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Methodological Challenges in Biomedical HIV Prevention Trials (2008)
Board on Global Health (BGH)

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Methodological Challenges in Biomedical HIV Prevention Trials

1
The Status and Challenges of Biomedical HIV Prevention Trials

A series of spectacular successes in biomedical prevention of HIV transmission occurred in the 1980s and 1990s. Beginning with protection of the blood, organ, and tissue supply with tests for antibodies and later antigens of HIV (see IOM, 1995), through trials of prevention of mother-to-child transmission with antiretrovirals, Caesarean sections, and formula feeding, nonvaccine biomedical interventions seemed to hold promise for large-scale control of HIV transmission (International Perinatal HIV Group, 1999; Bulterys et al., 2004).

However, some failures in biomedical trials began to appear by the late-1990s. Notably, only one of six randomized controlled trials (Grosskurth et al., 1995) showed that the control of bacterial sexually transmitted diseases and trichomonas reduced HIV incidence (Grosskurth et al., 1995; Wawer et al., 1999; Gray et al., 2001; Kamali et al., 2003; Kaul et al., 2004; Gregson et al., 2007).

Investigators have continued to pursue a number of new biomedical HIV prevention interventions. Phase 2 and phase 3 trials of several biomedical interventions—including male circumcision, vaginal microbicides, pre-exposure prophylaxis (PrEP), cervical barriers (the latex diaphragm), herpes simplex virus 2 (HSV-2) suppression, and vaccines—have recently been completed or are ongoing (see Table 1-1 and Figure 1-1 for trial specifics and timeline). Recently completed trials have been marked by both successes and disappointments. Male circumcision is the primary success story. Three randomized, controlled trials found that male circumcision reduced the risk of heterosexually acquired HIV infection among men by about 50–60 percent at 18–24 months of follow-up (Auvert et al., 2005;

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Methodological Challenges in Biomedical HIV Prevention Trials 1 The Status and Challenges of Biomedical HIV Prevention Trials A series of spectacular successes in biomedical prevention of HIV transmission occurred in the 1980s and 1990s. Beginning with protection of the blood, organ, and tissue supply with tests for antibodies and later antigens of HIV (see IOM, 1995), through trials of prevention of mother-to-child transmission with antiretrovirals, Caesarean sections, and formula feeding, nonvaccine biomedical interventions seemed to hold promise for large-scale control of HIV transmission (International Perinatal HIV Group, 1999; Bulterys et al., 2004). However, some failures in biomedical trials began to appear by the late-1990s. Notably, only one of six randomized controlled trials (Grosskurth et al., 1995) showed that the control of bacterial sexually transmitted diseases and trichomonas reduced HIV incidence (Grosskurth et al., 1995; Wawer et al., 1999; Gray et al., 2001; Kamali et al., 2003; Kaul et al., 2004; Gregson et al., 2007). Investigators have continued to pursue a number of new biomedical HIV prevention interventions. Phase 2 and phase 3 trials of several biomedical interventions—including male circumcision, vaginal microbicides, pre-exposure prophylaxis (PrEP), cervical barriers (the latex diaphragm), herpes simplex virus 2 (HSV-2) suppression, and vaccines—have recently been completed or are ongoing (see Table 1-1 and Figure 1-1 for trial specifics and timeline). Recently completed trials have been marked by both successes and disappointments. Male circumcision is the primary success story. Three randomized, controlled trials found that male circumcision reduced the risk of heterosexually acquired HIV infection among men by about 50–60 percent at 18–24 months of follow-up (Auvert et al., 2005;

