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

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 STATUS AND CHALLENGES Actual or Target Enrollment Country(ies) Results Approx. 3,100 Malawi, Expected 2009. sexually active South HIV-uninfected Africa, women United States, Zambia, Zimbabwe 6,202 sexually South The trial failed to demonstrate that Carraguard was active HIV- Africa effective in preventing HIV infection. There were 134 new uninfected infections in the Carraguard group (an incidence of 3.3 women 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 Benin, In early 2007, the trial was halted because of an apparent of 2,574 India, South increased risk of HIV infection in the CS arm, which targeted) Africa, was later confirmed in an analysis of the subset of data sexually active Uganda, derived from women who completed the study. HIV-uninfected Zimbabwe women 1,644 (out Nigeria In early 2007, the trial was stopped as a precautionary of 2,160 measure following the closure of the CONRAD CS trial, targeted) although there was no indications of increased risk of sexually active HIV infection in the Nigeria CS trial. HIV-uninfected women 9,673 sexually South Expected 2009. active HIV- Africa, uninfected Tanzania, women Uganda Continued

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

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 STATUS AND CHALLENGES Actual or Target Enrollment Country(ies) Results 892 HIV- Benin, Côte The trial did not show a protective effect of COL-1492 uninfected d’Ivoire, on HIV-1 transmission in high-risk women. Multiple use female sex South of nonoxynol-9 could cause toxic effects enhancing HIV-1 workers Africa, infection. HIV-1 frequency in nonoxynol-9 users was Thailand 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 Ghana The number of HIV seroconversion in participants (17 active HIV- total; 8 in the SAVVY and 9 in the placebo arm) was uninfected lower than expected. The study had insufficient power to women determine effectiveness of the intervention. 2,152 sexually Nigeria The data monitoring committee determined the trial was active HIV- unlikely to provide convincing evidence that SAVVY uninfected protects against HIV. women 980 sexually South Expected 2010. active HIV- Africa uninfected women 5,045 sexually South No added protective benefit against HIV infection active HIV- Africa, when the diaphragm and lubricant gel were provided uninfected Zimbabwe in addition to condoms and a comprehensive HIV women prevention package. 936 (out Cameroon, Daily use of TDF in HIV-uninfected women was not of 1,200 Ghana, associated with increased adverse events. Effectiveness targeted) Nigeria could not be conclusively evaluated because of premature sexually active trial closures in Cameroon and Nigeria which decreased HIV-uninfected planned person years of follow-up and study power. women Continued

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

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 STATUS AND CHALLENGES Actual or Target Enrollment Country(ies) Results 2,000 HIV- Thailand Expected 2008. uninfected IDUs 1,200 sexually Botswana Expected 2009. active HIV- uninfected young adults 3,000 high Ecuador, Expected 2010. risk HIV- Peru, Other uninfected sites TBD MSM 1,750 HIV- Brazil, Expected 2013. serodiscordant India, couples in Malawi, which the South HIV-infected Africa, partner is ART Thailand, naïve and has United a CD4+ cell States count of 350- 550 cells/mm3 3,274 HIV- South The incidence rate was 0.85 per 100 person years in the uninfected Africa intervention group and 2.1 per 100 person years in the heterosexual control group, corresponding to a RR of 0.40 (95% CI: men 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- Kenya The 2-year HIV incidence was 2.1% (95% CI: 1.2–3.0) uninfected in the circumcision group and 4.2% (95% CI: 3.0–5.4) heterosexual in the control group (p = 0.0065). Relative risk of HIV men 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. Continued

