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Methodological Challenges in Biomedical HIV Prevention Trials (2008)

Chapter: 1 The Status and Challenges of Biomedical HIV Prevention Trials

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Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 40
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 41
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 42
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 43
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 44
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 45
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 46
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 47
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 48
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 49
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 50
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 51
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 52
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 53
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 54
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 55
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 56
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 57
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 58
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 60
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 61
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
×
Page 62
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
×
Page 63
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
×
Page 64
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
×
Page 65
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
×
Page 66
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
×
Page 67
Suggested Citation:"1 The Status and Challenges of Biomedical HIV Prevention Trials." Institute of Medicine. 2008. Methodological Challenges in Biomedical HIV Prevention Trials. Washington, DC: The National Academies Press. doi: 10.17226/12056.
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Page 68

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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; 37

38 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

STATUS AND CHALLENGES 39 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

40 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

STATUS AND CHALLENGES 41 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

42 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

STATUS AND CHALLENGES 43 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

44 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.

STATUS AND CHALLENGES 45 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.

2007 2008 2009 2010 2013 46 FHI phase 3 trial of the Phase 3 trial to determine the Large-scale trial of a once- vaginal microbicide cellulose Large-scale trial of a once- effectiveness of two Phase 3 trial of the vaginal daily dose of Truvada to sulfate gel for the prevention daily dose of Truvada to antiretroviral treatment microbicide Carraguard for prevent HIV infection in high- of HIV infection in women prevent HIV infection in strategies in preventing the the prevention of HIV risk HIV-negative men who heterosexual men and women sexual transmission of HIV in [Trial stopped early January infection in women have sex with men (NIAID- (CDC-Botswana) HIV-serodiscordant couples 2007] Peru/Ecuador) 1 1 2 2 3 (HPTN 052) CONRAD phase 3 trial of the Phase 2/2b trial of the vaginal vaginal microbicide cellulose Large-scale trial of a once- Phase 2 trial of the vaginal microbicides BufferGel and sulfate gel for the prevention daily dose of tenofovir to microbicide Tenofovir gel for 0.5% PRO2000/5 gel (P) for of HIV infection in women prevent HIV infection in the prevention of HIV the prevention of HIV injecting drug users infection in women [Trial stopped early January infection in women (HPTN (CDC-Thailand) (CAPRISA 004) 2007] 035) 1 2 1 1 Phase 3 trial of the female Phase 3 trial of the vaginal Phase 3 trial of HSV-2 diaphragm to prevent HIV microbicide PRO 2000 for suppression in serodiscordant infection in women (MIRA) the prevention of HIV Key couples (Partners in [Results announced July infection in women (MDP Prevention) 5 2007] 1 301) 1 Microbicide 6 2 Preexposure prophylaxis (PrEP) Phase 3 trial of acyclovir for 3 Partner treatment the reduction of HIV Phase 3 trial of acyclovir for infection in high-risk, HIV- the reduction of HIV 4 Male circumcision negative, HSV-2 seropositive infection in high-risk, HIV- 5 Female-initiated barrier method individuals (Tanzania) negative, HSV-2 seropositive individuals (HPTN 039) 6 HSV-2 treatment/suppression [Results announced July 6 2007] 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 4 continue.] 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.

STATUS AND CHALLENGES 47 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. 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 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 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).

48 Clinical Trials Discovery/ Phase Phase Phase Phase Preclinical FDA I II III IV Testing Years 6.5 1.5 2 3.5 1.5 Laboratory 1,000 to 20 to 100 100 to 500 Test and 5,000 healthy patient Population animal patient volunteers volunteers studies volunteers Confirm Review Assess effectiveness, Additional process/ safety, Determine Evaluate monitor post- approval biological safety effectiveness, adverse marketing Purpose look for reactions testing File IND at FDA activity and and formulations dosage side effects from required File NDA/BLA at FDA long-term by FDA use 5,000 Success compounds 5 1 Rate enter trials approved evaluated Figure 1-2  The drug development and approval processin the United States, see also Box 1-1 on the facing page. SORUCE: Adapted with permission from PhRMA, 2007. Figure 1-1 Broadside