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Methodological Challenges in Biomedical HIV Prevention Trials TABLE 1-1 Ongoing and Recently Completed Phase IIB/III Trials of Biomedical Interventions for HIV Prevention Product Category and Study Namea Also Known As Phase Primary Sponsors and Funders Microbicides       Phase 2/2B Safety and Effectiveness Study of Vaginal Microbicides BufferGel and 0.5% PRO2000/5 Gel (P) for the Prevention of HIV Infection in Women HPTN 035 2/2B National Institute of Allergy and Infectious Diseases HIV Prevention Trials Network, Indevus, ReProtect Phase 3 Study of the Efficacy and Safety of the Microbicide Carraguard in Preventing HIV Seroconversion in Women Carraguard 3 United States Agency for International Development, Bill and Melinda Gates Foundation, Population Council Phase 3 Randomized Controlled Trial of 6% Cellulose Sulfate Gel and the Effect on Vaginal HIV Transmission (Multisite) Cellulose sulfate (CONRAD-multisite) 3 United States Agency for International Development, Bill and Melinda Gates Foundation, CONRAD Phase 3 Randomized Controlled Trial of Cellulose Sulfate Gel and HIV in Nigeria Cellulose sulfate (Nigeria) 3 United States Agency for International Development, CONRAD An International Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of 0.5% and 2% PRO 2000/5 Gels for the Prevention of Vaginally Acquired HIV Infection MDP 301 3 Indevus Pharmaceuticals, U.K. Medical Research Council, United Kingdom Department for International Development

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Methodological Challenges in Biomedical HIV Prevention Trials Actual or Target Enrollment Country(ies) Results Approx. 3,100 sexually active HIV-uninfected women Malawi, South Africa, United States, Zambia, Zimbabwe Expected 2009. 6,202 sexually active HIV-uninfected women South Africa The trial failed to demonstrate that Carraguard was effective in preventing HIV infection. There were 134 new infections in the Carraguard group (an incidence of 3.3 infections per 100 woman-years) and 151 new infections in a placebo group (an incidence of 3.7 per 100 woman-years). The difference between the two groups is not statistically significant. The gel was shown to be safe for vaginal use. 1,428 (out of 2,574 targeted) sexually active HIV-uninfected women Benin, India, South Africa, Uganda, Zimbabwe In early 2007, the trial was halted because of an apparent increased risk of HIV infection in the CS arm, which was later confirmed in an analysis of the subset of data derived from women who completed the study. 1,644 (out of 2,160 targeted) sexually active HIV-uninfected women Nigeria In early 2007, the trial was stopped as a precautionary measure following the closure of the CONRAD CS trial, although there was no indications of increased risk of HIV infection in the Nigeria CS trial. 9,673 sexually active HIV-uninfected women South Africa, Tanzania, Uganda Expected 2009.

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Methodological Challenges in Biomedical HIV Prevention Trials Product Category and Study Namea Also Known As Phase Primary Sponsors and Funders Effectiveness of COL-1492, a Nonoxynol-9 Vaginal Gel, on HIV-1 Transmission in Female Sex Workers COL-1492 or Nonoxynol-9 2/3 UNAIDS Randomized Controlled Trial of SAVVY (C31G) Gel for Prevention of HIV infection in Women (Ghana) Savvy (Ghana) 3 United States Agency for International Development, BIOSYN, Inc. Phase 3 Randomized Controlled Trial of SAVVY (C31G) Gel for Prevention of HIV infection in Women (Nigeria) Savvy (Nigeria) 3 United States Agency for International Development, BIOSYN, Inc. Phase 2B Trial to Assess the Safety and Effectiveness of the Vaginal Microbicide 1% Tenofovir Gel for the Prevention of HIV Infection in Women in South Africa CAPRISA 004 2B Centre for the AIDS Programme of Research in South Africa, CONRAD, Family Health International, United States Agency for International Development, LIFElab, Gilead Cervical Barriers (Diaphragm)       The Latex Diaphragm to Prevent HIV Acquisition Among Women: A Female-Controlled, Physical Barrier of the Cervix The MIRA trial 3 Bill & Melinda Gates Foundation Preexposure Prophlaxis (PrEP)b       Phase 2 Study of Tenofovir Disoproxil Fumarate (TDF) for Prevention of HIV West Africa Tenofovir study 2 Bill & Melinda Gates Foundation

