Executive Summary

The HIV/AIDS1 pandemic has evolved into the greatest global public health crisis, one that has progressed virtually unchecked in many of the poorest regions of the world for over two decades. Of the 40 million people worldwide infected with HIV, an estimated 6 million are in need of immediate, life-sustaining antiretroviral (ARV) therapy (ART). Yet fewer than 400,000 people in low- and middle-income countries have access to such treatment (WHO, 2003b). Most HIV-infected individuals live in severely resource-constrained settings, where the HIV epidemic continues to grow at a rate of 5 million infections per year, compounding the already enormous treatment challenge. The high AIDS mortality rate in sub-Saharan Africa, which remains the worst-affected region of the world, contrasts sharply with the decreasing HIV-related death rate in high-income countries where ARVs are widely available and affordable. Those acutely affected by a pervasive lack of treatment in resource-constrained environments include not only the millions of infected individuals, but also the millions of children orphaned when their parents die from HIV-related illness for want of these drugs. Moreover, because HIV-related deaths occur disproportionately among young, economically productive adults, the epidemic is undermining the economic development and social fabric of entire countries.

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Human immunodeficiency virus/acquired immunodeficiency syndrome.



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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Executive Summary The HIV/AIDS1 pandemic has evolved into the greatest global public health crisis, one that has progressed virtually unchecked in many of the poorest regions of the world for over two decades. Of the 40 million people worldwide infected with HIV, an estimated 6 million are in need of immediate, life-sustaining antiretroviral (ARV) therapy (ART). Yet fewer than 400,000 people in low- and middle-income countries have access to such treatment (WHO, 2003b). Most HIV-infected individuals live in severely resource-constrained settings, where the HIV epidemic continues to grow at a rate of 5 million infections per year, compounding the already enormous treatment challenge. The high AIDS mortality rate in sub-Saharan Africa, which remains the worst-affected region of the world, contrasts sharply with the decreasing HIV-related death rate in high-income countries where ARVs are widely available and affordable. Those acutely affected by a pervasive lack of treatment in resource-constrained environments include not only the millions of infected individuals, but also the millions of children orphaned when their parents die from HIV-related illness for want of these drugs. Moreover, because HIV-related deaths occur disproportionately among young, economically productive adults, the epidemic is undermining the economic development and social fabric of entire countries. 1   Human immunodeficiency virus/acquired immunodeficiency syndrome.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Growing recognition of the unprecedented nature and momentum of this human catastrophe, coupled with the increased understanding and growing availability of technical tools needed to halt its devastating progress, has mobilized political will and financial resources worldwide to bring treatment options to those most in need. Three initiatives highlight recent financial and operational steps being taken to accelerate access to ART and other HIV/AIDS care and prevention programs in resource-constrained settings. On December 1, 2003, also World AIDS Day, the World Health Organization (WHO) and Joint United Nations Programme on HIV/ AIDS (UNAIDS) launched the “3-by-5” campaign, with a global target of providing ART to 3 million people with HIV/AIDS in developing countries by the end of 2005 (WHO, 2003b). In November 2003, the government of South Africa approved its landmark Operational Plan for Comprehensive HIV and AIDS Care, Management and Treatment for South Africa (South Africa Department of Health, 2003). One of the goals of the plan is to administer ARVs to more than 1 million people with HIV infection by 2008–2009; this goal is to be accomplished by negotiating with multiple competing drug suppliers and eventually producing the drugs locally. Finally, in January 2003, during his State of the Union address, U.S. President George W. Bush promised $15 billion to international AIDS activities over the course of the next 5 years as part of the President’s Emergency Plan for AIDS Relief (U.S. Department of State, 2003). One of the goals of the plan is to provide ART to 2 million HIV-infected people in the poorest, most afflicted countries in Africa, the Caribbean, and Vietnam. The clinical, financial, and epidemiological effects of implementing such widespread treatment and prevention programs must be considered, and rational methods for informing such efforts developed. One major concern is that of fostering the premature emergence of widespread resistance to ARVs, thereby reducing the long-term viability of ART regimens in developing countries. In this context, the Institute of Medicine was asked to provide an independent review and assessment of ART scale-up programs currently under way and in development. The Committee on Examining the Probable Consequences of Alternative Patterns of Widespread Antiretroviral Drug Use in Resource-Constrained Settings was formed to conduct this study. The committee was charged to provide (1) an examination and evaluation of current ART implementation programs, efficacy studies, infrastructure costing models, existing guidelines for program implementation, and models that demonstrate successful scale-up of ART programs; (2) a study of the role of ongoing well-developed operations research in the field and in parallel with treatment implementation to establish sustainability outcome measures; (3) a determination of the components necessary for a system-

