretrial screening showed that they were already infected. Community nurses, shown here with concepts such as randomization and placebos FHI’s Stella Kirkendale, are working to potential participants can be difficult. As closely with microbicide trial a result, researchers have developed creative Funding for microbicide trials does not participants in Malili, Malawi, to materials such as illustrated booklets, videos, always include support for antiretroviral ther- address any concerns the women apy (ART) or other services for people living have about the trial. and interactive computer-based educational programs to help explain them. Many trials with HIV. However, cost is not the only barrier to treatment. The complexity of ensuring

page 6 JULY 2008 FAMILY HEALTH RESEARCH continuity of care over a person’s lifetime is The Global Campaign for Microbicides also a challenge for research organizations recommends that microbicide trials be conducting short-term studies. conducted at or in partnership with local HIV care centers, and that researchers use their A 2006 study by the Global Campaign for trials as opportunities to strengthen local Microbicides found that the standard of HIV standards of care for people living with HIV. Resources care for participants who seroconvert during Informed Consent in HIV References microbicide trials has varied. One trial set Prevention Trials: Report of aside funds to support five years of ART for 1 Heise H, Philpott S, Shapiro K, et al. Mapping access to an International Workshop. every woman who seroconverted during the HIV care in microbicide effectiveness trials. Microbicides www.popcouncil.org/pdfs/ trial. Others offered to enroll seroconverters 2008, New Delhi, India, February 24–27, 2008. ICWorkshop.pdf into trials of ART regimens. Most referred the 2 MacQueen KM, Namey E, Chilongozi DA, et al. Commu- women to the closest source of HIV care, and nity perspectives on care options for HIV prevention trial Partnering for Care in HIV/AIDS many were able to establish written agree- participants. AIDS Care 2007;19(4):554–60. Clinical Trials: A How-To Manual. ments with programs that provide free ART.1 Order a copy of this soon-to-be- A study by FHI suggests that such referrals released publication by writing to are acceptable to study participants.2 [email protected].

PROGRAM DISPATCH PREPARING FOR microbicide becomes available, health pro- fessionals would strongly influence whether MICROBICIDES women could access the product and how WHO NEEDS TO they would use it. BE READY Introducing new products is complex. To help ensure the acceptability and use of n Consumers As clinical trials continue, scientists and the microbicides outside of the research setting, n Health professionals broader microbicide community are also the microbicide community is also: preparing for the complex process of intro- n Reproductive health ducing a vaginal product once it has been n Considering the cost and affordability of programs shown to be effective. products for potential consumers, repro- n Service-delivery systems ductive health programs, and donors Foremost, scientists are evaluating whether n Identifying the most appropriate targets for women and men will actually use a microbicide initial introduction if it becomes available. Qualitative research on n Developing counseling messages and a product’s acceptability may help to inform deciding how microbicides would fit into a the design and development of new products, larger HIV-prevention strategy estimate how well women will adhere to an n Determining appropriate service-delivery eventual microbicide, and influence how micro- points and evaluating the capacity of bicides might one day be marketed. service-delivery systems and health care providers to offer the products Most acceptability studies focus on product n Collaborating with donors, regulatory characteristics such as formulation, color, tex- bodies, and other stakeholders who could ture, and the type of application. Others have influence introduction, since most of the investigated the importance of contracep- products would be manufactured and tive ability among potential consumers, the distributed in developing countries without influence of sexual partners on product use, the help of large pharmaceutical companies and other factors that could differ between individuals or communities. Reference Few studies have evaluated the role that 1 Mantell JE, Myer L, Carballo-Diéguez A, et al. Microbi- health care providers would play in promot- cide acceptability research: current approaches and future ing microbicides.1 Yet, if and when a vaginal directions. Soc Sci Med 2005;60(2):319–30. page 7 A FORUM FOR PUTTING KNOWLEDGE INTO PRACTICE FAMILY HEALTH RESEARCH RESOURCES the rapid development and availability of RESEARCH AND ADVOCACY microbicides. The partnership also conducts PARTNERSHIPS its own research, focused on developing and Family Health testing antiretroviral-based microbicides Research is a newsletter such as dapivirine gel. Learn about the part- Microbicide Trials Network of the FHI Contraceptive and nership’s clinical trials and how it supports This clinical trials network is dedicated to Reproductive Health access to future microbicides at: http://www. Technologies Research and developing and evaluating an effective ipm-microbicides.org/. Utilization (CRTU) program, microbicide. Funded by the U.S. National which is supported by the Institutes of Health, the network includes a U.S. Agency for International Alliance for Microbicide Development core center of operations (supported by the Development (USAID) under the This nonprofit organization is composed of University of Pittsburgh, FHI, and others) and terms of Cooperative Agreement representatives of more than 200 biophar- No. GPO-A-00-05-00022-00. 18 clinical research sites in seven countries. maceutical companies, research organiza- The contents do not necessarily Most recently, the network conducted a tions, and advocacy groups dedicated to reflect the views of USAID. Phase II trial in India and the United States accelerating the development of a safe, showing that tenofovir gel is safe and effective, and affordable microbicide. One of Managing Editor: acceptable for daily use. More information Kerry Wright Aradhya its many activities is to monitor and analyze Writers: about the network and its trials is available the current pipeline of microbicide candi- Kathleen Henry Shears, Jill Moffett at: http://www.mtnstopshiv.org/. Art and Production Editor: dates. View more about the alliance, includ- Karen Dickerson ing an up-to-date database of information Photos: Microbicides Development Programme Cover: Karen Tweedy-Holmes/ on microbicide research and development, Based in the United Kingdom, this partner- The Population Council, Inc. at: http://www.microbicide.org/. Page 2: Bev Symmonds/ ship of organizations in Europe and Africa The Population Council, Inc. primarily conducts research to develop an Page 4: CAPRISA; Global Campaign for Microbicides effective vaginal microbicide. Its research Elizabeth T. Robinson/FHI This network of more than 285 nongov- Page 5: Elizabeth T. Robinson/FHI includes studies to determine mechanisms ernmental organizations uses international Page 6: Michael Szpir/FHI of action for different products, preclinical advocacy, policy analysis, and social science Page 8: Microbicide Trials Network evaluations of potential microbicides, and Inclusion of persons in photos research to build support for microbicides should not be construed as clinical trials of promising candidates. The and other HIV-prevention options for women. indicating their HIV status. partnership is currently conducting a Phase The campaign’s regional activities include rais- III trial of PRO 2000 gel in Africa. Learn more ing awareness of microbicides and protecting at: http://www.mdp.mrc.ac.uk/. the needs and interests of trial participants and other potential users. Find out about International Partnership for Microbicides the campaign’s work at: http://www.global- This global collaboration between public- campaign.org. and private-sector organizations promotes

FHI Headquarters PO Box 13950 Research Triangle Park, NC 27709 USA Tel: 1.919.544.7040 www.fhi.org

Send comments to: Kerry Wright Aradhya [email protected] The Microbicide Trials Network—whose clinical research staff in Zambia are shown here—is one of several partnerships dedicated to developing and building support for microbicides. July 2008 Volume 2, Issue 2