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 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS TABLE 1-1 Continued Product Category and Also Known Primary Sponsors and Study Namea As Phase Funders RCT of male circumcision for Male 3 NIAID HIV prevention in men in Rakai, Circumcision Uganda Trial Rakai, Uganda Trial of male circumcision in HIV Rakai 3 Johns Hopkins University, positive men, Rakai, Uganda: Transmission Rakai Health Sciences Safety in HIV positive men study Project, Bill & Melinda and effects on women and the Gates Foundation community HSV-2 Suppression Phase III, Randomized, Double- HPTN 039 3 NIAID Blind, Placebo-Controlled Trial of Acyclovir for the Reduction of HIV Acquisition Among High Risk HSV-2 Seropositive, HIV- Seronegative Individuals Phase III Randomized Placebo- Partners in 3 Bill & Melinda Gates Controlled Trial of HSV-2 Prevention Foundation Suppression to Prevent HIV Transmission Among HIV Sero- Discordant Couples Impact of HSV-2 suppressive Tanzania 3 Wellcome Trust therapy on HIV incidence in HSV-2 HSV-2 seropositive women: A Suppression randomised controlled trial in Tanzania aTable excludes vaccine and prevention of mother-to-child transmission trials. bThree separate PrEP trials (in Cambodia, Cameroon, Malawi) were stopped before enroll- ment 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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 STATUS AND CHALLENGES Actual or Target Enrollment Country(ies) Results 4,996 HIV- Uganda HIV incidence over 24 months was 0.66 per 100 person- uninfected years and 1.33 per 100 person-years in the control group heterosexual (estimated efficacy of intervention was 51% (95% CI: men 16–72; p = 0.006). 1,015 HIV- Uganda Male circumcision was safe and reduced genitourinary seropositive disease in HIV-seropositive men. There were no direct men. Married HIV benefits to women, but potentially an increased risk men (n = 770) of transmission with early resumption of sex. were asked to invite their spouses: 556 enrolled of whom 245 were HIV- seronegative. 3,172 sexually Peru, Acyclovir 400 mg given twice daily (800 mg total) did active HIV- South not reduce the risk of HIV acquisition among high-risk uninfected Africa, HSV-2 seropositive MSM and women. HIV incidence was women who United 3.9/100 person-years in the acyclovir arm (75 events) and have sex with States 3.3/100 person-years in the placebo arm (64 events), with men and men Zambia, an overall hazard ratio of 1.16 (95% CI: 0.83–1.62). who have sex Zimbabwe with men 3,300 HIV- Botswana, Expected 2009. discordant Kenya, couples with Rwanda, HIV-infected South partner Africa, also HSV-2 Tanzania, coinfected Uganda, Zambia 820 HIV- Tanzania Acyclovir 400 mg given twice daily did not reduce uninfected, the risk of HIV acquisition among high-risk HSV-2 HSV-2 infected seropositive women. The HIV incidence rate was 4.29 per sex workers 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 Com- prehensive Timeline, Investigator Presentations to IOM Committee on the Methodological Challenges in HIV Prevention Trials; Publications of trial results.

