Methodological Challenges in Biomedical HIV Prevention Trials (2008) / Chapter Skim
Currently Skimming:
1 The Status and Challenges of Biomedical HIV Prevention Trials
1 The Status and Challenges of Biomedical HIV Prevention Trials
Pages 37-68
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 37... ...
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
|
From page 38... ...
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
|
From page 39... ...
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.
|
From page 40... ...
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)
|
From page 41... ...
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.
|
From page 42... ...
; 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
|
From page 43... ...
, corresponding to a reduction in risk of acquiring HIV infection by 53 percent. Median length of follow-up was 24 months.
|
From page 44... ...
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, HIVSeronegative 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 SeroDiscordant 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)
|
From page 45... ...
The difference was not statistically significant. Sources: Study protocols, www.clinicaltrials.gov, AVAC HIV Prevention Research: A Comprehensive Timeline, Investigator Presentations to IOM Committee on the Methodological Challenges in HIV Prevention Trials; Publications of trial results.
|
From page 46... ...
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)
|
From page 47... ...
. 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)
|
From page 48... ...
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.
|
From page 49... ...
In this phase, controlled trials of approximately 100 to 500 volunteers assess a drug's effectiveness. Clinical Trials, Phase III.
|
From page 50... ...
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 infection compared with women with similar levels of placebo use (Van Damme et al., 2002)
|
From page 51... ...
. Researchers are now conducting a phase 2B efficacy trial of a vaginal microbicide containing 1 percent tenofovir gel (CAPRISA 004)
|
From page 52... ...
• A phase 3 randomized, controlled trial of tenofovir chemoprophylaxis in sex workers in Cambodia was halted in August 2004 in response to statements by the Cambodian prime minister, and after community advocates 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 treatment and long-term care (potentially associated with trial-related adverse events)
|
From page 53... ...
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 systematic review and meta-analysis of studies from sub-Saharan Africa, have
|
From page 54... ...
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)
|
From page 55... ...
. Methodological Challenges in BIOMEDICAL HIV Prevention Trials This report examines methodological challenges in late-stage randomized prevention trials of nonvaccine biomedical interventions, and their impact on study design and conduct, site preparedness, interim monitoring and analysis, and interpretation of results.
|
From page 56... ...
, 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.
|
From page 57... ...
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.
|
From page 58... ...
Encouraging Correct and Consistent Condom Use Biomedical HIV prevention studies counsel participants on the importance of using either male or female condoms to prevent HIV infection. In some cultures, decisions on condom use rest largely with men.
|
From page 59... ...
. Preventing Pregnancy During a Trial In most biomedical HIV prevention trials, uncertainties and concerns about the effects of the intervention on pregnancy outcomes prompt investigators to counsel women to avoid pregnancy and to take them off product if they become pregnant.
|
From page 60... ...
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)
|
From page 61... ...
. Another important factor shaping recruitment and retention of participants in HIV prevention trials is the stigma associated with HIV.
|
From page 62... ...
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.
|
From page 63... ...
2005. ������ Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: The ANRS 1265 trial.
|
From page 64... ...
Paper read at the second public meeting for the Committee on Methodological Challenges in HIV Prevention Trials, London, UK. Celum, C., A
|
From page 65... ...
1995. Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: Randomised controlled trial.
|
From page 66... ...
Paper read at Microbicides Conference, Cape Town, South Africa. Morrow, K
|
From page 67... ...
2007a. Tenofovir disoproxil fumarate for prevention of HIV infection in women: A phase 2, double-blind, randomized, placebo-controlled trial.
|
From page 68... ...
1999. Control of sexually transmitted diseases for AIDS prevention in Uganda: A randomised community trial.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.