STATUS AND CHALLENGES 49 BOX 1-1 The Drug Development and Approval Process in the United States It takes 10–15 years, on average, for an experimental drug to travel from lab to U.S. patients. Only five in 5,000 compounds that enter preclinical testing make it to human testing. And only one of those five is approved for sale. Once a new compound has been identified in the laboratory, medicines are developed as follows: Preclinical Testing. A pharmaceutical company conducts laboratory and animal studies to show biological activity of the compound against the targeted disease, and the compound is evaluated for safety. Investigational New Drug Application (IND). After completing preclinical test- ing, a company files an IND with the U.S. Food and Drug Administration (FDA) to begin to test the drug in people. The IND becomes effective if FDA does not disapprove it within 30 days. The IND shows results of previous experiments; how, where and by whom the new studies will be conducted; the chemical structure of the compound; how it is thought to work in the body; any toxic effects found in the animal studies; and how the compound is manufactured. All clinical trials must be reviewed and approved by the Institutional Review Board (IRB) where the trials will be conducted. Progress reports on clinical trials must be submitted at least annually to FDA and the IRB. Clinical Trials, Phase I. These tests typically involve about 20 to 100 normal, healthy volunteers. The tests study a drug’s safety profile, including the safe dosage range. The studies also determine how a drug is absorbed, distributed, metabolized, and excreted as well as the duration of its action. Clinical Trials, Phase II. In this phase, controlled trials of approximately 100 to 500 volunteers assess a drug’s effectiveness. Clinical Trials, Phase III. This phase usually involves 1,000 to 5,000 partici- pants. Physicians monitor patients closely to confirm efficacy and identify adverse events. New Drug Application (NDA)/Biologic License Application (BLA). Following the completion of all three phases of clinical trials, a company analyzes all of the data and files an NDA or BLA with FDA if the data successfully demonstrate both safety and effectiveness. Approval. Once FDA approves an NDA or BLA, the new medicine becomes available for physicians to prescribe. A company must continue to submit periodic reports to FDA, including any cases of adverse reactions and appropriate quality- control records. For some medicines, FDA requires additional trials (Phase IV) to evaluate long-term effects. SOURCE: Adapted with permission from PhRMA, 2007.

50 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS applied to genital mucosal surfaces (Alliance for Microbicide Development, ND). Microbicides can be in the form of gel, film, cream, suppository, pre- loaded diaphragm or cervical cap; or vaginal ring that releases the active ingredient over time. Some vaginal microbicides may also have contracep- tive effects and help prevent other sexually transmitted infections, such as chlamydia or gonorrhea. Several vaginal microbicides are in late-stage efficacy testing (Box 1-2). Three candidates have failed to show a protective effect on HIV transmission: • COL-1492, a Nonoxynol-9–based gel, was the first vaginal micro- bicide to be tested in a phase 3 trial. The trial—conducted in female sex workers in Benin, Côte d’Ivoire, South Africa, and Thailand—found that the product had no protective benefit against HIV, and that women who were frequent users of the gel appeared to be at increased risk of HIV infec- tion compared with women with similar levels of placebo use (Van Damme et al., 2002). • Two phase 3 trials of Savvy vaginal microbicide in Ghana and Nigeria were stopped in 2005 and 2006, respectively, because lower-than- expected HIV incidence at the trial sites meant that the study had insuf- ficient power to determine efficacy (Peterson et al., 2007b). • In early 2007, a phase 3 multicountry trial of the cellulose sulfate (CS) microbicide 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 (Van Damme, 2007). A separate, concurrent trial of CS in Nigeria was stopped as a pre- cautionary measure, although there was no apparent increased risk in that trial (Cates, 2007; Van Damme, 2007). Three candidate microbicides (Carraguard [completed], PRO2000 and Buffer Gel) are now in phase 2B or phase 3 testing. The Carraguard trial results are expected in 2008 while the MDP 301 trial (of different formula- tions of PRO2000) and the HPTN 035 trial (of PRO2000 and BufferGel) results are expected in 2009. Researchers began enrolling participants in 2007 in CAPRISA 004, a phase 2B trial of a vaginal microbicide containing 1 percent tenofovir gel. The vaginal ring—a coitally independent device for delivering microbicides—and two microbicides (ACIDFORM© and Dapi- virine [TMC120]) are slated to begin phase 3 testing in 2008 (Alliance for Microbicide Development, 2008a). Products designed for vaginal use may or may not be appropriate for rectal use. The rectal lining is more fragile than most of the tissue lining the vagina, and is richer in cells that are particularly vulnerable to HIV infec- tion. These factors further enhance rectal susceptibility to irritation, tearing,