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2007 2008 2009 2010 2013  Phase 3 trial to determine the FHI phase 3 trial of the Large-scale trial of a once- Large-scale trial of a once- effectiveness of two vaginal microbicide cellulose Phase 3 trial of the vaginal daily dose of Truvada to daily dose of Truvada to antiretroviral treatment sulfate gel for the prevention microbicide Carraguard for prevent HIV infection in high- prevent HIV infection in strategies in preventing the of HIV infection in women the prevention of HIV risk HIV-negative men who heterosexual men and women sexual transmission of HIV in infection in women have sex with men (NIAID- [Trial stopped early January (CDC-Botswana) HIV-serodiscordant couples Peru/Ecuador) 2007] (HPTN 052) 1 1 2 2 3 CONRAD phase 3 trial of the Phase 2/2b trial of the vaginal Large-scale trial of a once- Phase 2 trial of the vaginal vaginal microbicide cellulose microbicides BufferGel and daily dose of tenofovir to microbicide Tenofovir gel for sulfate gel for the prevention 0.5% PRO2000/5 gel (P) for prevent HIV infection in the prevention of HIV of HIV infection in women the prevention of HIV injecting drug users infection in women infection in women (HPTN [Trial stopped early January (CDC-Thailand) (CAPRISA 004) 035) 2007] 1 2 1 1 Phase 3 trial of the vaginal Phase 3 trial of the female Phase 3 trial of HSV-2 microbicide PRO 2000 for diaphragm to prevent HIV suppression in serodiscordant the prevention of HIV infection in women (MIRA) Key couples (Partners in infection in women (MDP [Results announced July Prevention) 301) 1 Microbicide 2007] 5 1 6 2 Preexposure prophylaxis (PrEP) Phase 3 trial of acyclovir for 3 Partner treatment Phase 3 trial of acyclovir for the reduction of HIV 4 Male circumcision the reduction of HIV infection in high-risk, HIV- infection in high-risk, HIV- negative, HSV-2 seropositive 5 Female-initiated barrier method negative, HSV-2 seropositive individuals (Tanzania) 6 HSV-2 treatment/suppression individuals (HPTN 039) [Results announced July 2007] 6 6 Large-scale trial to evaluate the safety of male circumcision and its potential protective effect for HIV-negative female partners of HIV-positive circumcised males [Trial stopped enrollment and surgeries in December 2006. Follow-up and data collection continue.] 4 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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 STATUS AND CHALLENGES 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 pre- vention 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 trans- mission of HIV and/or other sexually transmitted infections (STIs) when 1The 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 infec- tion. 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 HIV PREVENTION TRIALS adequate retention is a challenge in many of the settings where HIV preven- tion trials are being conducted. Estimating HIV Incidence If a trial is to show that a prevention product is effective, some indi- viduals 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 inci- dence 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, preg- nancy, 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 partici- pants 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 instruc- tions, as the following sections illustrate. Encouraging Correct and Consistent Condom Use Biomedical HIV prevention studies counsel participants on the impor- tance 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 work- ers 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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 STATUS AND CHALLENGES 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 (Braun- stein 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 inves- tigators 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 unem- ployment 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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0 METHODOLOGICAL CHALLENGES IN 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 micro- bicide 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 micro- bicide gel without their male partner’s knowledge (Whitehead et al., 2006). Addi- tionally, 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, incarcera- tion, and sometimes execution of many drug users. In this environment, investigators of a PrEP trial that enrolled injecting drug users were con- cerned that some of their study participants could be incarcerated. Investi-

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 STATUS AND CHALLENGES 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 chal- lenge traditional gender norms. In some countries, males dominate sexual deci- sion 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 partici- pants 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 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 com- munities (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 vul- nerable 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 par- ticipants’ 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. Incor- porating 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 numer- ous 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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 STATUS AND CHALLENGES 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 00: 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 00. http://www.microbicide.org/ microbicideinfo/reference/Microbicides.Planned.Funded.Clinical.Trials1Feb08.pdf (ac- cessed February 8, 2008). Alliance for Microbicide Development. 2008b. Microbicide candidates in ongoing clinical trials: Summary as of February 00. 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 pre- vention 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 coun- tries. 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 con- ducted 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 lubri- cation: 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.

