6
The Path Forward

There is no proven “right” way toscale upantiretrovial therapy (ART) and HIV prevention programming in resource-constrained settings worldwide, especially since the diversity of those settings will necessitate differing approaches. As noted in the preceding chapter, however, any delay in moving forward on a large scale while the answers are being determined would clearly be wrong, as ART scale-up has become an ethical imperative. Given the lack of experience on such a large scale and the paucity of relevant data, capturing lessons learned along the way will be critical to ensuring the long-term sustainability of newly implemented programs. To this end, this chapter sets forth critical operations, applied clinical, and behavioral research that will be crucial in a number of key areas. It concludes by emphasizing that even with iterative improvements obtained through solid research, the path forward will require sustained, long-term commitment. This commitment must be not only to acting, but also to using the information generated through sound research to act well.

OPERATIONS RESEARCH: CLOSING THE GAP BETWEEN RESEARCH AND CARE

Successful pilot programs are proof of effectiveness only in particular circumstances; their replicability in many other settings remains unproven. For example, although Haiti’s GHESKIO program (see Chapter 3) demonstrates that ART programs can be successful in resource-constrained settings, it does not necessarily provide a replicable model that can be general-



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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities 6 The Path Forward There is no proven “right” way toscale upantiretrovial therapy (ART) and HIV prevention programming in resource-constrained settings worldwide, especially since the diversity of those settings will necessitate differing approaches. As noted in the preceding chapter, however, any delay in moving forward on a large scale while the answers are being determined would clearly be wrong, as ART scale-up has become an ethical imperative. Given the lack of experience on such a large scale and the paucity of relevant data, capturing lessons learned along the way will be critical to ensuring the long-term sustainability of newly implemented programs. To this end, this chapter sets forth critical operations, applied clinical, and behavioral research that will be crucial in a number of key areas. It concludes by emphasizing that even with iterative improvements obtained through solid research, the path forward will require sustained, long-term commitment. This commitment must be not only to acting, but also to using the information generated through sound research to act well. OPERATIONS RESEARCH: CLOSING THE GAP BETWEEN RESEARCH AND CARE Successful pilot programs are proof of effectiveness only in particular circumstances; their replicability in many other settings remains unproven. For example, although Haiti’s GHESKIO program (see Chapter 3) demonstrates that ART programs can be successful in resource-constrained settings, it does not necessarily provide a replicable model that can be general-

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities ized to enable 3 million people to be on treatment by 2005. Indeed, one critique of a published evaluation of Haiti’s success (Gilks et al., 2001) contends that the human resources and capacities employed (i.e., the logistics with regard to clinical input and staff time) were not clearly listed in the evaluation and that the criteria for selecting individuals for treatment were not stringent. These observations highlight the need for scientific evaluation criteria, without which important lessons that might be applied in other settings cannot be derived. Pilot initiatives are by design relatively limited in size, often directed toward a small fraction of those in need and supported by unusually committed and resourced staff. Scale-up activities will introduce factors that may not be especially relevant in a pilot implementation. If a particular health resource is scarce in a country—for example, trained people who may already be staffing other essential health services—a large program scale-up effort may have collateral negative effects on already marginal health care systems by diverting a critical fraction of the limited human resource pool. These threats would not necessarily be evident in a pilot program whose relatively modest requirements were, in the grander scheme, absorbable or even resourced external to the underlying health care infrastructure. Various avenues might be pursued to mitigate this risk of collateral negative effects, although scientific evidence would likely be needed to assess the advisability of different options. Vertical Versus Integrated Care as an Operations Research Issue A common discussion in international health revolves around the relative advantages of “stovepiped” or “vertical” condition-specific implementation programs, versus the integration of condition-specific programs into a health sector–wide approach whereby the resources of various programs are effectively integrated into one system, usually under government leadership (see Box 6-1). The care of HIV/AIDS patients is not as easily “stovepiped” as that provided in, for example, an immunization program or even a tuberculosis (TB) program. Rather, HIV/AIDS patients require care that has longitudinal continuity, care that is often complex considering the myriad of opportunistic infections that can occur. The care they receive must also encompass reliable access to quality pharmaceuticals, attention to nutritional and psychosocial needs, counseling to prevent the spread of infection, and the requirements of palliative care. Thus the establishment of programs for HIV/AIDS care requires access to a wide range of services that need to exist for many other purposes as well. On the other hand, while it would appear that the ideal HIV/AIDS care program would be integrated so as to strengthen the entire health care system, to accomplish such integration in a nondisruptive way takes time.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities BOX 6-1 Some Theoretical Advantages of Integrated and Vertical Programs Integrated Programs Minimize duplication in administration staffing, infrastructure, logistical, and procurement systems. Often are more cost-effective. Can be more efficient for patients through consolidation of care in a few places. Involve less chance of gaps in care because of fewer referrals out of the program. Are more responsive to local, decentralized management. Foster the building of government capacity as opposed to management by donors. Lower transaction costs between governments and donors as a result of harmonized administrative methods. Unify government and donor priorities and funding targets. Foster programmatic fiscal security through pooled funding. May help avert resource imbalances and negative collateral effects that can occur with well-funded vertical programs. Vertical Programs May be easier to maintain quality and effectiveness with a narrower focus. Require less complex operational planning and thus potentially less time-consuming. Make use of more readily mobilized funding, which can be used more easily, reliably, and quickly. Make it easier to protect key interventions (e.g., a TB program) where political commitment is weak. May provide more comprehensive and linked monitoring and management response to problems. Make it easier to target interventions specifically to places or populations with greatest needs. Make it easier to maintain the technical quality of services. SOURCE: Adapted with modifications from Brown, 2001. And time is in particularly short supply under the stated President’s Emergency Plan for AIDS Relief (PEPFAR) and World Health Organization (WHO) imperatives of placing millions of people under treatment over the next several years. Thus a focus of operations research must clearly be on how models of HIV/AIDS care in settings characterized by different underlying infrastructures can be rapidly established without seriously disrupting