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities atic, structured framework to achieve a balance between resistance development and transmission and the need to provide treatment in resourceconstrained settings; and (4) an assessment of current research on ARV resistance and toxicity, and the likely effects on the malnourished individuals with high disease burden found in resource-poor settings. In response to this charge, the committee developed its findings, conclusions, and recommendations using evidence derived from the scientific literature, commissioned papers, and unpublished data drawn from workshop presentations made by individuals currently researching and implementing ART programs in resource-constrained environments. The combined weight of this evidence contributed to the committee’s formulation of strategies that require immediate attention and action, as well as recommendations regarding programs, policies, and research that must continue to evolve if efforts aimed at treating millions of individuals in need are to be improved and sustained. MOVING FORWARD NOW: FINDINGS AND RECOMMENDATIONS ART scale-up in resource-constrained settings worldwide must proceed immediately. Although there may be no definitive single solution regarding how best to introduce ART into such settings, the committee identified a rational framework and key principles to guide the people and institutions that are providing resources for and leading ART scale-up programs worldwide. The committee undertook this effort with a keen awareness of the potential dangers of the suboptimal introduction of ARVs on a large scale, as well as the complex ethical challenges stemming from the reality that there will not be enough treatment for everyone who needs it. Recognizing these challenges, there remains an urgency to provide ART as rapidly as is feasible in order to extend the duration of as many lives as possible and reverse the course of social collapse in many countries heavily afflicted by HIV/AIDS. Coordinating and Sustaining the Global Response The widespread introduction of ARVs into resource-constrained settings worldwide is expected to result in exciting and life-extending successes. The much-anticipated influx of funds and resources to be made available by initiatives such as those noted earlier—including the U.S. President’s Emergency Plan for AIDS Relief; WHO’s 3-by-5 campaign; and continued efforts of the Global Fund to Fight AIDS, Tuberculosis, and Malaria—as well as the World Bank’s Multi-Country HIV/AIDS Program

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities for the Africa Region and a growing number of national HIV/AIDS programs worldwide, are generating great enthusiasm and hope that this human tragedy can be abated. The reach of these investments will continue to be enhanced by the efforts of global health and political leaders to achieve maximal efficiencies through innovative price reduction mechanisms, such as the procurement strategies for drugs and equipment developed by the William J. Clinton Foundation and Médicins sans Frontières (MSF). As these programs develop and expand, it will be essential for all people involved, including international and national leaders and those living with HIV/AIDS, to remain aware of the medical, social, and ethical challenges, complexities, and risks associated with taking on a global problem of such enormous proportions. A considerable challenge for ART scale-up is that unreliable or interrupted drug supplies, combined with poor treatment procedures and program management, could promote treatment failure as well as the emergence of ARV-resistant virus, thereby reducing the long-term durability of more-affordable first-line drug regimens. Therefore, paramount to the long-term success of these programs will be recognition on the part of international and national leaders of the lifelong nature of ART and the need to sustain a constant supply of quality drugs and services in the context of quality supportive care. Both clinical success and ethical imperatives will demand lifelong therapy. Unlike most interventions deployed for infectious diseases (e.g., vaccines and short-course drug therapy), then, ART is a lifelong treatment that will require resources, clinical management, and patient adherence consistent with chronic disease management strategies not often appreciated in developing countries. Therefore, new attitudes, training, and programmatic approaches will be needed (WHO, 2002). In addition, the natural progression of untreated HIV infections will result in a growing call to place millions of new patients on treatment within the next few years. These growing needs will demand long-term commitments from the international donor community and countries burdened with a high HIV prevalence. To ensure the sustainability of ART scale-up for the next generation, these commitments must be accompanied by new strategies for promoting self-sufficiency in countries with a high HIV/AIDS disease burden. Antiretroviral therapy scale-up in resource-constrained settings should proceed immediately through coordinated, aggressive action by national governments, donors, international agencies, and nongovernmental organizations. Donors must attempt to maximize the distribution of scarce resources—human, financial, and technical—for people in need within and among all resource-constrained countries and areas. To this end, multiple HIV/AIDS prevention and treatment initiatives need to be coordinated and integrated through national leadership and

