Introduction

If the world is to successfully address the HIV epidemic, preventing new infections will be as important as treating those who are infected (see Box I-1). However, in the foreseeable future, there will be no single prevention product (“magic bullet”) that will prevent the spread of HIV. Thus the need to identify a range of effective, practical, and affordable preventive strategies, and to determine how best to combine them, is critical. A number of promising new HIV prevention strategies and products are currently being tested in late-stage clinical trials. Yet HIV prevention trials face a myriad of methodological challenges which slow the pace of research and limit the ability to identify and fully evaluate effective biomedical interventions.

Key methodological challenges include the lack of a surrogate marker for HIV infection, the choice of a control group and type of trial design, the loss of study power due to lower than expected incidence rates and higher than expected pregnancy rates, high rates of participant attrition, suboptimal adherence among participants to the product being tested, and challenges in measuring participants’ adherence to the product and risk behavior.

Although not discussed in this report, trials also face major ethical and regulatory challenges. Key ethical concerns include ensuring access to antiretroviral treatment for individuals who become infected during a trial, adequate informed consent, and compensation to participants for adverse medical events related to the trial. Another important concern is ensuring adequate engagement of community members prior to, during, and after the trial. Regulatory hurdles—such as the limited capacity of developing



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Introduction I f the world is to successfully address the HIV epidemic, preventing new infections will be as important as treating those who are infected (see Box I-1). However, in the foreseeable future, there will be no single prevention product (“magic bullet”) that will prevent the spread of HIV. Thus the need to identify a range of effective, practical, and affordable preventive strategies, and to determine how best to combine them, is criti- cal. A number of promising new HIV prevention strategies and products are currently being tested in late-stage clinical trials. Yet HIV prevention trials face a myriad of methodological challenges which slow the pace of research and limit the ability to identify and fully evaluate effective bio- medical interventions. Key methodological challenges include the lack of a surrogate marker for HIV infection, the choice of a control group and type of trial design, the loss of study power due to lower than expected incidence rates and higher than expected pregnancy rates, high rates of participant attrition, suboptimal adherence among participants to the product being tested, and challenges in measuring participants’ adherence to the product and risk behavior. Although not discussed in this report, trials also face major ethical and regulatory challenges. Key ethical concerns include ensuring access to antiretroviral treatment for individuals who become infected during a trial, adequate informed consent, and compensation to participants for adverse medical events related to the trial. Another important concern is ensuring adequate engagement of community members prior to, during, and after the trial. Regulatory hurdles—such as the limited capacity of developing 

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 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS Box I-1 The Global HIV Epidemic In 2007, an estimated 2.5 million people became infected with HIV, 33.2 million individuals were living with HIV, and 2.1 million people died from AIDS (uNAIDS, 2007). Sub-Saharan Africa continues to bear the largest burden of the HIV epidemic, accounting for an estimated 68 percent of new infections, 68 per- cent of adults and 90 percent of children living with HIV worldwide, and 76 percent of all deaths from AIDS (uNAIDS, 2007). unprotected vaginal intercourse accounts for the vast majority of new infec- tions worldwide (uNAIDS, 2006). The HIV epidemic in many parts of Asia and eastern europe, which is also growing rapidly in some countries, is spreading from more isolated drug user networks and female sex workers to their sexual partners and the broader population (uNAIDS, 2006). Latin and North American countries have recorded high levels of HIV infection among men who have sex with men (uNAIDS, 2006). In many countries, women—especially young women—are disproportionately affected by HIV. The problem is particularly acute in some parts of sub-Saharan Africa, where women ages 15-24 are up to three times more likely to be infected than men of the same age (uNAIDS, 2006). uNAIDS estimates that women ac- count for about half of the people living with HIV worldwide, and 60 percent of those living with HIV in Africa (uNAIDS, 2007). Several factors contribute to this disparity. Women are more physiologically vulnerable to acquisition of HIV infection than men. Women also face numerous social, economic, and legal disadvantages that interfere with their ability to pro- tect themselves against HIV infection. And because of gender norms and power imbalances, women are often unable to negotiate the use of condoms with their male partners (uNAIDS, 2006). Women who have had violent or controlling male partners also may be at increased risk for infection (Maman et al., 2000; Dunkle et al., 2004; Jewkes et al., 2006). Thus, the need for female-controlled methods of preventing HIV infection is urgent. countries to approve products, and complex requirements for licensing products with multiple active compounds—further complicate biomedical prevention trials. These challenges underscore the need for well-conceived and conducted late-stage intervention trials of biomedical HIV preventive interventions, using the best available methodologies, that can identify different (combina- tions of) interventions for different populations. CHARGE TO THE COMMITTEE The Bill & Melinda Gates Foundation requested in November 2006 that the Institute of Medicine (IOM) convene a committee to examine the