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities what previously worked well, and ideally with the potential for positive collateral effects on the broader system through leveraging of new resources. Some have argued that tight integration with existing programs, such as those to diagnose and treat TB, may stretch limited resources in an efficient way. However, it has also been suggested that such integration with a long-established TB program may result in its being swallowed up by the bigger ART program, with negative consequences for TB control. Certainly the contribution of various factors to this issue will vary from country to country and even more locally. Rural health infrastructures may be more susceptible to negative collateral effects from new resource demands than urban systems, in which the concentration of trained providers is greater. Operations research and the development of models to better understand the health system dynamics relevant to this issue should be priorities. The hoped-for outcome is that the infusion of resources to provide ART would, in a collateral fashion, strengthen the overall health care infrastructure. Indeed, this has been observed in some pilot projects, such as the GHESKIO program in Haiti. In that program, building on what already existed made it easier to scale up more rapidly while at the same time improving not only HIV/AIDS services, but also primary care (personal communication, Dan Fitzgerald, June 2004). There will clearly be a tension as PEPFAR, the WHO 3-by-5 campaign, and other donor-driven initiatives may tend to favor a vertical approach, as opposed to an approach emphasizing integrated sustainability based on health sector–wide government programs. While integration is the ultimate and indeed a necessary goal, the advantages of vertical programs should not be lost, as they also contribute to quality and effectiveness, two characteristics that must be part of the foundation of ART scale-up programs. In some settings, premature dependence on an integrated approach before capacity has been established could be disastrous. Not infrequently, newly integrated health-sector programs have shown signs of failure due to such factors as lack of capacity among managers to deal with new tasks, inadequate technical supervision as hierarchies are removed, weak logistic support for carrying out necessary procurement, weak monitoring systems, misplaced foci in capacity building, change that was too swift with resultant gaps, and immature planning systems. Sometimes resources to support a particular activity end up reduced as vertical programs are integrated and resources shifted. Critical programs can also suffer from “invisibility” and slippage in their priority as they disappear into the larger health system (Brown, 2001). Understandably, it can be difficult for donors to cede control of programmatic responsibilities, such as drug procurement, to inexperienced or overburdened host government agents. This is the case in part because local government shortcomings in

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities the management of donor funds may open donors up to criticism from their constitutiencies, and in part because gaps in performance can have serious consequences, as is certainly the case with ART. Nongovernmental organizations (NGOs) frequently represent a large proportion of the existing capacity for providing ART, and this adds complexity as their valuable initiatives are coordinated with sector-wide governmental efforts. Striking a proper balance between vertical and integrated approaches and between governmental and nongovernmental mechanisms will depend on particular local and national circumstances, offering fertile ground for documenting and disseminating lessons learned. Learning by Doing Through Operations Research Regardless of whether specific pilot initiatives prove to be replicable or integrated programs become the favored option, the complexities and challenges of implementing ART programs countrywide and on a much larger scale than that of any pilot initiative conducted thus far highlight the reality, emphasized earlier, that ART scale-up will largely be a learn-by-doing process. By feeding lessons learned back into the treatment and care systems, ART scale-up can be accelerated; become more effective in terms of improving both patient and population health, as well as increasing cost-effectiveness; and achieve the success needed to ensure continued donor support. The only way lessons will be learned, however, other than through a generally intuitive sense of what might work, is for ART scale-up programs to have the funds and capacity needed to conduct rigorous, data-based operations research. Operations research is not the same as monitoring and evaluation (discussed in Chapter 5), and funds budgeted for one are not necessarily available for the other. Also, although many organizations and institutions, particularly academic institutions where research expertise is concentrated, can conduct operations research, the funding for such research must be clearly set aside in ART scale-up budgets. It must be recognized that many donors, who are focused on supporting care, group operations research with other more basic and clinical research activities that they view as outside of their mandate. Similarly, funders of traditional basic, epidemiologic, or clinical research often see operations research as beyond their focus. Hence operations research can fall into a funding gap. Operations research (also known as management science) involves the use of advanced analytical techniques to achieve better outcomes, define optimal processes of service delivery, and develop more cost-effective systems. It encompasses a wide range of studies, including observational and outcome studies, epidemic modeling, and cost-effectiveness studies. Observational studies, for example, have been used a great deal in the United