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Methodological Challenges in Biomedical HIV Prevention Trials Actual or Target Enrollment Country(ies) Results 892 HIV-uninfected female sex workers Benin, Côte d’Ivoire, South Africa, Thailand The trial did not show a protective effect of COL-1492 on HIV-1 transmission in high-risk women. Multiple use of nonoxynol-9 could cause toxic effects enhancing HIV-1 infection. HIV-1 frequency in nonoxynol-9 users was 59 (16%) of 376 compared with 45 (12%) [corrected] of 389 in placebo users (402.5 vs. 435.0 woman-years; hazard ratio adjusted for centre 1.5; 95% CI:1.0–2.2; p = 0.047). 239 (32%) women reported use of a mean of more than 3.5 applicators per working day, and in these women, risk of HIV-1 infection in nonoxynol-9 users was almost twice that in placebo users (hazard ratio 1.8; 95% CI:1.0–3.2). 516 (68%) women used the gel less frequently than 3.5 times a day, and in these, risk did not differ between the two treatments. 2,142 sexually active HIV-uninfected women Ghana The number of HIV seroconversion in participants (17 total; 8 in the SAVVY and 9 in the placebo arm) was lower than expected. The study had insufficient power to determine effectiveness of the intervention. 2,152 sexually active HIV-uninfected women Nigeria The data monitoring committee determined the trial was unlikely to provide convincing evidence that SAVVY protects against HIV. 980 sexually active HIV-uninfected women South Africa Expected 2010. 5,045 sexually active HIV-uninfected women South Africa, Zimbabwe No added protective benefit against HIV infection when the diaphragm and lubricant gel were provided in addition to condoms and a comprehensive HIV prevention package. 936 (out of 1,200 targeted) sexually active HIV-uninfected women Cameroon, Ghana, Nigeria Daily use of TDF in HIV-uninfected women was not associated with increased adverse events. Effectiveness could not be conclusively evaluated because of premature trial closures in Cameroon and Nigeria which decreased planned person years of follow-up and study power.

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Methodological Challenges in Biomedical HIV Prevention Trials Product Category and Study Namea Also Known As Phase Primary Sponsors and Funders Study of the Safety and Efficacy of Daily Tenofovir to Prevent HIV Infection Among Injection Drug Users in Bangkok, Thailand Bangkok Tenofovir study 2/3 Centers for Disease Control Study of the Safety and Efficacy of Daily Tenofovir Disoproxil Fumarate and Emtricitabine (Truvada) for the Prevention of HIV Infection in Heterosexually Active Young Adults in Botswana Truvada Botswana study 3 Centers for Disease Control Chemoprophylaxis for HIV Prevention in Men Truvada Peru/Ecuador study 3 National Institute of Allergy and Infectious Diseases Index Partner Treatment with ARV       A Randomized Trial to Evaluate the Effectiveness of Antiretroviral Therapy Plus HIV Primary Care versus HIV Primary Care Alone to Prevent the Sexual Transmission of HIV-1 in Serodiscordant Couples HPTN 052 3 National Institute of Allergy and Infectious Diseases Male Circumcision       Effect of Safe Male Circumcision on Incidence of Infection by HIV, HSV-2, and of Genital Ulceration ANRS 1265 (Orange Farm) 3 Agence Nationale de Recherches sur le SIDA (ANRS); National Institute for Communicable Diseases (Johannesburg, SA); Institut National de la Sante et de la Recherche Medicale RCT of male circumcision for HIV prevention in young men in Kisumu, Kenya Male Circumcision Trial Kisumu, Kenya 3 National Institute of Allergy and Infectious Diseases, Canadian Institute of Health Research

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Methodological Challenges in Biomedical HIV Prevention Trials Actual or Target Enrollment Country(ies) Results 2,000 HIV-uninfected IDUs Thailand Expected 2008. 1,200 sexually active HIV-uninfected young adults Botswana Expected 2009. 3,000 high risk HIV-uninfected MSM Ecuador, Peru, Other sites TBD Expected 2010. 1,750 HIV-serodiscordant couples in which the HIV-infected partner is ART naïve and has a CD4+ cell count of 350-550 cells/mm3 Brazil, India, Malawi, South Africa, Thailand, United States Expected 2013. 3,274 HIV-uninfected heterosexual men South Africa The incidence rate was 0.85 per 100 person years in the intervention group and 2.1 per 100 person years in the control group, corresponding to a RR of 0.40 (95% CI: 0.24–0.68, p < 0.001 and a reduction in HIV risk of 60 percent. Average duration of follow-up was 18 months. 2,784 HIV-uninfected heterosexual men Kenya The 2-year HIV incidence was 2.1% (95% CI: 1.2–3.0) in the circumcision group and 4.2% (95% CI: 3.0–5.4) in the control group (p = 0.0065). Relative risk of HIV infection in circumcised men was 0.47 (95% CI: 0.28–0.78), corresponding to a reduction in risk of acquiring HIV infection by 53 percent. Median length of follow-up was 24 months.