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 INTRODUCTION methodological challenges entailed in HIV prevention trials. The commit- tee was asked to report on how to improve the methodology, design, and conduct of biomedical HIV prevention trials—focusing on those involving microbicides and PrEP—to increase the likelihood of success, and to enable donors to invest their resources optimally. The foundation’s charge to the committee included several specific tasks: 1. The committee will review select phase 2 and 3 HIV prevention tri- als in order to provide an assessment of best practices for site preparedness and estimation of incidence. 2. The committee will make recommendations regarding method- ological best practices for microbicide and PrEP efficacy trials. Issues to be addressed include but are not limited to • loss of study power through lower-than-expected incidence and high pregnancy rates, • other design considerations such as choice of endpoints and control groups, • methods for monitoring the interim results of trials (including adjustments to trial size and duration), • pooling of data from trials testing the same product, • methods for improving adherence to study regimens and the quality of self-reported behavioral data, and • optimizing retention of trial participants. The Gates Foundation also asked the committee to consider the eth- ical challenges directly related to these methodological issues, such as those that might arise during interim monitoring of trials. These challenges include whether to modify or stop a trial if information from another trial shows that the intervention is either working or not working. Other ethical concerns—including the adequacy of informed consent, compensation for participants who experience trial-related adverse events, access to treatment for people who become HIV infected during the trial, and best practices for fully engaging community members in trials conducted in their areas—were explicitly excluded from the committee’s statement of task (Box I-2). SCOPE OF WORK This report recommends ways to improve the design, monitoring, and analysis of clinical trials evaluating nonvaccine biomedical interventions to prevent HIV infection, so that these trials can increase the chances of detecting and quantifying a beneficial intervention effect, more fully assess the efficacy and effectiveness of interventions, reduce biases that can lead

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0 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS Box I-2 Statement of Task The Institute of Medicine (IoM) will convene a committee to examine meth- odological challenges in HIV prevention trials. The committee will prepare a report to improve the methodology, design, and conduct of HIV prevention trials, focusing on microbicide and pre-exposure prophylaxis (PreP) trials, in order to increase their likelihood of success and to enable donors to optimally invest resources. The committee will undertake a study with the following tasks: 1. The committee will review select phase 2 and 3 HIV prevention trials in order to provide an assessment of best practices for site preparedness and esti- mation of incidence. 2. The committee will make recommendations regarding methodological best practices for microbicide and PreP efficacy trials. Issues to be addressed include but are not limited to loss of study power through lower-than-expected incidence and high pregnancy rates, other design considerations such as choice of endpoints and control groups, methods for monitoring the interim results of trials (including adjustments to trial size/duration), pooling of data from trials testing the same product, methods for improving adherence to study regimens and the quality of self-reported behavioral data, and optimizing retention of trial participants. The committee will also consider the ethical issues directly related to methodological issues under study, such as those that might arise during interim monitoring of trials. This study will not address broader ethical issues such as adequacy of informed consent, compensation for trial-related adverse events, access to HIV treatment for seroconverters, and best practices for engaging community members. to false positive trial results, and be terminated early if warranted by their interim results or external information. At the committee’s first workshop, the Gates Foundation clarified that its review should focus on late-stage microbicide and PrEP trials, although where appropriate, the committee could consider lessons that might be learned from other late-stage biomedical trials. Given the broad scope of research on HIV vaccines and the limited time available, the sponsor speci- fied that the committee’s review should not include vaccine trials. The committee’s charge assumes that funders and investigators have made a decision to plan and undertake a late-stage randomized HIV pre- vention trial of a biomedical intervention. The charge therefore focuses on the methodological challenges that arise in planning, conducting, and analyzing such a trial.