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities States for determining the best way to deliver HIV/AIDS care. Such research must be seen as a routine, essential dimension of effective program management. The capacity—both financial and operational—to conduct integrated operations research should be put into place explicitly at the start of scale-up even if the actual research is not yet under way. At the very least, the capacity to collect the data necessary for operations research should be in place. Box 6-2 provides additional detail on operations research and its role in ART scale-up. Given the magnitude of the HIV/AIDS problem, there have been few operations research studies, clinical or otherwise, conducted in sub-Saharan Africa or other resource-constrained settings. But as scale-up proceeds and as ART programs expand, so will the need and opportunity to conduct such research in parallel with program implementation. As noted, one of the most critical concerns with regard to operations research pertains to funding and the reality that most medical research worldwide is not linked to the provision of health care. Clearly, from both public health and ethical perspectives, research and care should be linked in the optimization of ART programs. Yet in most budgets, research and care are funded separately, and dedicated funds for one cannot be used for the other. Thus the need for dedicated operations research funding is again highlighted. Recommendation 6-1. Operations research should begin at the initiation of scale-up and continue to inform the future direction and sustainable success of antiretroviral treatment and HIV prevention programs in resource-constrained settings. Priorities for operations research should be identified by national programs and funded by donors through an explicit allocation that will address the need for rapid development of evidence for policy. Input from national authorities working with donors should be supplemented by consultation with WHO and other multilateral agencies to obtain technical advice and to help maximize regional synergies, share information, and avoid unnecessarily duplicative studies within a given region. Recommendation 6-2. Research priorities should be informed by the perspectives of local researchers, health workers, and community representatives and reflect respect for the cultures of affected communities. Just as every pilot initiative functions uniquely, every scale-up initiative and national program will have its own way of functioning and should be shaped by the perspectives of those with a stake in its success. Ideally, if a well-developed operations research agenda is established early on, these different ways of functioning can be objectively evaluated in a timely fashion and the results used to inform managers of other scale-up programs about newly identified best practices. Collabo-

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities   BOX 6-2 The Role of Operations Research During ART Scale-Up Given the incomplete evidence base on how to scale up ART in resourceconstrained settings, a learn-by-doing approach will be necessary. As ART programs are rolled out and scaled up, continual process and program evaluation will need to be done to assess success and identify obstacles and failures. Guiding questions will be what works, what does not work, and why. Operations research is a means of carrying out these evaluations and has been used in many health and development fields. Its overall aim is to improve the delivery of services (i.e., the operations of programs) by identifying problems and focusing attention and resources on searching for solutions. There are five basic steps in the process: Problem identification and diagnosis Strategy selection Strategy testing and evaluation Information dissemination Information utilization Policy makers, program managers, and donors will face many operations research questions as ART is scaled up. Examples of such questions include the following: What is the best way to ensure that a logistics system provides an uninterrupted supply of drugs? How can high levels of adherence to ARVs be maintained among patients? What is the role of community-based organizations in ART programs? When should ARVs be administered? Can nonphysicians administer ARVs safely and with high standards of care? rative partnerships and endeavors between the research and health care communities should be encouraged. Although the most obvious unanswered question to be addressed by research may be “What is the best ARV regimen?” with respect to ART in resource-constrained settings, it is by no means the only or even the most important one. Moreover, even that single question involves many nuances and complexities, as the best regimen in one set of circumstances (e.g., biological, medical, behavioral, social, economic, ethical) may not be the best in other contexts. For example, a multitude of operations research questions are raised by the critically important role of human resource capacity in ART scale-up and the urgent need to find innovative ways of

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Engaging program managers, health care workers, community members, and people living with HIV/AIDS in operations research projects should help those in the field recognize such research as a valuable tool for decision making. Additionally, involving stakeholders throughout the process may heighten their interest in reviewing and using the results of the completed research. By engaging in operations research before and during program implementation, it is hoped that efficiency, effectiveness, and quality will be achieved. The World Health Organization’s 3-by-5 campaign has focused on six areas of activity for operations research during the scale-up of ART programs (WHO, 2004): To coordinate and help develop an appropriate operations research agenda relevant to the needs of ART programs. To seek data on the impact of scaling up ART on prevention and risk behavior, on mitigation, and on stigma and discrimination. To identify ways of defining the externalities of ART scale-up with regard to health system performance. To identify ways of costing ART programs and to link costs to impact and effectiveness. To improve program design and find better tools for reducing risky behavior and the evolution of drug resistance based on the analysis of data. To rapidly incorporate new knowledge back into ART program policy and practice. SOURCES: Fisher and Foreit, 2002; WHO, 2004. addressing human resource deficiencies and improving training programs (see also Chapter 5): What is the best way to strengthen workforce capacity? What are the most effective ways to train health care and other workers involved with ART scale-up? How can the utility of community-based and nurse-based care be maximized given the medical complexities associated with ART? How can laboratory training be improved to minimize worker-related errors? What are the best programmatic mechanisms to minimize negative collateral effects of scale-up on other essential programs?