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Methodological Challenges in Biomedical HIV Prevention Trials Product Category and Study Namea Also Known As Phase Primary Sponsors and Funders RCT of male circumcision for HIV prevention in men in Rakai, Uganda Male Circumcision Trial Rakai, Uganda 3 NIAID Trial of male circumcision in HIV positive men, Rakai, Uganda: Safety in HIV positive men and effects on women and the community Rakai Transmission study 3 Johns Hopkins University, Rakai Health Sciences Project, Bill & Melinda Gates Foundation HSV-2 Suppression       Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Acyclovir for the Reduction of HIV Acquisition Among High Risk HSV-2 Seropositive, HIV-Seronegative Individuals HPTN 039 3 NIAID Phase III Randomized Placebo-Controlled Trial of HSV-2 Suppression to Prevent HIV Transmission Among HIV Sero-Discordant Couples Partners in Prevention 3 Bill & Melinda Gates Foundation Impact of HSV-2 suppressive therapy on HIV incidence in HSV-2 seropositive women: A randomised controlled trial in Tanzania Tanzania HSV-2 Suppression 3 Wellcome Trust aTable excludes vaccine and prevention of mother-to-child transmission trials. bThree separate PrEP trials (in Cambodia, Cameroon, Malawi) were stopped before enrollment due to controversy about ethical issues and standard of care and concerns about possible resistance. See http://www.prepwatch.org/pdf/Trials/PrEP_trials_table.pdf.

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Methodological Challenges in Biomedical HIV Prevention Trials Actual or Target Enrollment Country(ies) Results 4,996 HIV-uninfected heterosexual men Uganda HIV incidence over 24 months was 0.66 per 100 person-years and 1.33 per 100 person-years in the control group (estimated efficacy of intervention was 51% (95% CI: 16–72; p = 0.006). 1,015 HIV-seropositive men. Married men (n = 770) were asked to invite their spouses: 556 enrolled of whom 245 were HIV-seronegative. Uganda Male circumcision was safe and reduced genitourinary disease in HIV-seropositive men. There were no direct HIV benefits to women, but potentially an increased risk of transmission with early resumption of sex. 3,172 sexually active HIV-uninfected women who have sex with men and men who have sex with men Peru, South Africa, United States Zambia, Zimbabwe Acyclovir 400 mg given twice daily (800 mg total) did not reduce the risk of HIV acquisition among high-risk HSV-2 seropositive MSM and women. HIV incidence was 3.9/100 person-years in the acyclovir arm (75 events) and 3.3/100 person-years in the placebo arm (64 events), with an overall hazard ratio of 1.16 (95% CI: 0.83–1.62). 3,300 HIV-discordant couples with HIV-infected partner also HSV-2 coinfected Botswana, Kenya, Rwanda, South Africa, Tanzania, Uganda, Zambia Expected 2009. 820 HIV-uninfected, HSV-2 infected sex workers Tanzania Acyclovir 400 mg given twice daily did not reduce the risk of HIV acquisition among high-risk HSV-2 seropositive women. The HIV incidence rate was 4.29 per 100 person-years in the acyclovir arm and 4.25 per 100 person-years in the placebo arm. The difference was not statistically significant. SOURCES: Study protocols, www.clinicaltrials.gov, AVAC HIV Prevention Research: A Comprehensive Timeline, Investigator Presentations to IOM Committee on the Methodological Challenges in HIV Prevention Trials; Publications of trial results.

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Methodological Challenges in Biomedical HIV Prevention Trials FIGURE 1-1 Timeline for results of non-vaccine biomedical HIV prevention research trials. SOURCE: Adapted from AIDS Vaccine Advocacy Coalition, 2007, http://www.avac.org/tmeline-website/index.htm.