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 INTRODUCTION The committee affirms the central role of randomized controlled trials in evaluating the effectiveness of HIV prevention interventions. However, less rigorous quasi-experimental and observational studies can provide evidence to motivate more definitive randomized trials. For example, three recent randomized, controlled trials of male circumcision (Auvert et al., 2005; Bailey et al., 2007; Gray et al., 2007) were motivated by earlier observational studies that circumcised men had lower rates of HIV infec- tion. Quasi-experimental and observational studies have also been used as evidence to support implementation of prevention interventions, such as needle and syringe exchange and post-exposure prophylaxis (PEP) when randomized, controlled trials were not considered ethical. The committee recognizes that a number of issues can arise prior to, during, and following the planning and conduct of randomized, controlled trials that are critical to HIV prevention research but outside the commit- tee’s charge. One such issue is ensuring that the early process for developing biomedical HIV interventions, before late-stage trials begin, is thorough and effective. Another concern is ensuring a sound system for prioritizing the most promising candidate interventions in the face of uncertainties about safety and efficacy, to allow those interventions to move to large, late-stage randomized trials. Biological plausibility is central to ensuring effective preclinical testing and sound prioritization of interventions. Ideally, substantial evidence from basic research and animal models on an intervention’s potential for prevent- ing HIV transmission would be available before initiation of late-stage clini- cal trials. Although the committee did not assess the biological plausibility or implausibility of various biomedical prevention interventions, it believes that funders and investigators need to carefully consider biological plausi- bility during preclinical testing and when prioritizing interventions. Other critical issues surrounding late-stage trials include regulatory concerns and the impact of a trial on the community. For example, the con- duct of a PrEP trial in areas where access to antiretroviral therapy is limited, and thus rationed, may raise concerns about fairness or the possible spread of resistant strains of HIV from trial participants to other members of the community. While this report emphasizes the importance of community involvement in the planning of a late-stage trial, the committee does not assess best practices for how to engage communities. Finally, a late-stage trial that shows that an intervention is effective in reducing the risk of HIV infection raises a number of key policy issues about how to implement that intervention on a wider scale. Although all these issues are outside its charge, the committee wishes to underscore their critical importance in efforts to identify effective preven- tion interventions.

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 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS STUDY PROCESS The committee convened a public workshop in Washington, DC, in February 2007 to gather information on methodological challenges in HIV prevention trials. The committee heard from principal investigators of late- stage microbicide and PrEP trials and other experts in HIV prevention. The committee then held a second public workshop in London in April 2007, to gather additional information on issues in trial design and implementa- tion, as well as other recent late-stage biomedical HIV prevention trials, including male circumcision, suppression of genital herpes (HSV-2), and cervical barriers. The committee held 2-day closed meetings immediately after each workshop. (See Appendix A for workshop agendas.) The com- mittee also reviewed the literature on methodological issues arising in HIV prevention trials. Several committee members and IOM staff conducted site visits to Uganda (April 2007) and South Africa (July 2007) to meet with principal investigators, staff, and participants of several prevention trials, as well as community, government, and research stakeholders. The purpose of these visits was to learn from those with experience on the ground, thus helping to inform the committee’s recommendations. The committee then assessed the evidence it had gathered and reviewed drafts of this report during two closed meetings, one in Woods Hole, Mas- sachusetts, in July 2007, and the other in Washington, DC, in September 2007. STUDY CONSIDERATIONS Several considerations strongly affected the committee’s thinking on methodological challenges arising in HIV prevention trials: • A biomedical intervention with near-perfect protective efficacy that can be fully delivered as intended is unlikely to be available in the near future. Until then, ultimate effectiveness of any biomedical intervention will be closely tied to individual behavior and the multiple factors that shape it. This underscores the need for multidisciplinary research expertise, including a strong behavioral and social science component, in designing, conduct- ing, and analyzing clinical trials, to ensure that they are feasible, ethical, relevant, and efficient. • Although biomedical HIV prevention trials must provide risk reduc- tion counseling to all participants, these trials are typically not designed to evaluate the effectiveness of the behavioral risk reduction intervention(s) they employ. • Pregnancy is a common event in many biomedical HIV prevention