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities entitities that best meet the needs of their populations and of all individuals. (Recommendation 2-1)2 Donors should commit to continuous funding of antiretroviral therapy scale-up for decades to ensure the sustainability necessary to avert the medical hazard of interruptions in the continuity of treatment. Delays in donor funding after treatment programs are initiated will jeopardize the long-term durability of treatment regimens. Because it is estimated that 40 million people are currently infected with HIV, and 5 million new infections occur each year, donors should plan now for increasing support in the future. To this end, innovative mechanisms should continue to be pursued by national governments and donors in partnership with industry to ensure the continuous procurement of quality drugs, diagnostics, and other commodities at the lowest possible cost. At the same time, national governments in countries severely affected by HIV/ AIDS must begin to invest in and develop priorities for prevention and treatment programs to ensure those programs’ long-term sustainability and effectiveness. (Recommendation 2-2) Developing and Managing Treatment Strategies The lack of robust data and evidence-based evaluation makes it difficult to use best practices to guide initial program design within these countries. ART programs in middle- and low-income countries provide some important lessons (Galvao, 2002; Weidle et al., 2002), but population- and resource-specific guidelines tailored to individual country needs will ultimately prove most effective. Program Design WHO’s 2003 guidelines (WHO, 2003a, presented in Appendix C) may simplify and make feasible an otherwise prohibitively complex therapy, but there are still many unanswered clinical questions regarding the most effective, safe use of ARVs in resource-constrained settings. In particular, although the guidelines include recommendations for pregnant women, patients coinfected with tuberculosis,3 and infants and children, WHO acknowledges the guidelines’ limitations given the critical lack of knowl- 2   The numbers in parentheses after each recommendation correspond to the numbering scheme used in the main text. Thus, for example, Recommendation 2-1 is the first recommendation in Chapter 2. 3   In 2002, 42 million people were living with HIV/AIDS, and 11 million adults living with HIV/AIDS were estimated to be coinfected with Mycobacterium tuberculosis.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities edge and urgent need for research in these areas. Nonetheless, the WHO guidelines are endorsed in this report for use as a working template that should be modified according to specific country needs and the findings of ongoing operational research. Before countries develop their own directives, the World Health Organization’s 2003 guidelines for the treatment of adults, children, and pregnant women should serve as an initial template for the design of antiretroviral therapy programs with respect to when to start therapy, which regimens to use, how to monitor the progress of therapy, and when to switch drugs or terminate therapy. As new evidence becomes available through the efforts of international, national, and local research, the WHO guidelines, particularly with regard to pregnant women and those coinfected with tuberculosis, may require refinement or modification. (Recommendation 4-2) Program managers, international donors, and national policy makers should ensure that strong tuberculosis control programs continue in parallel with antiretroviral treatment scale-up programs, given that nearly one-third of HIV-infected persons in the world are coinfected with tuberculosis. Because dual infection with HIV and tuberculosis poses a life-threatening diagnostic and therapeutic dilemma, strong HIV care programs must include capabilities for diagnosis, treatment, and prophylaxis of tuberculosis. Tuberculosis treatment programs should be supported as an important point of entry for HIV testing and consideration for ART. It is critical to overall treatment success that these coexisting epidemics be addressed in parallel. (Recommendation 4-6) Integration of Prevention and Treatment Strategies ART can and should serve a critical secondary role in the prevention of HIV/AIDS, both clinically and behaviorally. It may be hoped that, beyond reducing both sexual and maternal-to-infant transmission of infection by decreasing patient viral load (Quinn et al., 2000; Gray et al., 2001; Ometto et al., 2000; John et al., 2001) in those being treated, the availability of ART will motivate many millions more people to seek voluntary counseling and testing—a critical component of any prevention or care intervention—and help diminish the stigma associated with HIV/AIDS (Nierengarten, 2003). National and international program planners should coordinate and integrate stronger and more effective HIV/AIDS prevention initiatives concurrently with the scale-up of antiretroviral therapy programs. Pre-