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Methodological Challenges in Biomedical HIV Prevention Trials Bailey et al., 2007; Gray et al., 2007). As a result, an expert consultation convened by the World Health Organization (WHO) and UNAIDS recently recommended increasing the scale-up of male circumcision as an HIV prevention strategy (UNAIDS, 2007). Other late-stage trials have failed to demonstrate a benefit in reducing HIV infection risk, including a phase 3 trial of the diaphragm and Replens gel (Padian et al., 2007) and two phase 3 trials of HSV-2 suppression with acyclovir (Watson-Jones et al., 2007; Celum et al., 2008). Two vaginal microbicide trials (of N-9 and cellulose sulfate [CS]) were halted because of evidence that they may have a harmful effect (Van Damme et al., 2002; Van Damme, 2007), and a separate trial of CS was stopped as a precautionary measure based on evidence from the other CS trial (Cates, 2007). Several PrEP trials were prematurely closed or canceled because of ethical concerns raised by advocates, governments, and community members (IAS, 2005). One PrEP trial and two microbicide trials (Savvy in Ghana and Nigeria) did not have sufficient power to determine efficacy of the intervention (Peterson et al., 2007a,b). In addition, two trials of an HIV vaccine that were recently stopped based on a lack of evidence of benefit and concerns that they might also increase HIV infection risk.1 This chapter begins with an overview of recent late-stage biomedical trials of interventions designed to prevent primary infection of HIV (see Figure 1-2 and Box 1-1 for an overview of clinical trial phases for product development). It then examines the methodological challenges that can undermine trial outcomes, including the design and conduct of such trials, site preparedness, interim monitoring and analysis, and interpretation of results. The chapter concludes with a discussion of how behavior driven by diverse sociocultural and economic factors plays a critical role in the overall effectiveness of most biomedical interventions, as well as in the success of clinical trials themselves. RECENT LATE-STAGE TRIALS OF NON-VACCINE BIOMEDICAL PREVENTIONS Topical Microbicides Microbicides are topical agents designed to reduce or prevent transmission of HIV and/or other sexually transmitted infections (STIs) when 1 The STEP study was discontinued based on recommendations made by a Data and Safety Monitoring Board, which concluded that the vaccine neither prevented HIV infection nor reduced the amount of virus in those who became infected with HIV (http://www.avac.org/pdf/STEP_data_release.7Nov.pdf), and possibly might have increased the risk of HIV infection. Based on review of the STEP data, the Phambili study in South Africa was also stopped (http://www.hvtn.org/media/pr/PhambiliSAAVIstatement.pdf).

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Methodological Challenges in Biomedical HIV Prevention Trials adequate retention is a challenge in many of the settings where HIV prevention trials are being conducted. Estimating HIV Incidence If a trial is to show that a prevention product is effective, some individuals must become HIV infected during a trial. The sample size and duration of a trial are based on the number of people expected to become infected during the trial’s follow-up period. Thus an accurate estimate of the background HIV incidence at the trial site is critical to determining the required sample size and duration. As noted, several trials have been unable to reach definitive conclusions because of a lower-than-expected HIV incidence rate and the resulting insufficient study power. BEHAVIORAL AND SOCIOCULTURAL INFLUENCES ON BIOMEDICAL TRIALS Although some of the challenges facing biomedical trials are more technical—including estimating HIV incidence and identifying surrogate markers—other challenges, such as product adherence, condom use, pregnancy, and retention, are profoundly affected by the behavior of trial participants and the macro-level factors (e.g., social, political, economic, environmental) that influence that behavior. Indeed, the level of product adherence and risk-taking behavior of trial participants has a large impact on the safety and success of clinical trials of biomedical interventions. For example, trial staff members instruct participants to protect themselves from HIV by using condoms, to adhere to study products, to remain in the study, and, in most trials, to avoid pregnancy. However, macro-level factors often work in opposition to these instructions, as the following sections illustrate. Encouraging Correct and Consistent Condom Use Biomedical HIV prevention studies counsel participants on the importance of using either male or female condoms to prevent HIV infection. In some cultures, decisions on condom use rest largely with men. For example, in some communities, men use condoms with sex workers and not with their wives or regular sexual partners, and women may be reluctant to ask their partners to use condoms because of their association with sex workers and infidelity (Veldhuijzen et al., 2006). Power dynamics, especially between young women and older sexual partners, may also prevent the former from using condoms and following study instructions regarding the use of HIV prevention products (Kuate-Defo, 2004).