OCR for page 37
 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS Bunnell, R., J. P. Ekwaru, P. Solberg, N. Wamai, W. Bikaako-Kajura, W. Were, A. Coutinho, C. Liechty, E. Madraa, G. Rutherford, and J. Mermin. 2006. Changes in sexual behavior and risk of HIV transmission after antiretroviral therapy and prevention interventions in rural Uganda. AIDS 20(1):85-92. Cates, W. 2007. Effectiveness of cellulose sulfate gel for prevention of HIV: Results of the phase III trial in Nigeria. Paper read at the Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, July 25, Sydney, Australia. CDC (Centers for Disease Control and Prevention). 2007. CDC trials of pre-exposure pro- phylaxis for HIV prevention. http://www.cdc.gov/hiv/resources/factsheets/PDF/prep.pdf (accessed January 15, 2008). Celum, C. 2007. Phase III randomized placebo-controlled trial of HSV- suppression to pre- vent HIV transmission among HIV-discordant couples. Paper read at the second public meeting for the Committee on Methodological Challenges in HIV Prevention Trials, London, UK. Celum, C., A. Wald, J. Hughes, J. Sanchez, S. Reid, S. Delaney-Moretlwe, F. M. Cowan, J. Fuchs, B. Koblin, L. Corey, and HPTN-039. 2008. HSV- suppressive therapy for prevention of HIV acquisition: Results of HPTN 0. Paper presented at Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts. Chaix, M. L., D. K. Ekouevi, G. Peytavin, F. Rouet, B. Tonwe-Gold, I. Viho, L. Bequet, C. Amani-Bosse, H. Menan, V. Leroy, C. Rouzioux, and F. Dabis. 2007. Impact of nevirapine (NVP) plasma concentration on selection of resistant virus in mothers who received single-dose NVP to prevent perinatal human immunodeficiency virus type 1 transmission and persistence of resistant virus in their infected children. Antimicrobial Agents and Chemotherapy 51(3):896-901. Cohen, M. S., C. Gay, A. D. Kashuba, S. Blower, and L. Paxton. 2007. Narrative review: Antiretroviral therapy to prevent the sexual transmission of HIV-1. Annals of Internal Medicine 146(8):591-601. Dunkle, K. L., R. K. Jewkes, H. C. Brown, G. E. Gray, J. A. McIntryre, and S. D. Harlow. 2004. Transactional sex among women in Soweto, South Africa: Prevalence, risk factors and association with HIV infection. Social Science and Medicine 59(8):1581-1592. Freeman, E. E., H. A. Weiss, J. R. Glynn, P. L. Cross, J. A. Whitworth, and R. J. Hayes. 2006. Herpes simplex virus 2 infection increases HIV acquisition in men and women: System- atic review and meta-analysis of longitudinal studies. AIDS 20(1):73-83. Glasgow, R. E., E. Lichtenstein, and A. C. Marcus. 2003. Why don’t we see more translation of health promotion research to practice? Rethinking the efficacy-to-effectiveness transi- tion. American Journal of Public Health 93(8):1261-1267. Global Campaign for Microbicides. 2007. Rectal microbicides. http://www.global-campaign. org/rectal.htm (accessed 2007). Global HIV Prevention Work Group. 2004. HIV prevention in the era of expanded treat- ment access. Prepared for the Bill & Melinda Gates Foundation and Kaiser Family Foundation. Global HIV Prevention Work Group. 2006. New approaches to HIV prevention: Accelerating research and ensuring future access. Prepared for the Bill & Melinda Gates Foundation and Kaiser Family Foundation. Global HIV Prevention Work Group. 2007. Bringing HIV prevention to scale. Prepared for the Bill & Melinda Gates Foundation and the Henry J. Kaiser Family Foundation. Gray, R. H., F. Wabwire-Mangen, G. Kigozi, N. K. Sewankambo, D. Serwadda, L. H. Moulton, T. C. Quinn, K. L. O’Brien, M. Meehan, C. Abramowsky, M. Robb, and M. J. Wawer. 2001. Randomized trial of presumptive sexually transmitted disease therapy dur- ing pregnancy in Rakai, Uganda. American Journal of Obstetrics and Gynecology 185(5):1209-1217.