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities vention initiatives should focus on those at risk for acquiring or transmitting HIV infection, in addition to those receiving treatment. To be optimally successful, voluntary counseling and testing programs and programs to prevent mother-to-child transmission should encompass both preventive and therapeutic dimensions. National and community leaders should be strong advocates for effective HIV prevention efforts and engage government agencies and community groups in sectors beyond health, including education and public relations, as well as legislative leaders (to prevent discrimination). (Recommendation 4-8) Governmental and community leaders at all levels of civic life should spearhead an effort to create a culture of openness and support in order to eliminate stigma and ensure the successful continuance of antiretroviral treatment and HIV prevention programs. (Recommendation 4-1) Adherence and Drug Quality Adherence to drug regimens will be a critical factor in determining the success of ART programs, but it is also expected to be one of the greatest clinical challenges of ART scale-up. Although studies have shown that good adherence is quite feasible in resource-constrained settings under certain circumstances (e.g., in clinical settings where the studies are conducted) (Laniece et al., 2003; Orrell et al., 2003), the reproducibility of these results in other settings involving widespread scale-up cannot be assured. The challenge is made more difficult by the lack of conclusive evidence on what factors contribute to poor adherence and what interventions would likely be most effective at maximizing adherence in resource-constrained settings. It has been suggested that ease of administration, timing and dosing requirements, drug efficacy, improved well-being, and patient education are all important elements contributing to adherence. Antiretroviral therapy program managers, international donors, and national planners should take the necessary measures and provide resources to ensure the strict adherence to therapy that is fundamental to program success. Such measures should include timely and adequate provision of drugs and health care, knowledgeable and available providers, and appropriate patient education. ART programs should encourage community involvement in the development of adherence interventions. This involvement should include people living with HIV/ AIDS, family members, and community and religious leaders. Additionally, in special populations—such as migrant workers, trucking and transportation workers, and the military—special multisite and