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities What are the most effective mechanisms to retain critical health care workers who might either be subject to “burnout” or enticed by lucrative overseas offers of employment? Although some competition is healthy to encourage rigorous research and rapid results, having too many ongoing studies within a country, particularly within a concentrated area, can become confusing and even counterproductive. Thus the question arises of how operations research can be coordinated in a way that best suits the needs of the country in which it is being conducted. Another issue is how the conclusions drawn from operations research results should be shared and disseminated. Operations research must be designed such that comparisons among different approaches and outcomes can be readily distinguished from the inevitable differences that exist among the various populations in which the approaches are being tested. For example, if one intervention has an 85 percent success rate in one population and another only a 65 percent success rate elsewhere, how can it be determined to what extent the difference is due to the intervention or the population? As the number of research studies increases worldwide, there is a growing need to establish common research protocols so results will be more comparable and the exchange of information more efficient. HIV-NAT (The Netherlands, Australia, Thailand Research Collaboration) has been cited as one example of a program specifically developed to facilitate and coordinate the exchange of clinical research information, in this case between scientists in The Netherlands and Australia and Thai investigators in an effort to address treatment questions of particular relevance to Thailand (The HIV Netherlands Australia Thailand Research Collaboration, 2004). As new evidence regarding the safest and best use of ARVs in resource-limited settings accumulates, the need to integrate new policies or recommendations into already existing and implemented guidelines and protocols will grow. Thus questions arise regarding how existing guidelines, including those of WHO and others, allow for the ready adoption of important new evidence and how revised guidelines will be disseminated and integrated into community health programs worldwide. Moreover, greater clarity is needed regarding the ethical imperative to ensure that clinical guidelines for ARV usage in resource-constrained settings adhere to the same type of evidence-based criteria required for guidelines of the United States and other resource-rich countries. Given the likely but still largely unknown (i.e., unsupported by a detailed evidence base) impacts of nutrition, coinfection with other endemic diseases, concurrent treatment for TB, and other factors on adherence to medications and the efficacy of ART, issues surrounding the need to test newly developed ARVs in resource-constrained settings need to be clarified