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 INTRODUCTION trials and reflects the high background pregnancy rate in the target popula- tion for these interventions. Because an approved prevention product will, on introduction into a community, likely be used by many women even after they become pregnant, it is critical that an overall product evalua- tion plan include specific and realistic plans for assessing the intervention’s impact on pregnant women and their fetuses. • Researchers conducting HIV prevention trials need to develop a deep understanding of and close collaboration with the communities in which trials are conducted, and where the results will ultimately be applied to ensure the interventions are relevant to and sustainable in the commu- nity and that efforts to promote recruitment, retention, product adherence, and risk reduction behaviors are based on an understanding of community norms and behaviors. • Most late-stage biomedical HIV prevention trials have used a two- arm superiority design, which compares a new biomedical intervention, such as a PrEP or a microbicide gel, to a control arm—often a placebo. Such trials aim to assess whether the new intervention is superior to a stan- dard prevention method, in which case it would become the new standard. However, other designs can sometimes have advantages over this approach by addressing different scientific goals or by allowing investigators to study multiple prevention methods that can be used in combination. • Finally, although this report focuses specifically on non-vaccine biomedical HIV prevention interventions, a comprehensive approach to prevention is needed to control the HIV pandemic. Components of such an approach include effective behavioral and biomedical HIV prevention interventions, widespread access to treatment, destigmatization of HIV, care for vulnerable populations, policy environments supportive of change, and structural interventions targeting poverty, gender equity, nutritional status, living conditions, education, and health care infrastructure in developing countries. Achieving success in fighting the pandemic will require the coop- eration and collaboration of multiple stakeholders, including national and local governments, private and public health care institutions, communities, researchers, donors, civil society, employers and business, and the media. REPORT STRUCTURE Chapter 1 provides an overview of the status of biomedical HIV pre- vention trials and highlights the methodological challenges that commonly occur in these trials. The chapter also highlights the influence of behavioral and sociocultural factors on biomedical trials and calls for investigators to integrate behavioral and social science research into such trials. Chapter 2 examines the choices available to investigators regarding the size and duration of a randomized phase 3 trial to achieve a desired power

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 METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS to detect an intervention effect. The chapter also shows how inaccuracies in the assumed HIV incidence rates, intervention effect size, and partici- pant adherence and attrition rates used to determine the size and duration of the trial can seriously undermine the power of the study. The chapter then examines two other design considerations: whether to undertake an efficacy trial, a phase 2B trial, or an effectiveness trial; and the choices and consequences of using different types of control groups. Chapters 3 through 6 review specific design considerations, including risk-reduction counsel- ing (as a cointervention in a biomedical HIV prevention trial), pregnancy, adherence, and retention. Chapters 7 and 8 address issues in site preparedness. In Chapter 7, the committee highlights the important concerns for investigators and sponsors to consider when developing the research protocol and human and physical infrastructure for late-stage trials. In Chapter 8, the committee recommends best practices for estimating HIV incidence prior to the trial start. Chapter 9 discusses the importance of interim monitoring of trial results and best practices for analyzing interim and well as final results. In conclusion, Chapter 10 proposes alternative study designs that can some- times offer advantages over the current two-arm superiority design used in most biomedical HIV prevention trials. Appendixes A–E include agendas for the committee’s public meetings, a list of acronyms used in the report, supporting materials for Chapter 2, details on methods for analyzing adherence data, and committee member biographies. REFERENCES 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 preven- tion in young men in Kisumu, Kenya: A randomised controlled trial. Lancet 369(9562): 643-656. Dunkle, K. L., R. K. Jewkes, H. C. Brown, G. E. Gray, J. A. McIntryre, and S. D. Harlow. 2004. Gender-based violence, relationship power, and risk of HIV infection in women attending antenatal clinics in South Africa. Lancet 363(9419):1415-1421. 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. Jewkes, R., K. Dunkle, M. Nduna, J. Levin, N. Jama, N. Khuzwayo, M. Koss, A. Puren, and N. Duvvury. 2006. Factors associated with HIV sero-status in young rural South African women: Connections between intimate partner violence and HIV. International Journal of Epidemiology 35(6):1461-1468.

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 INTRODUCTION Maman, S., J. Campbell, M. D. Sweat, and A. C. Gielen. 2000. The intersections of HIV and violence: Directions for future research and interventions. Social Science and Medicine 50(4):459-478. UNAIDS. 2006. Report on the global epidemic: A UNAIDS 0th anniversary special edition. Geneva, Switzerland: UNAIDS. UNAIDS. 2007. 00 AIDS Epidemic Update. Geneva, Switzerland: UNAIDS.

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