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities transnational program links may need to be established. (Recommendation 4-7) Some experts have called for the use of fixed-dose combinations (FDCs) to improve adherence. There is controversy, however, regarding how to best measure the quality and effectiveness of FDCs. It is not well understood whether adequate procedures are in place to ensure ongoing drug quality after initial qualification (surveillance and specimen inspection) or to identify the emergence of drug-related adverse events (postmarket). The benefits of high levels of adherence to ARV regimens would not be realized if those drugs were not themselves efficacious, safe, and of consistent quality. Therefore, ongoing, rigorous quality assurance throughout the manufacturing and distribution chain will be essential to ensure that cost savings are not routinely or intermittently sought at the expense of quality. The committee endorses as critical the use of the cheapest, safest, most effective high-quality antiretroviral drugs that can be procured. Fixed-dose combinations are recommended as most desirable if they are also of high quality, safe, effective, and inexpensive. The committee also strongly endorses a rigorous, standardized international mechanism to support national quality assurance programs for antiretroviral drugs. This mechanism should be timely, transparent, and independent of conflicts of interest; employ evidence-based standards; and provide ongoing assurance of consistent high-quality manufacture and handling. In particular, the pharmacological issues associated with fixed-dose combinations must be rigorously and rapidly addressed. (Recommendation 5-6) Initiation and Monitoring of Treatment As medically, fiscally, and logistically challenging as the consequences of treatment failure due to toxicity or drug resistance may be, they should not be construed as a reason to discourage or unnecessarily delay the introduction of responsibly designed ART scale-up programs in resource-limited settings. On the other hand, the risk of widespread treatment failure due to resistance and other factors demands a careful, rational, evidence-based public health approach to ART scale-up and the capacity to know when therapeutic and programmatic changes are needed. To this end, the immediate application of basic longitudinal clinical care, surveillance, and laboratory tools will be necessary. Although many patients in resource-rich countries have continued to derive immunological and clinical benefit from ART even after the emergence of highly resistant viral strains (Deeks et al., 2000), the more-expensive drug options, monitoring tools, sequential therapeutic schemes, and provider expertise that allow for this continuing benefit are lacking in most resource-constrained settings.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Antiretroviral therapy programs should be designed to optimize the balance between individual efficacy and population effectiveness while minimizing toxicity and resistance. ART regimens or programs shown to be significantly less effective or ineffective—such as mono- or dualtherapy and nucleoside-only regimens—must be avoided. Because resources and population and patient needs will vary considerably among different countries and regions, countries should develop population-specific guidelines. (Recommendation 4-5) For individual patients about to embark on therapy, general clinical screening for resistance to antiretroviral drugs is not recommended at this time for two reasons: because the prevalence of resistance in HIVinfected individuals not previously exposed to antiretroviral therapy is expected to be undetectable or low, and because the proportion of total persons with HIV who are receiving therapy in a given country will also be relatively small in the short term. Coordinated, systematic testing for resistance to antiretroviral drugs should, however, be conducted among a subset of patients failing treatment. These latter results will be critical in evaluating ART programs and in determining whether and when routine population-based resistance testing might eventually prove effective. Sentinel surveillance of treatment-naïve HIV-positive persons may also be indicated in the future. (Recommendation 3-1) Donors and program managers should plan and budget for laboratory activities that will foster more accurate and effective HIV diagnosis and management, using the World Health Organization’s 2003 guidelines as the initial template. Incorporating emerging evidence and resources into their decision-making process, countries should consider developing population-specific guidelines reflective of the best possible practices in their particular circumstances. In those localities where it is possible to go beyond the WHO guidelines, treatment failure should be defined through viral RNA determination; otherwise, it should be defined by means of clinical or other laboratory markers consistent with the guidelines. (Recommendation 4-3) Under the leadership of their ministries of health and national reference laboratory experts, all countries should develop hierarchical laboratory networks that integrate the local, district, and referral hospital levels through tiered quality assurance programs and provide referral support for increasingly complex laboratory assays. Full development of these networks is not required before the initiation of scaled-up antiretroviral therapy programs, however. National reference laboratories should promulgate tier-specific quality assurance protocols, and donors supporting ART programs should provide the means to properly ensure acceptable technical performance by these laboratory networks. Dedi-

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities cated funds, training, and other resources to ensure the maintenance of the laboratory equipment employed in these networks should be provided. To better facilitate the diagnosis and treatment of HIV infection in infants less than 18 months of age, the laboratory networks should put in place a capacity for the direct detection of HIV, such as HIV DNA, HIV RNA, or HIV p24 antigen. (Recommendation 4-4) Building a Comprehensive Infrastructure for Scaling Up While the declining costs of ARVs have removed a significant impediment to ART scale-up, successful efforts will depend on much more than inexpensive drugs. The drugs must be delivered into an infrastructure with the capacity to distribute them and other commodities rapidly and securely while also ensuring the readiness of facilities and personnel to provide complex lifelong medical treatment and associated monitoring to millions of people. Success will require serious attention to address critical shortcomings in infrastructure, particularly with regard to human resource capacity. Ensuring Equitable Care Even in countries such as South Africa, which is not as severely resource-constrained as most of its sub-Saharan neighbors, the vast health and wealth disparities that exist between the “urban poor” and the “rural poorer” create extraordinary logistical and ethical challenges to delivering equitable ART. Resolving such disparities will require immediate investments in rural areas in the basic infrastructure needed for ART programs. By ensuring that contributions can be used for infrastructure and workforce development, international and national decision makers will enhance the equitable delivery of ART. Mobilizing a Workforce The shortage of workers in all areas of the health care sector has been identified as a rate-limiting constraint to rolling out large, countrywide ART programs. The progress of scale-up in many, if not most, areas will require signficantly greater workforce capacity; without this increased capacity, scale-up could potentially fail on these grounds alone. WHO has estimated that its 3-by-5 campaign will require an additional 100,000 health providers and community treatment supporters trained to deliver ARVs in accordance with national standards (WHO, 2003b). Care must be taken to maintain existing health care services and not to weaken current infrastruc-