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities and appropriately addressed. More broadly, in light of the larger social, cultural, environmental, and economic context of the HIV/AIDS pandemic, how can the research agenda be expanded such that the upstream determinants of infectious disease emergence, including poverty, are addressed in a meaningful and adequate way? Can poverty-reduction programs and ART programs be coordinated so as to be complementary and synergistic? Other cultural dimensions must also be considered. For example, in South Africa the majority of HIV-infected people use traditional medicines. Thus the consequences and effectiveness of using these treatments (as well as other non-ARV immune regulators) need to be objectively examined to better inform those prescribing ARVs about how to treat these patients. It must be recognized that HIV/AIDS is not just a medical problem. Rather, to address the problem it is necessary to examine the total system—with its many complex negative and positive feedbacks—from a systems perspective. The question arises, however, of how this framework can and should be applied to research in the field. What are the practical implications of this type of thinking for budgeting for operations research to support ART scale-up? Finally, the importance of modeling cost-effectiveness considerations and incorporating them into operations research questions should be neither underestimated nor overestimated. Models that can be used to predict demand for drugs and other resource requirements need to be developed and validated so that planners can ensure continuity of drugs and care in the face of changing needs. Regardless of how important the immediate health outcomes of any intervention or practice may be, the more cost-effective a process is, the more people will benefit. For example, although the expensive state-of-the-art laboratory monitoring standards applied in the United States may minimize treatment failure, reliance on such standards in resource-limited settings would also minimize the number of people who could receive treatment. Thus it is important to consider cost-effective-ness in addition to clinical outcomes when testing various treatment or other ARV-related interventions. APPLIED CLINICAL RESEARCH The WHO guidelines provide an excellent, evidence-based set of criteria for determining when to initiate therapy, how to monitor therapy, when to change drugs or regimens, how to incorporate care and treatment for opportunistic infections into ART, and so on. Nonetheless, the recommendations are intended to serve only as a starting point for the development of national guidelines. Some of the WHO guidelines are necessarily vague because of incomplete clinical knowledge. An example is the recommended treatment for women of childbearing potential or those who are pregnant.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Because of mutations associated with resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs), the use of nevirapine for the prevention of mother-to-child transmission of HIV could potentially limit subsequent treatment of the mother and her infected infant. Similar concerns exist for 3TC-containing regimens. As stated in the guidelines: The clinical consequences of selection of these resistance mutations in terms of response to future antiretroviral therapy of the woman or the infected infant are unknown…. This is one of the most pressing operational research questions facing the field and must be answered with appropriately conducted studies…. Until definitive data are available to answer these questions, treatment of women who have previously received single dose [nevirapine] prophylaxis or 3TC prophylaxis for prevention of MTCT [mother-to-child transmission] should be considered eligible for NNRTI-based regimens and not be denied access to life-sustaining therapy (WHO, 2003a:23). This example illustrates the need for immediate applied research to inform national and international guidelines with regard to certain clinical components of ART scale-up in resource-constrained settings. Attendees at a 2001 conference held in San Francisco, California, to develop a research agenda on HIV/AIDS therapy for resource-limited countries identified three categories of topics: when therapy should be initiated, what therapies should be used, and what methods are most appropriate for patient monitoring when CD4+ cell count and viral load tests are not available. (A summary of the recommendations from that conference is provided by Vermund and Powderly [2003].) Moreover, the need for patient monitoring raises the question, especially in resource-constrained settings, of how frequently that monitoring should be done. Operations research can also help develop optimal programs for ARV resistance screening in individuals and surveillance in larger community populations. Several different methodological approaches could be used in applied clinical research. For example, to address the question of when to start therapy, investigators could conduct prospective randomized trials (e.g., to compare the effectiveness of different times of treatment initiation), conduct observational database studies, or pursue pathogenesis studies (e.g., to identify lower-cost, clinically significant immunological parameters to track). Because prospective randomized trials are costly and lengthy and involve large sample sizes, they would need to be conducted in countries with the necessary infrastructure. Observational studies would be ideal for countries with widely available ART, such as Brazil, where a variety of patient groups and treatment regimens are available for comparison.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities whose annual costs could themselves be comparable to those of the ARVs to be used. For resource-constrained countries, less-costly measurement tools, such as viral load and CD4 counts, are needed to stretch limited budgets and enable technicians trained at a more basic level to perform the tests. Another priority for applied clinical research arises from the vital role of prophylaxis for opportunistic infections, including TB, in reducing AIDS-related mortality, at least in the short and medium terms. This point is illustrated by the experience of both Brazil and South Africa. Thus there is an urgent need for more research on related topics, including the wider applicability of cotrimoxazole and its use in children and infants, care for Kaposi’s sarcoma in resource-constrained settings, the use of isoniazid in treating TB, and the use of antifungals. Finally, as many of the clinical trials and prospective studies of ARVs and their effects have been conducted in the developed world, the extent to which the relationships among disease, drugs, and nutrition are a factor of the developed world’s diet and nutritional status is unclear. At this time, therefore, the effect malnutrition will have on the success of ART scale-up on a broad scale is unknown. It is clear that many people living with HIV/ AIDS in the developing world lack access to sufficient quantity and quality of nutritious foods (see Chapter 4). WHO (2003b) has recognized the limited research done on this issue—specifically in resource-constrained settings—and identified research questions it believes to be crucial for gaining a better understanding in this area (see Box 6-3). It is known, however, BOX 6-3 Nutrition and HIV/AIDS: Addressing Knowledge Gaps Questions to be addressed by research on nutrition and HIV/AIDS include the following: What is the impact of ART in malnourished populations? Does nutritional status affect the efficacy of therapy and the risk or severity of associated adverse events? Would nutrition interventions—particularly in undernourished populations and lactating mothers—provided concurrently with ART result in better health outcomes? Should there be a different mix of lifestyle change strategies (e.g., for dietary intake and physical activity) in resource-limited settings, where undernutrition is prevalent, than in developed countries? SOURCE: WHO, 2003b.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities that micro- and macronutrients affect the progression of HIV and the bioavailability and efficacy of particular drugs. Therefore, food and nutrition assistance programs should be a resource available to those using ART. Additional nutrition-related research questions include the following: What are the benefits of nutritional supplementation? What are the pharmacokinetics of ARVs in populations with poor nutrition? BEHAVIORAL RESEARCH Implementing ART in resource-poor settings poses difficult, complex medical, technical, and logistical questions, many of which have yet to be addressed through operations research programs. Yet many would argue that the social and behavioral dimensions of scaling up ART programs raise equally, if not more, challenging questions. HIV is as much a psychosocial as a biomedical phenomenon. A behavioral science research agenda is critical to elucidating underlying factors and achieving a better understanding with regard to improving adherence to ARVs, reducing risk behaviors associated with transmission of HIV, improving the accessibility of ARVs and treatment and prevention programs, and reducing the stigma associated with being at risk and living with HIV/AIDS. Improving Adherence Given the high degree of susceptibility to resistance of some of the less expensive, WHO-recommended NNRTI-based ARV regimens in resourceconstrained settings, adherence will be a critically important factor in preventing or reducing treatment failure and the consequences of such failure for both patients and the population at large (see Chapter 3). Thus one of the most urgent behavioral research needs is to identify and better understand the underlying factors that contribute to poor adherence, as well as ways to improve adherence. While adherence has been determined in a variety of ways among persons living with HIV/AIDS in wealthy countries, it remains to be determined which measurement approaches are culturally best suited to resource-poor countries and whether innovative alternatives have the potential to serve as more accurate and acceptable measures. According to a recent assessment of available evidence for HIV/AIDS interventions performed by the Cochrane Collaborative Review Group on HIV Infection and AIDS (2004), controlled trials are urgently needed to determine which interventions can improve adherence to highly active antiretroviral therapy (HAART) and whether those interventions also suppress viral load and improve clinical outcome. More research is also needed