STATUS AND CHALLENGES 51 BOX 1-2 Microbicide Candidates Microbicides can be divided into first- and second-generation candidates. Six candidates in the first generation have advanced to phase 3 efficacy trials. These candidates are nonspecific compounds that work by disrupting the viral envelope, or by electrostatically binding to the virus and preventing it from interacting with its target cells in the vagina (Nuttall et al., 2007). All six candidates are for vaginal use, and require adherence to a coitally dependent dosing strategy. First-generation products include the following: • COL-1492 is a Nonoxynol-9–based surfactant that disrupts the cell mem- branes and protects against pregnancy (Van Damme et al., 2002). • C31G (Savvy) is a surfactant compound designed to disable HIV by breaking down its outer membrane. C31G may also protect against pregnancy (Global HIV Prevention Work Group, 2007). • Carbopol 974p (BufferGel) is a vaginal-defense enhancer designed to maintain the vagina’s acidity in the presence of semen, to help kill or disable the virus (Global HIV Prevention Work Group, 2007). • Cellulose sulfate (Ushercell) is an “attachment inhibitor,” which prevents HIV from attaching to cells in the vaginal wall. This compound may also prevent pregnancy (Global HIV Prevention Work Group, 2007). • Naphthalene sulfonate (PRO2000/5) is an “entry/fusion inhibitor,” which binds to HIV pathogens to prevent them from entering and infecting healthy human cells (Global HIV Prevention Work Group, 2007). • PC-515 (Carraguard) is also an entry/fusion inhibitor (Global HIV Preven- tion Work Group, 2007). Trials of three of these microbicide candidates (COL-1492, C31G, and cel- lulose sulfate) failed to show a protective effect on HIV transmission. The efficacy of the remaining three candidates (BufferGel, Carraguard, and PRO2000/5) is also being evaluated (Carraguard, HPTN 035, and MDP 301). The Carraguard trial was recently completed and could show results by the end of 2007; the results of the remaining two trials are expected in 2009. Second-generation microbicide candidates include those that specifically target HIV or the molecules of the cells it infects, and those that use existing or new classes of antiretroviral compounds (Global HIV Prevention Working Group, 2006). Researchers are now conducting a phase 2B efficacy trial of a vaginal microbicide containing 1 percent tenofovir gel (CAPRISA 004), and two more second-generation vaginal microbicides (ACIDFORM© and Dapivirine [TMC120]) are slated for phase 3 testing in 2008. Researchers are investigating new ways of formulating these microbicides, such as delivering them through a vaginal ring. Early-stage testing of rectal microbicides is also under way. (See Nuttall et al., 2007, for more on these classes.)

52 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS and infection during sex (Global Campaign for Microbicides, 2007). One microbicide compound, a topical formulation of the antiretroviral drug UC-781, is in early phase-testing for rectal use (Alliance for Microbicide Development, 2008b). Pre-Exposure Prophylaxis with Antiretrovirals Animal studies suggest that antiretroviral drugs used for HIV treatment may also be effective in preventing HIV infection. This approach is known as pre-exposure prophylaxis, or PrEP. Several early PrEP studies were closed to further enrollment or canceled because of ethical concerns raised by advocates, governments, and community members. • A phase 3 randomized, controlled trial of tenofovir chemoprophy- laxis in sex workers in Cambodia was halted in August 2004 in response to statements by the Cambodian prime minister, and after community advo- cates raised attention to concerns regarding needs among trial participants for medical treatment. An avalanche of commentary regarding the trial highlighted the need for community consultation and review of policies worldwide regarding how HIV prevention trials address antiretroviral treat- ment and long-term care (potentially associated with trial-related adverse events) for participants. • In 2004, a phase 2 trial of daily oral tenofovir began in Ghana, Nigeria, and Cameroon in women at high risk for infection. However, research in Cameroon was halted in 2005 after advocates, and later the government and community members, raised similar issues about commu- nity involvement in research, and the rights and protections afforded trial participants (IAS, 2005). The Nigerian trial site was closed in 2005 because of an inability to meet protocol requirements. The premature closure of two sites meant that study power was insufficient to assess the efficacy of tenofovir in preventing HIV acquisition among women. • A planned PrEP trial in Malawi never began because of government concerns that it would foster HIV resistance to tenofovir, which is being used as a treatment for HIV (Prep Watch, 2007). Three late-stage efficacy trials using two antiretroviral agents— specifically, tenofovir disoproxil fumarate (tenofovir or TDF, brand name Viread®), used alone or in combination with emtricitabine (together TDF/ FTC, known by the brand name Truvada®)—are under way. The first trial is testing the efficacy of tenofovir in preventing HIV infection among male and female injecting drug users in Thailand (CDC, 2007). The second trial is testing Truvada® for the prevention of HIV infection in heterosexually active young men and women in Botswana (CDC, 2007). The third trial