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities tures. Of concern is that as health care systems receive an infusion of fiscal resources for new HIV prevention and treatment programs, there could be a migration of already scarce workers to these new programs and away from other critical public health endeavors, such as maternal and child health and malaria control. Efforts should be made to augment mechanisms that can be used to mobilize larger numbers of trained professionals from resource-rich countries with extensive and relevant expertise to provide technical assistance and training to countries in need. Such an HIV/AIDS corps would serve to strengthen long-term ties among health professionals working to fight HIV/AIDS in all countries. A variety of innovative governmental and private-sector mechanisms should be designed and expanded to bring qualified volunteer medical professionals into both urban and rural areas to support prevention, care, and training programs relevant to ART scale-up. The required expertise and skills and the areas for placement in country should be determined by local programs. (Recommendation 5-1) In addition to the immediate human resource needs that must be addressed to initiate ART, a well-trained and sufficiently populated workforce will be needed to provide care through the next several decades. Improved educational opportunities and training programs will be necessary to build a critical mass of health care professionals, program managers, and technology professionals to meet the continuing needs of programs for HIV/ AIDS prevention, treatment, and care. Methods and tools for assessing and monitoring human resource needs will improve and inform decision making in the areas of both investment and training. Donors and organizations with relevant expertise (e.g., academia, industry, public health agencies, nongovernmental organizations) should support active partnerships among all institutions possessing such expertise and those seeking to acquire the benefits of training; mentoring; and the transfer of antiretroviral therapy–related medical, technical, and managerial knowledge and skills. Partnerships among medical institutions within and across national borders should be encouraged by donors and governmental authorities. These twinning relationships should support the transfer of appropriate technology; expertise in medicine, monitoring and evaluation, and applied and operations research; and lessons learned. Physical and electronic means should be used to provide ongoing support for these partnerships. (Recommendation 5-2)

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities Expertise within the AIDS Education and Training Center networks sponsored by the U.S. government and similar initiatives by other countries should be utilized to support the development of effective training programs in HIV care in order to prepare local physicians, nurses, community health workers, laboratory professionals, pharmacists, and logisticians in heavily HIV-afflicted countries facing severe human resource shortages. (Recommendation 5-3) Countries should establish information systems at the regional and national levels so they can regularly assess and coordinate their evolving human resource needs. Both countries with relatively adequate human resources and those that are more resource-constrained should pursue appropriate policies and programs to stem the “brain drain” of local expertise that is critically needed for the scale-up of ART programs. The current shortage of trained, dedicated personnel for monitoring and evaluation programs should be rectified in conjunction with meeting other training and personnel needs. (Recommendation 5-4) Securing the Delivery of Effective Drugs In addition to clinical and human resource issues surrounding ART scale-up, the logistics of drug delivery pose a complex challenge. An interruption in the drug supply line—whether caused by transportation, financial, corruption, or other problems—will increase the risk of treatment failure regardless of how adherent a patient is or how knowledgeable providers are about HIV/AIDS treatment and care. To provide continuous, secure delivery of quality drugs, diagnostics, and other products, national and international program managers of antiretroviral scale-up efforts should ensure that well-coordinated commodity and logistics systems are in place from the outset of program initiation. Technical leadership, governmental commitment, and institutional support are needed to ensure the secure delivery of quality drugs and supplies. Methods to avert the interruption of drug supplies include information systems to facilitate the projection of needs and track the distribution of available stocks. Such planning and investment should also account for the consequences of civil disruption or natural disasters, which would require adequate contingencies to avoid disruption to the supply and treatment systems. (Recommendation 5-5) Learning by Doing: The Essential Role of Monitoring and Evaluation As much as ART scale-up can and should be founded in evidence-based public health knowledge, it will also depend largely on a learn-by-doing