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Methodological Challenges in Biomedical HIV Prevention Trials Maintaining High Adherence to Instructions for Using a Product Suboptimal adherence to the product regimen can obscure the efficacy of a product during trials and reduce its effectiveness in the real world. And adherence may vary depending on the attitudes and practices of individuals within a particular setting. For example, several studies of the acceptability of microbicides have noted that women may not attempt to use a product or may discontinue or reduce the amount they apply, if gel wetness raises concerns among male sexual partners (Bentley et al., 2004; Braunstein and van de Wijgert, 2005). In some areas of South Africa, cultural norms dictate that women dry their vaginas, and some women may want their vaginas to remain dry to avoid being stigmatized as prostitutes or unfaithful to their partners (Braunstein and van de Wijgert, 2005). In some Rwandan communities, in contrast, vaginal lubrication is the desired norm. The custom is to stimulate vaginal secretions, and women who fail to produce enough during intercourse are sometimes given derogatory names (Veldhuijzen et al., 2006). Thus, sociocultural norms around sexual practices may influence the ability and willingness of individuals and couples to use microbicides (see Box 1-3). Preventing Pregnancy During a Trial In most biomedical HIV prevention trials, uncertainties and concerns about the effects of the intervention on pregnancy outcomes prompt investigators to counsel women to avoid pregnancy and to take them off product if they become pregnant. Yet pregnancy is a common and often desired outcome for women of child-bearing age who are likely to use a biomedical intervention after it is introduced into the community. In some cultures, women are expected to have children, and in some marriages, a lack of children may be grounds for divorce (Yale Law Journal, 1946). Young women may also feel pressure to prove they are fertile, and to increase their chances of getting married by becoming pregnant (Loosli, 2004). In-depth interviews with a subset of women who participated in a PrEP trial in Ghana, Nigeria, and Cameroon revealed the importance of understanding local context when determining how to reduce pregnancies during HIV prevention trials (MacQueen and Karim, 2007). Maintaining High Recruitment and Retention Rates Effectively recruiting and retaining trial participants is essential for obtaining meaningful study results. However, while poverty and unemployment may initially encourage participants to enroll to receive financial compensation, these factors can also lead to poor retention. During a site

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Methodological Challenges in Biomedical HIV Prevention Trials BOX 1-3 HIV Biomedical Interventions May Enhance Women’s Control Over Their Sexual Decision Making But They Are Not a Panacea Sexual decision making is embedded within complex societal expectations in which both men and women exercise different kinds of control. A female-controlled HIV prevention product that could be used covertly (Morrow and Ruiz, 2007; Morrow et al., 2007) and provide long-lasting protection (Orner et al., 2006) could be a tremendous benefit in reducing women’s vulnerability to HIV. Mathematical models have shown that even if a small proportion of women in lower income countries used a 60 percent efficacious microbicide in half of the sexual encounters where condoms are not used, 2.5 million HIV infections could be averted over 3 years (Watts and Vickerman, 2001). Microbicides and other new biomedical interventions such as PrEP may be able to afford women greater control over their sexual decision making. However, the introduction of these new technologies is not a panacea for women’s sexual decision making, as illustrated in the examples below. Many women must still seek partner permission In Zimbabwe more than 90 percent of the women eligible to participate in a microbicide and diaphragm safety study indicated that they sought permission of their partners to participate in the study and about two-thirds said if they did not do so, they would experience difficulties in their marriage (Montgomery et al., 2006). Covert use may be difficult In a simulated vaginal microbicide pilot study done in Massachusetts, more than 86 percent of respondents indicated that their primary sexual partners knew that they were using Replens (Mosack et al., 2005). In an acceptability study of the Carraguard microbicide, only 15 percent of women said they could use the microbicide gel without their male partner’s knowledge (Whitehead et al., 2006). Additionally, many women who use microbicides experience vaginal wetness. In some visit in South Africa, study staff told the committee that some participants had left the study area because of work-related migration or dropped out of a trial once they became employed. Studies may also fail to enroll participants or lose them to follow-up because of imprisonment or fear of imprisonment, if the study population engages in illegal activities, such as injecting drug use or commercial sex work. For example, in Thailand, the government undertook an aggressive campaign to crackdown on drug use, which resulted in the arrest, incarceration, and sometimes execution of many drug users. In this environment, investigators of a PrEP trial that enrolled injecting drug users were concerned that some of their study participants could be incarcerated. Investi-