OCR for page 37
 STATUS AND CHALLENGES Gray, R. H., G. Kigozi, D. Serwadda, F. Makumbi, S. Watya, F. Nalugoda, N. Kiwanuka, L. H. Moulton, M. A. Chaudhary, M. Z. Chen, N. K. Sewankambo, F. Wabwire-Mangen, M. C. Bacon, C. F. Williams, P. Opendi, S. J. Reynolds, O. Laeyendecker, T. C. Quinn, and M. J. Wawer. 2007. Male circumcision for HIV prevention in men in Rakai, Uganda: A randomised trial. Lancet 369(9562):657-666. Gregson, S., S. Adamson, S. Papaya, J. Mundondo, C. A. Nyamukapa, P. R. Mason, G. P. Garnett, S. K. Chandiwana, G. Foster, and R. M. Anderson. 2007. Impact and process evaluation of integrated community and clinic-based HIV-1 control: A cluster- randomised trial in eastern Zimbabwe. PLoS Medicine 4(3):e102. Grosskurth, H., F. Mosha, J. Todd, E. Mwijarubi, A. Klokke, K. Senkoro, P. Mayaud, J. Changalucha, A. Nicoll, and G. ka-Gina. 1995. Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: Randomised controlled trial. Lancet 346(8974):530-536. Hogrefe, W., X. Su, J. Song, R. Ashley, and L. Kong. 2002. Detection of herpes simplex virus type 2-specific immunoglobulin g antibodies in African sera by using recom- binant gG2, western blotting, and gG2 inhibition. Journal of Clinical Microbiology 40(10):3635-3640. Horton, E. 1995a. A provider to managed care. Behavioral Healthcare Tomorrow 4(6):22, 75. Horton, R. 1995b. African traditional thought and western science. In African philosophy. A. Mosely, ed. Englewood Cliffs, NJ: Prentice Hall. HPTN (HIV Prevention Trials Network). 2007. http://www.hptn.org/research_studies/hptn052. asp (accessed December 1, 2007). IAS (International AIDS Society). 2005. Building collaboration to advance HIV prevention: Global consultation on tenofovir pre-exposure prophylaxis research. Geneva, Switzer- land: International AIDS Society. International Perinatal HIV Group. 1999. The mode of delivery and the risk of vertical trans- mission of human immunodeficiency virus type 1—a meta-analysis of 15 prospective cohort studies. New England Journal of Medicine 340(13):977-987. IOM (Institute of Medicine). 1995. HIV and the blood supply. Washington, DC: National Academy Press. IOM and NAS (Institute of Medicine and National Academy of Sciences). 1994. Assessing the social and behavioral science base for HIV/AIDS prevention and intervention. Washing- ton, DC: National Academy Press. Jewkes, R. K., J. B. Levin, and L. A. Penn-Kekana. 2003. Gender inequalities, intimate partner violence and HIV preventive practices: Findings of a South African cross-sectional study. Social Science and Medicine 56(1):125-134. Kamali, A., M. Quigley, J. Nakiyingi, J. Kinsman, J. Kengeya-Kayondo, R. Gopal, A. Ojwiya, P. Hughes, L. M. Carpenter, and J. Whitworth. 2003. Syndromic management of sexually- transmitted infections and behaviour change interventions on transmission of HIV-1 in rural Uganda: A community randomised trial. Lancet 361(9358):645-652. Kaul, R., J. Kimani, N. J. Nagelkerke, K. Fonck, E. N. Ngugi, F. Keli, K. S. MacDonald, I. W. Maclean, J. J. Bwayo, M. Temmerman, A. R. Ronald, and S. Moses. 2004. Monthly antibiotic chemoprophylaxis and incidence of sexually transmitted infections and HIV-1 infection in Kenyan sex workers: A randomized controlled trial. JAMA 291(21):2555-2562. Kayitenkore, K., B. Bekan, J. Rufagari, S. Marion-Landais, E. Karita, S. Allen, and RZHRG. 2006. The impact of art on HIV transmission among HIV serodiscordant couples. Paper presented at the XVI International AIDS Conference, Toronto, Canada.