STATUS AND CHALLENGES 53 is testing Truvada® in high-risk men who have sex with men in Peru and Ecuador. Results from the Thai study could be available as early as 2008, with Botswana expected in 2009, and the Peru/Ecuador study expected in 2010. Planned for 2008, the VOICE Study—Vaginal and Oral Interventions to Control the Epidemic—will compare the safety and efficacy of oral versus topical PrEP in preventing sexual transmission of HIV (Microbicide Trials Network, 2007). VOICE is designed as a five-arm, double-blinded study. Women will first be randomized to receive either gel or oral PrEP. Then, within each group, the women will be randomly assigned to either tenofovir topical gel or placebo gel; or to oral tenofovir, oral Truvada, or oral placebo. The study plans to enroll 4,200 women at 10 sites in sub- Saharan Africa. In addition to PrEP studies, several observational studies of serodis- cordant couples suggest that treating HIV infected persons with ART may reduce the sexual transmission of HIV (Bunnell et al., 2006; Kayitenkore et al., 2006). A randomized control trial (HPTN 052) to determine the effects of antiretroviral drugs on HIV transmission in serodiscordant couples is underway (HPTN, 2007). Although not addressed in this report, emergency post-exposure (PEP) prophylaxis with antiretroviral drugs is the standard of care for occupa- tional exposures to HIV through infected tissues or fluids, and is increas- ingly used for nonoccupational exposures (Cohen et al., 2007). It is well documented that antiretroviral treatment of HIV-infected persons may result in emergent viral resistance, particularly in the setting of monotherapy. For example, use of single dose intrapartum nevirapine results in emergence of resistant HIV in 19–87 percent of mothers (Chaix et al., 2007). However, it is unknown whether the use of antiretroviral agents (either as pre-exposure prophylaxis or as vaginal/rectal microbicides) to prevent HIV acquisition in HIV-uninfected persons will result in infection with resistant viruses or the emergence of resistant virions. In particular, the use of nonnucleoside reverse transcriptase inhibitors as microbicides may be of concern as the genetic barrier for resistance of that class of agents is quite low. Although an assessment of this topic is outside the scope of the report, prevention trials using antiretroviral agents must rigorously address this question, including assessing incident HIV infections for presence of antiretroviral resistance and considering the prevalence of agent-specific resistance. Male Circumcision A number of observational and ecological studies, including a system- atic review and meta-analysis of studies from sub-Saharan Africa, have

54 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS suggested that male circumcision may reduce men’s risk of becoming HIV infected. The effectiveness of male circumcision was recently confirmed in three randomized, controlled trials conducted in Kenya, Uganda, and South Africa, which found that male circumcision reduced the risk of het- erosexually acquired HIV infection among men by about 50–60 percent at 18–24 months of follow-up (Auvert et al., 2005; Bailey et al., 2007; Gray et al., 2007). A recent expert consultation convened by WHO and UNAIDS (UNAIDS, 2007) characterized this evidence as compelling, and recommended that public health officials include male circumcision in a comprehensive HIV prevention package, particularly, expanding it to areas where rates of heterosexually acquired HIV infection among men is high. A follow-up study was initiated in Rakai, Uganda, to determine whether circumcision among HIV-infected men reduces HIV transmission to female partners (Wawer, 2007). However, after reviewing the data in late 2006, the trial’s Data Safety Monitoring Board stopped further enrollment based on futility. The data suggested that transmission of HIV from circumcised, infected men to women may actually rise if they resume sex before the wound is fully healed (Wawer, 2007). Cervical Barriers Researchers hypothesized that cervical barriers may help protect women from HIV by covering the cervix and blocking the upper genital track, areas with cells that are more susceptible to certain STIs and HIV infection (Padian et al., 2007). Observational studies have suggested that women using diaphragms have a reduced risk of cervical STIs, pelvic inflammatory disease, and human papillomavirus-associated cervical neoplasia (Padian et al., 2007). In a recent phase 3 trial, researchers evaluated whether the diaphragm, lubricant gel, and condoms/counseling (intervention arm), com- pared to condoms/counseling alone (control arm) had a protective effect on HIV incidence among women in South Africa and Zimbabwe (Padian et al., 2007). The trial failed to show any additional benefit of a latex diaphragm and lubricant gel (Replens) over standard risk reduction and condom coun- seling in preventing acquisition of HIV in women, corresponding to a rela- tive hazard of 1.05 (95% confidence interval [CI]: 0.84–1.32). Notably, the proportion of women who reported using condoms was significantly lower in the intervention than in the control group (54 percent versus 85 percent of visits, p < 0.0001) (Padian et al., 2007). Herpes Suppression Multiple studies have found that individuals with herpes simplex virus- 2 (HSV) are at increased risk of HIV infection (Freeman et al., 2006). HIV-