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Methodological Challenges in Biomedical HIV Prevention Trials cultures, people believe that vaginal wetness must be due to improper hygiene or a sexually transmitted infection, may also limit women’s ability to use microbicide products (Bentley et al., 2004; Braunstein and van de Wijgert, 2005). Fear of violence Compared to microbicides, women may be able to use oral PrEP more covertly. However, in some instances, women may find it difficult to conceal medication, especially in small households. During the committee’s site visits to several African trial sites, some female participants expressed the need to hide pills from their partners for fear of violence stemming from a link between pills and illness. Trial site staff noted that women in the trial are counseled on how to discuss the use of pills for prevention with their partners and families. Challenging traditional gender norms Methods that provide women with more control over their sexual lives might challenge traditional gender norms. In some countries, males dominate sexual decision making, and pervasive gender inequities underpin the HIV/AIDS epidemic (Jewkes et al., 2003; Dunkle et al., 2004; Pettifor et al., 2004; Abdool Karim, 2005). Little data exist on what women and men would think of women initiating and controlling sexual decision making and methods of preventing HIV. Moreover, many HIV biomedical interventions will require acknowledgement and discussion of sexuality and sexual practices, issues that policy makers, providers and users can find difficult. Partially effective products Microbicides and other biomedical products are likely to be only partially effective and could lead to risk compensation or disinhibition among some people. Thus, new HIV biomedical interventions may be best conceptualized as part of a broader package that should complement traditional HIV prevention strategies, such as condoms, whenever possible. Educating women about a “combination” approach to HIV prevention could also prove challenging. gators received permission to continue to follow incarcerated participants and give them the study product during incarceration (Smith, 2007). Another important factor shaping recruitment and retention of participants in HIV prevention trials is the stigma associated with HIV. Participants in HIV-related research may experience stigma regardless of their HIV status. Individuals may therefore choose not to participate in trials because others may believe they are HIV infected or at risk of infection. Indeed, a systematic review of 26 HIV vaccine studies found that social discrimination is one of the leading factors that may limit participation in future HIV prevention research (Mills et al., 2004). Some people may be wary of participating in a trial because they do

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Methodological Challenges in Biomedical HIV Prevention Trials not want to know or do not feel it is important to know their HIV status. Participants in HIV prevention trials must undergo routine HIV testing, and be prepared to not only know their status but sometimes discuss it with their partner. The stigma associated with HIV, as well as a lack of access to antiretrovirals, can discourage individuals from being tested (Global HIV Prevention Working Group, 2004). A cross-sectional, population-based study in Botswana found that the key barriers to HIV testing included fear of learning one’s status (49 percent), lack of perceived HIV risk (43 percent), and fear of having to change sexual practices after a positive HIV test (33 percent) (Weiser et al., 2006). Researchers and participants may also differ in their perspectives on what participation in clinical trials can offer individuals and their communities (Benatar, 2002). Divergence between the goals of researchers and the realties of participants often reflects disparities in wealth and health (Benatar, 2004). Many research subjects are among the world’s most vulnerable populations. Thus, it is important for investigators to understand the factors that shape individuals’ perceptions of research. For example, investigators may need to determine whether participants see research as distinct from health care (Horton, 1995a,b). Investigators may further need to consider the historical and ideological forces that may shape participants’ perceptions of research (Loue et al., 1996a,b), how they expect research to benefit them and their society (Benatar and Fleischer, 2005), and whether research will mesh or conflict with community norms and values (Molyneux et al., 2005). Research that takes such concerns into account and incorporates methods to evaluate them is more likely to succeed in addressing health issues that are heavily influenced by complex social and behavioral factors. Yet many studies of the importance of behavioral change in reducing people’s risk of HIV infection have focused on individuals and often ignored the social and cultural context. This thinking has influenced the conduct of biomedical HIV prevention trials, which also target individual risk behavior, such as having multiple sexual partners, engaging in unprotected sex, and sharing needles with other drug users. Increasingly, the emphasis in social science research is on understanding individual behavior within a broader sociocultural and economic context. The promise of new HIV prevention technologies underscores the need for multidisciplinary teams to be involved in all stages of the trial. Incorporating behavioral and social science research into biomedical research could improve the design, implementation, and analysis of clinical trials, and thus render new technologies more effective. However, despite numerous calls for integrating traditional biomedical and social science research, most biomedical HIV prevention trials have rather limited behavioral and social science research components (IOM and NAS, 1994; Auerbach and