OCR for page 37
 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS Kuate-Defo, B. 2004. Young people’s relationships with sugar daddies and sugar mummies: What do we know and what do we need to know? African Journal of Reproductive Health 8(2):13-37. Loosli, B. C. 2004. Traditional practices and HIV prevention in sub-Saharan Africa. Geneva, Switzerland. http://www.gfmer.ch/GFMER_members/pdf/Traditional_HIV_Loosli.pdf (accessed March 25, 2008). Loue, S., L. Lloyd, and L. Loh. 1996a. HIV prevention in U.S. Asian Pacific Islander com- munities: An innovative approach. Journal of Health Care for the Poor and Underserved 7(4):364-376. Loue, S., D. Okello, and M. Kawuma. 1996b. Research bioethics in the Ugandan context: A program summary. Journal of Law, Medicine and Ethics 24(1):47-53. MacQueen, K. M., and Q. A. Karim. 2007. Practice brief: Adolescents and HIV clinical tri- als: Ethics, culture, and context. Journal of the Association of Nurses in AIDS Care 18(2):78-82. Microbicide Trials Network. 2007. http://www.MtnstopsHIV.Org/ (accessed October 25, 2007). Mills, E., C. Cooper, G. Guyatt, A. Gilchrist, B. Rachlis, C. Sulway, and K. Wilson. 2004. Barriers to participating in an HIV vaccine trial: A systematic review. AIDS 18(17):2235-2242. Molyneux, C. S., D. R. Wassenaar, N. Peshu, and K. Marsh. 2005. “even if they ask you to stand by a tree all day, you will have to do it (laughter) . . . !”: Community voices on the notion and practice of informed consent for biomedical research in developing countries. Social Science and Medicine 61(2):443-454. Montgomery, L., S. Napierala, P. Zvivamwe, S. Mtetwa, N. Hammond, T. Chipato, and A. van der Straten. 2006. Male involvement in a diaphragm and microbicide safety study in Zimbabwe. Paper read at Microbicides Conference, Cape Town, South Africa. Morrow, K. M., and M. S. Ruiz. 2007. Assessing microbicide acceptability: A comprehensive and integrated approach. AIDS and Behavior. http://www.springerlink.com/content/ 30u617k8j2203703/fulltext.html (accessed March 25, 2008). Morrow, K. M. P., J. L. P. Fava, R. K. P. Rosen, S. B. A. Vargas, C. Barroso, A. L. B. A. Christensen, C. P. Woodsong, and L. P. Severy. 2007. Willingness to use microbicides is affected by the importance of product characteristics, use parameters, and protective properties. Journal of Acquired Immune Deficiency Syndromes 45(1):93-101. Mosack, K. E., M. R. Weeks, L. Novick Sylla, and M. Abbott. 2005. High-risk women’s willingness to try a simulated vaginal microbicide: Results from a pilot study. Women & Health 42(2):71-88. Nagot, N., A. Ouedraogo, P. Mayaud, I. Konate, L. Vergne, H. Weiss, V. Foulongne, D. Djagbare, M. Segongy, P. Vande Perre, and ANRS 1285 Study Group. 2006. Effect of HSV- suppressive therapy on HIV- genital shedding and plasma viral load: A proof-of- concept randomized doubleblind placebo controlled trial (ANRS trial). Paper read at 13th Conference on Retroviruses and Opportunistic Infections, Denver, Colorado. Nuttall, J., J. Romano, K. Douville, C. Galbreath, A. Nel, W. Heyward, M. Mitchnick, S. Walker, and Z. Rosenberg. 2007. The future of HIV prevention: Prospects for an effec- tive anti-HIV microbicide. Infectious Disease Clinics of North America 21(1):219-239. Orner, P., J. Harries, D. Cooper, J. Moodley, M. Hoffman, J. Becker, E. McGrory, R. Dabash, and H. Bracken. 2006. Challenges to microbicide introduction in South Africa. Social Science and Medicine 63(4):968-978.