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities on interventions that support or foster adherence, as well as on personal triggers for nonadherence. This research should encompass the provider and the provider–patient relationship, variables related to the treatment regimen (e.g., FDCs), and contextual factors. Specific behaviors to be better understood include the seeking of help from family and friends; the seeking of health care from traditional healers through primary care clinics; the seeking of treatment for a diagnosis; behaviors involved in obtaining and using medications correctly; supportive behaviors of partners, parents, and others; and coping behaviors in the face of stigma. More research is needed as well on the timing of adherence interventions and strategies focused on particular groups of patients (e.g., children and drug users). Changing Behaviors That Place People at Risk As ART scale-up proceeds, the intimate relationship between treatment and prevention must be recognized. The HIV/AIDS pandemic demands intensive prevention campaigns, along with accelerated ARV coverage. Short of a cure or highly effective vaccine, the adoption of informed and safe behavior in the entire population at risk of acquiring and transmitting HIV will remain critical to slowing the epidemic. A crucial focus for the behavioral science research agenda should be discovering ways to change the behaviors and conditions that lead to HIV transmission (Eaton et al., 2003; Reddy and Meyer-Weitz, 1999; Reddy et al., 2003). It will be important to identify what determinants (knowledge, attitudes, and beliefs), processes, and cultural and other contextual factors are keeping people from utilizing prevention and treatment services and from changing their behavior in ways that will reduce the transmission of HIV. Although the increased availability and accessibility of ARVs and ART programs may make the HIV/AIDS pandemic more visible and infection with HIV more accepted, thus reducing some of the stigma associated with being infected or sick (see below) and encouraging more people to seek counseling and ART, it cannot be assumed that this will inevitably happen. Since prevention and treatment programs must be intertwined for optimal synergy, behavioral research is needed to better understand how not only to foster adherence to ARV regimens, but also to improve primary prevention. Specific objectives should be to understand how to: Increase a person’s knowledge about HIV risk reduction and HIV treatment. Increase perceptions of personal risk for HIV. Enhance motivations for behavioral change. Identify personal triggers for engaging in risky behaviors.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Teach people how to communicate to their partners about the need to use condoms. Motivate people to use condoms correctly when appropriate. Teach proper condom use. Increase access to voluntary counseling and testing. Research is needed as well to understand and improve the organization, management, accessibility, delivery, cost-effectiveness, and cost-utility of each of the following services with regard to reducing HIV risk behaviors and transmission: Health care Family planning Social services Drug treatment services Alcoholism treatment centers Addressing the Familial and Social Context of HIV/AIDS Designing interventions that help partners improve their communication skills and foster safer sex norms within relationships is critical to controlling the HIV/AIDS pandemic. There has been growing recognition of the importance of family, community, and society at large in the adoption and utilization of HIV prevention efforts. Strategies in this area encompass creating settings that support testing and counseling and encouraging practices that prevent transmission between HIV positive and negative persons, such as delaying the onset of sexual activity in young people and encouraging proper use of condoms when serostatus is unknown. Using the family to foster norms supportive of safer sexual practices and therapeutic adherence, providing HIV/AIDS education within the context of the family, and enhancing communication skills between parents and their children can be effective strategies for reducing detrimental behaviors. Effective interventions at the community level (e.g., neighborhoods, social network members, organizations, institutions) involve enhancing community norms that favor safer sex practices and adherence to therapeutic regimens. Societal-level interventions involve modifying economic, legal, policy, and regulatory practices such that they foster safer sex and support therapeutic efforts. Given this familial and community context of HIV/AIDS, research should be directed toward identifying family- and community-level behavioral intervention strategies that promote prevention among both infected and uninfected individuals, as well as adherence among individuals under treatment. The engagement of families and communities in providing pal-

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities liative care as AIDS patients approach the end of life is another worthy research focus. How can family providers best be supported at this stressful time? How can they be prepared most effectively to support the medical, emotional, and spiritual needs of the dying? Treating Women with HIV/AIDS Women experience HIV/AIDS differently from men in a number of important respects, both physiological and social (see also Chapter 4). They are more vulnerable to HIV infection as a result of cultural attitudes and their general social and economic position. Within the context of heterosexual relationships and social arrangements, they often have less power than men, which further exacerbates their risk of contracting HIV (Dunkle et al., 2004). It is crucial to understand these socially constructed aspects of male and female relationships, including the economic dependence of women, their role in political decision making, and the resulting impacts on access to health services and education, all of which may influence access to ART and the practice of safer sex. Domestic and sexual violence are common additional obstacles to the ability of women and girls to protect themselves even if they are well informed. Although HIV-infected pregnant women have received a great deal of attention, the focus has been primarily on preventing transmission to their offspring (as discussed in Chapter 4). Greater attention must be given to women, particularly since they are often infected earlier and at higher rates: the HIV prevalence among those aged 15–24 is 2.5 times higher among women than men in some African communities (UNAIDS, 2003). Accordingly, a priority research objective is to better understand how to design effective HIV prevention and treatment interventions for women and girls, including how to improve adherence. Interventions should be gender-specific, as well as involve couples and be culturally appropriate and acceptable. Box 6-4 summarizes key points to be considered in addressing this research objective. Reducing Stigma Research is needed on how to develop, evaluate, and encourage the adoption of strategies to prevent or minimize the negative physical, psychological, cognitive, and social consequences of HIV, including the stigmatization of persons with or at risk for HIV infection (see Chapter 4). An important issue to be investigated is how to promote modifications in the health care delivery system that lead to more effective, culturally sensitive treatment of infected individuals. For example, what can be done to modify the behavior of health care providers in ways that will enhance health care