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Methodological Challenges in Biomedical HIV Prevention Trials Coates, 2000; Glasgow et al., 2003; Tolley and Severy, 2006). Failure to rectify this shortcoming will frustrate progress in developing effective HIV prevention methods. REFERENCES Abdool Karim, Q. 2005. Heterosexual transmission of HIV: The importance of a gendered perspective in HIV prevention. In HIV/AIDS in South Africa, edited by S. S. Abdool Karim and Q. Abdool Karim. Cambridge, UK: Cambridge University Press. AIDS Vaccine Advocacy Coalition. 2007. AVAC Report 2007: Resetting the Clock. http://www.avac.org (accessed January 2008). Alliance for Microbicide Development. ND. http://www.microbicide.org/ (accessed November 1, 2007). Alliance for Microbicide Development. 2008a. Microbicide candidates and ancillary devices in planned and funded clinical trials as of February 2008. http://www.microbicide.org/microbicideinfo/reference/Microbicides.Planned.Funded.Clinical.Trials1Feb08.pdf (accessed February 8, 2008). Alliance for Microbicide Development. 2008b. Microbicide candidates in ongoing clinical trials: Summary as of February 2008. http://www.microbicide.org/microbicideinfo/reference/Microbicide.Ongoing.Clinical.Trials.Summary1Feb08.pdf (accessed February 8, 2008). Auerbach, J. D., and T. J. Coates. 2000. HIV prevention research: Accomplishments and challenges for the third decade of AIDS. American Journal of Public Health 90(7): 1029-1032. Auvert, B., D. Taljaard, E. Lagarde, J. Sobngwi-Tambekou, R. Sitta, and A. Puren. 2005. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: The ANRS 1265 trial. PLoS Medicine 2(11):e298. Bailey, R. C., S. Moses, C. B. Parker, K. Agot, I. Maclean, J. N. Krieger, C. F. Williams, R. T. Campbell, and J. O. Ndinya-Achola. 2007. Male circumcision for HIV prevention in young men in Kisumu, Kenya: A randomised controlled trial. Lancet 369(9562):643-656. Benatar, S. R. 2002. Reflections and recommendations on research ethics in developing countries. Social Science and Medicine 54(7):1131-1141. Benatar, S. 2004. Rationally defensible standards for research in developing countries. Review of Macklin’s “Double standards in medical research in developing countries.” Health and Human Rights 8(1):197-202. Benatar, S., and T. Fleischer. 2005. Ethical and policy implications of clinical drug trials conducted in developing countries. Harvard Health Policy Review 6(1):9. Bentley, M. E., A. M. Fullem, E. E. Tolley, C. W. Kelly, N. Jogelkar, N. Srirak, L. Mwafulirwa, G. Khumalo-Sakutukwa, and D. D. Celentano. 2004. Acceptability of a microbicide among women and their partners in a 4-country phase I trial. American Journal of Public Health 94(7):1159-1164. Braunstein, S., and J. van de Wijgert. 2005. Preferences and practices related to vaginal lubrication: Implications for microbicide acceptability and clinical testing. Journal of Women’s Health (Larchmt) 14(5):424-433. Bulterys, M., M. G. Fowler, K. K. Van Rompay, and A. P. Kourtis. 2004. Prevention of mother-to-child transmission of HIV-1 through breast-feeding: Past, present, and future. Journal of Infectious Diseases 189(12):2149-2153.

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