OCR for page 37
 STATUS AND CHALLENGES Padian, N., A. van der Straten, G. Ramjee, T. Chipato, G. de Bruyn, K. Blanchard, S. Shiboski, E. Montgomery, H. Fancher, H. Cheng, M. Rosenblum, M. van der Loan, N. Jewell, J. McIntyre, and The MIRA Team. 2007. Diaphragm and lubricant gel for prevention of HIV acquisition in southern African women: A randomised controlled trial. Lancet 370:251-261. Peterson, L., D. Taylor, R. Roddy, G. Belai, P. Phillips, K. Nanda, R. Grant, E. E. K. Clarke, A. S. Doh, R. Ridzon, H. S. Jaffe, and W. Cates. 2007a. Tenofovir disoproxil fumarate for prevention of HIV infection in women: A phase 2, double-blind, randomized, placebo-controlled trial. PLoS Clinical Trials 2(5). Peterson, L., K. Nanda, B. K. Opoku, W. K. Ampofo, M. Owusu-Amoako, A. Y. Boakye, W. Rountree, A. Troxler, R. Dominik, R. Roddy, and L. Dorflinger. 2007b. Savvy(R) (C31g) gel for prevention of HIV infection in women: A phase 3, double-blind, random- ized, placebo-controlled trial in Ghana. PLoS ONE 2(12):e1312. Pettifor, A. E., D. M. Measham, H. V. Rees, and N. S. Padian. 2004. Sexual power and HIV risk, South Africa. Emerging Infectious Diseases 10(11):1996-2004. PhRMA. 2007. PhRMA, HIV/AIDS medicines in development. Washington, DC: PhRMA. (adapted for use by NAS). Prep Watch. 2007. Ongoing prep trials as of January 2007. http://prepwatch.org/pdf/Trials/ PrEP_trials_table.pdf (accessed November 1, 2007). Smith, D. 2007. CDC PrEP trials. Presentation read at the first public meeting for the Com- mittee on Methodological Challenges in HIV Prevention Trials, Washington, DC. Tolley, E. E., and L. J. Severy. 2006. Integrating behavioral and social science research into microbicide clinical trials: Challenges and opportunities. American Journal of Public Health 96(1):79-83. UNAIDS. 2007. New data on male circumcision and HIV prevention: Policy and programme implications. Geneva, Switzerland: UNAIDS. Van Damme, L. 2007. Phase III trial of % cellulose sulfate (CS) gel for the prevention of HIV transmission. Paper read at the Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia. Van Damme, L., G. Ramjee, M. Alary, B. Vuylsteke, V. Chandeying, H. Rees, P. Sirivongrangson, L. Mukenge-Tshibaka, V. Ettiegne-Traore, C. Uaheowitchai, S. S. Karim, B. Masse, J. Perriens, and M. Laga. 2002. Effectiveness of col-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: A randomised controlled trial. Lancet 360(9338):971-977. Veldhuijzen, N., J. Nyinawabega, M. Umulisa, B. Kankindi, E. Geubbels, P. Basinga, J. Vyankandondera, and J. Van De Wijgert. 2006. Preparing for microbicide trials in Rwanda: Focus group discussions with Rwandan women and men. Culture, Health and Sexuality 8(5):395-406. Watson-Jones, D., M. Rusizoka, H. Weiss, K. Mugeye, K. Baisley, J. Changalucha, D. Everett, C. Tanton, T. Clayton, D. Ross, and R. Hayes. 2007. Impact of HSV- suppressive therapy on HIV incidence in HSV- seropositive women: A randomised controlled trial in Tanzania. Paper read at the Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia. Watts, C., and P. Vickerman. 2001. The impact of microbicides on HIV and STD transmission: Model projections. AIDS 15(Suppl 1):S43-S44. Wawer, M. 2007. Lessons learned from STD treatment trials for HIV prevention. Paper read at Presentation at the second public meeting for the Committee on Methodological Chal- lenges in HIV Prevention Trials, London, UK.

OCR for page 37
 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS Wawer, M. J., N. K. Sewankambo, D. Serwadda, T. C. Quinn, L. A. Paxton, N. Kiwanuka, F. Wabwire-Mangen, C. Li, T. Lutalo, F. Nalugoda, C. A. Gaydos, L. H. Moulton, M. O. Meehan, S. Ahmed, and R. H. Gray. 1999. Control of sexually transmitted diseases for AIDS prevention in Uganda: A randomised community trial. Rakai Project Study Group. Lancet 353(9152):525-535. Weiser, S. D., M. Heisler, K. Leiter, F. Percy-de Korte, S. Tlou, S. DeMonner, N. Phaladze, D. R. Bangsberg, and V. Iacopino. 2006. Routine HIV testing in Botswana: A population-based study on attitudes, practices, and human rights concerns. PLoS Medicine 3(7):e261. Whitehead, S. J., P. H. Kilmarx, K. Blanchard, C. Manopaiboon, S. Chaikummao, B. Friedland, J. Achalapong, M. Wankrairoj, P. Mock, S. Thanprasertsuk, and J. W. Tappero. 2006. Ac- ceptability of Carraguard vaginal gel use among Thai couples. AIDS 20(17):2141-2148. Yale Law Journal. 1946. Willful refusal to have or bear children as grounds for divorce or annulment. The Yale Law Journal 55(3):596-599.