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities BOX 6-4 Women and HIV/AIDS: Implications for Treatment Women play a central role in family life and in the provision of care for children, spouses, and other relatives with HIV infection. This role highlights the familial impact associated with the fact that women represent 50 percent of the victims of the global AIDS pandemic. In the worst-affected region of the world, sub-Saharan Africa, this figure is 58 percent. As a result of disparities linked to sexual abuse, coercion, discrimination, and poverty, teenage girls in sub-Saharan Africa are infected at rates four to seven times those of their male counterparts. Moreover, while women are more likely to become infected, they may be less likely to get tested or to seek and receive treatment because of gender-based inequalities. Factors affecting access to and use of ART by women include the following: Level of recognition of the need to treat women with HIV outside of the context of preventing perinatal transmission Household and childrearing responsibilities affecting the priority accorded to a woman obtaining health care The need to pay for therapy when women are not in control of financial resources The threat of violence as a disincentive for women to get tested Pressure women may feel to share ARVs with infected children, spouses, and other family members HIV treatment programs should be sensitive to the roles in which women find themselves as both patients and providers. Factors that pose additional barriers to their accessing needed HIV-related care deserve specific attention by program managers, especially given the importance of supporting the role of women in family life. SOURCES: Fleischman, 2004; Gruskin and Maluwa, 2002; Tlou, 2002. utilization; improve screening, counseling, and testing services; and decrease the stigma associated with seeking preventive care and treatment for HIV/AIDS? What can be done to improve providers’ communication skills and ability to make shared decisions with their patients about how and when to initiate therapy? Improving Methodological Tools To address the above behavioral research needs rapidly and in a meaningful manner, the qualitative and quantitative methodological tools used in behavioral research, including those for evaluating HIV prevention interventions, need to be strengthened and expanded. New and rigorous methodological and statistical techniques should be encouraged.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities More-effective methods are needed to increase recruitment, retention, and compliance with protocols for research on interventions aimed at HIV prevention and adherence to treatment. The efficacy of such interventions should be evaluated using rigorous research methods, including randomized controlled behavioral trials. Evaluations of behavioral interventions should use behavioral self-reports as outcome measures, as well as HIV seroincidence data and other biological markers. In addition to assessing efficacy, researchers should assess the cost-effectiveness of interventions. Finally, more research and debate are needed to address the pressing ethical issues involved in the conduct of such research. Addressing Comorbidity and Poverty It is increasingly being recognized that many individuals who are at risk of and become infected with HIV are also impoverished and afflicted with a number of comorbid conditions, including other infectious diseases (hepatitis, sexually transmitted diseases, TB, malaria, and other endemic diseases), substance abuse, and mental illness. The potential for negatively synergistic interactions between comorbidities and poverty is obvious. Research is needed to test the efficacy of interventions that simultaneously address multiple diagnoses and risks, including how to improve adherence to ART among those suffering from any number of other diseases and substance abuse problems. Means of mitigating the complications imposed by coexistent poverty should also be investigated. Research is needed as well to better understand the underlying factors that contribute to the co-occurrence of HIV/AIDS and the progression of AIDS with other infectious diseases, substance abuse, alcohol abuse, and mental illness. Such research should encompass how to design efficacious and cost-effective strategies for addressing such comorbid conditions. It will be essential to better understand the intersection of HIV/AIDS with these related conditions if the treatment and prevention programs now being implemented are to be sustained for the decades that will be necessary to bring the pandemic under control. ENSURING SUSTAINABILITY ALONG THE PATH FORWARD Sustained action along the path forward presumes solutions to numerous discrete scientific and management challenges. At the same time, as wealthy, middle-income, and poor nations join together in perhaps an unprecedented way to tackle the overarching challenge of bringing the pandemic under control, it bears emphasizing that the global problem of HIV/ AIDS will likely be present for decades despite research findings and optimized interventions. In a few years, when it may be hoped that the initial

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities objectives of WHO’s 3-by-5 campaign and the U.S. Emergency Plan will have been met, we must not abandon the millions started on therapy or ignore the pleas of the tens of millions more who will soon need these medicines and subsequently make a claim on our humanity. Even short-term interruptions in support could be clinically disastrous and ethically problematic by allowing successfully suppressed HIV infections to emerge in drug-resistant forms. Thus, ART must not be seen simply as a short-term goal or the end point of a 5-year plan. The world is indeed at the beginning of a very long path forward. The role of donors, whether they be funders from government, foundations, or international banks or individuals and organizational partners providing care-related services, will steadily increase for decades to come. The legacy of the United States and its international partners, and indeed of the entire global community in the early twenty-first century, will be measured against how we respond to the challenges of the day with the resources at our disposal. The response to the global HIV/AIDS pandemic must be a sustained claim on those resources. Lifetime ART for 30–40 million people will likely require annual investments of at least US$9–12 billion (Council on Foreign Relations, 2004). In parallel, sufficient funding must be sustained for prevention activities to curb the emergence of new cases that will demand therapy. Considering the familial, political, economic, and institutional destabilization that could well occur without these infusions of assistance, as well as the costly international military responses that could be required to restore and maintain peace (and ensure access to important natural resources) as a result of such breakdowns, ongoing support for ART programs may well be more economically prudent than the alternative. Indeed, the ongoing erosion of state capacity in sub-Saharan Africa associated with uncontrolled HIV/AIDS contributed to the Bush Administration’s assertion in the current National Security Strategy that “America is now threatened less by conquering states than we are by failing ones,” and the will to sustain investments for HIV/AIDS prevention and treatment will be threatened for states that appear to be failing (White House, 2004). Ensuring the sustainability of political will, funding, and service will be a challenge even if initial scale-up activities are deemed generally successful. The measure of success in the intermediate term will be treatment outcomes (measured by decreased morbidity and mortality and durable suppression of viral loads). To achieve these objectives will require unprecedented attention to quality of care in resource-constrained settings, along with constant learning. Quality needs to be viewed as a necessity, not a luxury, because only quality programs will be able to sustain favorable treatment effects for a decade or more. The potential for negative collateral effects of scale-up programs, such as the diversion of workers and resources from other criti-