STATUS AND CHALLENGES 55 infected individuals who are coinfected with HSV-2 are also more likely to transmit HIV to others (Nagot et al., 2006). HSV-2 is one of the most common STIs worldwide. In some parts of Africa, more than 70 percent of adults are infected with HSV-2 (Hogrefe et al., 2002). Several studies have examined whether acyclovir, a widely used drug to suppress HSV-2, can reduce sexual acquisition and transmission of HIV (Global HIV Prevention Work Group, 2007). Two recently completed trials failed to demonstrate that acyclovir treatment had a protective effect on HIV acquisition. The first was a randomized, placebo controlled trial of acyclovir treatment (400 mg BD) among initially HIV-seronegative, HSV-2 seropositive women in northern Tanzania (Watson-Jones et al., 2007). The trial found no protective effect of acyclovir against HIV acquisition. High rates of pregnancy (resulting in 25 percent of participants being withdrawn from study medication), poor reported participant adherence (50 percent of the women provided with acyclovir failed to achieve the target 90 percent adherence rate), and poor participant retention (60 percent of the women completed the trial) were reported (Watson-Jones et al., 2007). A second randomized, placebo-controlled trial (HPTN 039) was designed to assess whether HSV-2 suppression twice-daily oral acyclovir of 400 mg (800 mg total) reduced the rate of HIV acquisition among high- risk women in Africa and men who have sex with men in the United States and Peru. The regimen failed to show a protective benefit against HIV. 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). There were no significant differences by gender or reported adherence to the drug. A third phase 3 trial examining the impact of HSV-2 suppression in HIV-infected individuals on transmission of HIV to their partners is under- way. Results from this trial (Partners in Prevention study) are due in 2008 (Celum, 2007). Methodological Challenges in BIOMEDICAL HIV Prevention Trials This report examines methodological challenges in late-stage random- ized prevention trials of nonvaccine biomedical interventions, and their impact on study design and conduct, site preparedness, interim monitoring and analysis, and interpretation of results. Key challenges include the lack of a reliable surrogate marker for HIV infection: the difficulty of accurately estimating HIV incidence; the need to provide risk-reduction counseling, which is of uncertain benefit; high rates of pregnancy among trial partici- pants; the difficulty measuring and maintaining adequate levels of product