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities cal health programs, must also be anticipated and dealt with in a preventive fashion. Because success is the best justification for sustained and increasing investments, the lessons learned that are documented in this report and the management and clinical principles that are recommended must not be ignored in the urgency to move forward. The path forward has been illuminated. It is imperative to act now, but also to act well. REFERENCES Brown A. 2001. Integrating Vertical Health Programs into Sector Wide Approaches: Experiences and Lessons. [Online]. Available: http://www.ihsd.org [accessed June 5, 2004]. Cochrane Collaborative Review Group on HIV Infection and AIDS. 2004. Evidence Assessment: Strategies of HIV/AIDS Prevention, Treatment, and Care. [Online]. Available: http://www.igh.org/Cochrane/pdfs/EvidenceAssessment.pdf [accessed August 31, 2004]. Council on Foreign Relations. 2004. Addressing the HIV/AIDS Pandemic: A U.S. Global AIDS Strategy for the Long Term. New York: Council on Foreign Relations and Milbank Memorial Fund. Dunkle K, Jewkes R, Brown H, Gray G, McIntryre J, Harlow S. 2004. Gender-based violence, relationship power, and risk of HIV infection in women attending antenatal clinics in South Africa. Lancet 363(9419):1415–1421. Eaton L, Flisher AJ, Aaro LE. 2003. Unsafe sexual behaviour in South African youth. Social Science and Medicine 56:149–165. Fisher A, Foreit J. 2002. Designing HIV/AIDS Intervention Studies: An Operations Research Handbook. New York: The Population Council, Inc. Fleischman J. 2004. Breaking the Cycle: Ensuring Equitable Access to HIV Treatment for Women and Girls. Center for Strategic and International Studies. [Online]. Available: http://www.csis.org/africa/0402_breakingcycle.pdf [accessed August 24, 2004]. Gilks C, Abouzhar C, Turmen T. 2001. HAART in Haiti: Evidence needed. Bulletin of the World Health Organization 79(12):1154–1155. Gruskin S, Maluwa M. 2002. Human Rights and HIV/AIDS. In: Essex M, Mboup S, Kanki P, Marlink R, Tlou S, eds. AIDS in Africa. 2nd Edition. New York: Kluwer Academic/ Plenum Publishers. Pp. 641–651. Reddy SP, Meyer-Weitz A. 1999. Sense and Sensibilities: The Psychosocial and Contextual Determinants of STD Related Behaviours. Cape Town, South Africa: South African Medical Research Council. Reddy SP, Panday S, Swart D, Jinabhai CC, Amosun SL, James S, Monyeki KD, Stevens G, Morejele N, Kambaran NS, Omardien RG, Van den Borne RG. 2003. UmthemtheUhlaba Usamila: The South African Youth Risk Behaviour Survey 2002. Cape Town, South Africa: South African Medical Research Council. The HIV Netherlands Australia Thailand Research Collaboration. 2004. The HIV Netherlands Australia Thailand Research Collaboration Homepage. [Online]. Available: http://www.hivnat.org/ [accessed January 5, 2004]. Tlou SD. 2002. Gender and HIV/AIDS. In: Essex M, Mboup S, Kanki P, Marlink R, Tlou S, eds. AIDS in Africa. 2nd Edition. New York: Kluwer Academic/Plenum Publishers. Pp. 654–663. UNAIDS (Joint United Nations Programme on HIV/AIDS). 2003. AIDS Epidemic Update 2003. [Online]. Available: http://www.unaids.org/EN/other/functionalities/document.asp?href=http%3A%2F%2Fwww%2Eunaids%2Eorg%2Fhtml%2Fpub%2FPublications%2FIR%2Dpub06%2FEpi03%5F00%5Fen%5Fhtml%2Ehtm&PDFHref=&FileSize=120 [accessed August 24, 2004].

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Vermund SH, Powderly WG. 2003. Developing a human immunodeficiency virus/acquired immunodeficiency syndrome therapeutic research agenda for resource-limited countries: A consensus statement. Clinical Infectious Diseases 37(Suppl 1):S4–S12. White House. 2004. Overview of America’s International Strategy. [Online]. Available: http://www.whitehouse.gov/nsc/nss1.html [accessed April 2, 2004]. WHO (World Health Organization). 2003a. Scaling up Antiretroviral Therapy in ResourceLimited Settings: Treatment Guidelines for a Public Health Approach, 2003 Revision. [Online]. Available: http://www.siecus.org/inter/WHO_ARV_Guidelines2003.pdf [accessed August 24, 2004]. WHO. 2003b. Nutrient Requirements for People Living with HIV/AIDS: Report of a Technical Consultation. Geneva: WHO. WHO. 2004. Operational Research for the 3 by 5 Initiative. [Online]. Available: http://www.who.int/3by5/publications/briefs/operational_research/en/ [accessed August 24, 2004].

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