56 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS adherence and inadequate participant retention. These challenges are briefly highlighted below. Subsequent chapters contain a more in-depth discussion of these issues. Although the committee’s charge did not include examining vaccine, pMTCT trials, and some behavioral risk-reduction trials (outside of their use as a cointervention in biomedical HIV prevention trials), many of the potential responses to these challenges may also have implications for those studies. Lack of a Surrogate Marker for HIV Infection HIV infection is, appropriately, by default the primary endpoint in both Phase 2 and 3 HIV randomized prevention trials, because researchers have not identified and validated a surrogate marker of product efficacy. Because HIV infection is a relatively uncommon event even in high-incidence areas, these trials must enroll very large numbers of participants to have the power to detect that a product has a beneficial effect. This requirement increases both the time needed to conduct trials and their cost. Risk-Reduction Counseling There is broad agreement among multiple stakeholders that partici- pants in HIV prevention trials should receive behavioral risk-reduction counseling. Trials must therefore show that the biomedical intervention has a benefit in a setting where this counseling also may reduce the HIV inci- dence rate. That is, if the counseling strategy were effective, it could reduce the study’s power to detect a beneficial effect of the biomedical intervention. Yet little is known about the effectiveness of behavioral counseling in many of the settings where biomedical HIV prevention takes place. Pregnancy Despite intensive counseling on family planning, and access to contra- ceptives through referrals to family planning clinics or onsite provision, many women enrolled in HIV prevention trials, particularly in Africa, become pregnant. Trials testing new products and new drug indications typically restrict pregnant women from enrolling and require women to use some form of contraceptive while participating in the trials. Women who become pregnant during a trial are typically taken off the product, either permanently or for the duration of their pregnancy. Time off the product owing to pregnancy has adversely affected study power in trials whose sample size and power calculations do not account for this, or where higher-than-expected pregnancy rates occur. Discontinuing product use among pregnant women also prevents

STATUS AND CHALLENGES 57 researchers from learning about the effects of the interventions on pregnant women and on pregnancy outcomes. That presents a problem because once a biomedical intervention is found to be efficacious and approved for use, a recommendation against use during pregnancy is unlikely to be widely followed, particularly when women may use such products throughout childbearing age. This raises ethical questions about how to best collect safety data, and about whether women participating in trials should have the option of remaining on the product if they become pregnant. Adherence and Reporting of Sexual Behavior Imperfect adherence to prescribed randomized regimens is common in HIV prevention trials and can obscure the efficacy of a product. If a trial fails to show a protective effect, investigators need to understand whether that failure occurred because the product was not biologically efficacious, or because participants failed to adhere to the product regimen. Each biomedical intervention has its own adherence challenges. For example, coitally dependent products, such as the current generation of microbi- cides, require women to use the product before or after each sex act. This may pose challenges because sex is not always predictable or controlled by women. With respect to both adherence and risk behavior, many studies with no or limited objective measures of product adherence rely heavily on self- reported measures of product use and sexual behavior. The accuracy of such data is sometimes questionable, and few objective measures exist to corroborate these reports. Recruitment and Retention Effectively recruiting and retaining trial participants is essential for obtaining meaningful study results. A slowly accruing trial can delay the widespread use of an efficacious treatment, or expose participants to an ineffective treatment for longer than necessary. A prolonged trial may also divert resources from newer and more promising approaches. However, while recruiting participants in a timely manner is important, an emphasis on doing so at all costs can undermine the ability of investiga- tors to retain them. And while enrolling participants from a large region may allow for faster recruitment, the resulting population may be more challenging to retain as access to the clinic and follow-up in the partici- pants’ homes would be more difficult. To ensure confidence in their outcomes, trials must achieve high reten- tion. Lower-than-expected participant recruitment and retention can mean that a trial will be underpowered and its results biased. Yet maintaining

58 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).

STATUS AND CHALLENGES 59 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

60 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-

STATUS AND CHALLENGES 61 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

62 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

STATUS AND CHALLENGES 63 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 (ac- cessed 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 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.

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66 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-2 suppressive therapy on HIV-1 genital shedding and plasma viral load: A proof-of- concept randomized doubleblind placebo controlled trial (ANRS1285 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.

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The number of people infected with HIV or living with AIDS is increasing at unprecedented rates as various scientists, organizations, and institutions search for innovative solutions to combating and preventing the disease. At the request of the Bill & Melinda Gates Foundation, Methodological Challenges in Biomedical HIV Prevention Trials addresses methodological challenges in late-stage nonvaccine biomedical HIV prevention trials with a specific focus on microbicide and pre-exposure prophylaxis trials. This book recommends a number of ways to improve the design, monitoring, and analysis of late-stage clinical trials that evaluate nonvaccine biomedical interventions. The objectives include identifying a beneficial method of intervention, enhancing quantification of the impact, properly assessing the effects of using such an intervention, and reducing biases that can lead to false positive trial results.

According to Methodological Challenges in Biomedical HIV Prevention Trials, the need to identify a range of effective, practical, and affordable preventive strategies is critical. Although a large number of promising new HIV prevention strategies and products are currently being tested in late-stage clinical trials, these trials face a myriad of methodological challenges that slow the pace of research and limit the ability to identify and fully evaluate effective biomedical interventions.

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