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities approach. Global efforts to control the pandemic in severely resourceconstrained environments are still too new to have yielded extensive evidence-based best practices. Much of the medical and public health knowledge garnered to date is based on research conducted in the context of the United States and other resource-rich countries. Although some of this knowledge is transferable to a multitude of settings, much will need to be reassessed. In this process, mistakes and setbacks should be construed as learning experiences, not excuses to withhold treatment from those in need. In fact, formal methods for recognizing program success and failure and then effecting change as a result of what is observed should be incorporated into all clinical care and management strategies. Improving Effectiveness and Sustainability Through Monitoring and Evaluation There are concerns about whether and how dedicated ART scale-up funds will be allocated to the often-overlooked but vitally important monitoring and evaluation components of program design. Monitoring and evaluation are based on intensive data collection and analysis and assessment of programmatic outcomes, not simply process indicators; both are vital to the long-term sustainability of ART scale-up. Monitoring and evaluation involves the routine assessment of ongoing activities and progress and the episodic assessment of overall achievements. Given that there are serious short- and long-term risks associated with widespread treatment failure and resistance, it is critical that the future direction of national ART programs be continuously informed by a robust monitoring and evaluation system. National program leaders must know when their treatment guidelines are failing and when changes need to be made. Monitoring and evaluation can be used to assure the global community, including funders and decision makers, that ART scale-up is achieving its intended goals. Such assurance will be vital to the long-term fiscal sustainability of ART programs. Monitoring and evaluation processes should be put in place by program managers at all levels at the start of scale-up initiatives. A fixed percentage (approximately 5–10 percent) of ART program funding should be budgeted strictly for monitoring and evaluation (exclusive of support for hypothesis-driven operations research). (Recommendation 5-7) Program managers should measure the effectiveness of HIV prevention and treatment efforts by means of scientifically valid and systematically conducted surveys of HIV prevalence and incidence, HIV morbidity and mortality, and risk behaviors. ART programs should be designed

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities to improve the quality of life and add many years of productivity for as many people as possible. The success of ART scale-up should be evaluated on the basis of the extent to which these specific goals are achieved. (Recommendation 5-8) Monitoring and evaluation measures and requirements, as directed by various donors and other stakeholders, should be harmonized across programs to minimize time-consuming inefficiencies in data collection and program management. Additional efficiencies would be achieved if these efforts were coordinated by a single national ministry or agency. Donors should avoid attempting to ascribe results solely to individual funding sources in order to minimize the in-country confusion and inefficiency created by mandates to conduct multiple, uncoordinated monitoring and evaluation efforts in the midst of rapid scale-up. (Recommendation 5-9) IMPROVING FUTURE OUTCOMES Recognizing the limited infrastructure, tools, knowledge, and personnel currently available in resource-constrained settings, it is clear that future efforts in the provision of ART will benefit from expanded investments and research. Given the limited experience with large-scale ART programs in resource-constrained countries, the capturing of lessons learned from newly implemented programs will be essential to informing the direction and priorities that will ensure long-term sustainability, quality, and success. Gaps in knowledge still inhibit our efforts to prevent, diagnose, and treat HIV/AIDS more effectively. Such discoveries will ultimately facilitate not only more cost-effective care, but also the saving of millions of lives. Formulating a Research Agenda Operations Research Operations research involves the planned, systematic experimental design, testing, and analysis of different processes or practices. A well-designed operations research program will be critical to gathering as much information as possible during what will of necessity be learning by doing. Lessons learned can be used to establish national guidelines specific to a country’s needs, to correct mistakes, and to inform changes and new initiatives. Well-designed programs based on the best available objective evidence stand a better chance of success—not only because of the direct benefit to those patients receiving treatment, but also because of the greater number of people that can be treated as a result of the cost savings realized by such programs. At the same time, it is essential not to become paralyzed

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities by the desire to have all of the details in place before beginning. The HIV/ AIDS tragedy demands urgent action. 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 resourceconstrained 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 6-1) 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. Collaborative partnerships and endeavors between the research and health care communities should be encouraged. (Recommendation 6-2) Applied Clinical and Behavioral Research In addition to operations research that will identify and optimize clinical and management processes, it will be important to address the numerous gaps in knowledge and tools that still limit our ability to respond effectively to the global HIV/AIDS pandemic. Support for applied clinical and behavioral research is of fundamental importance. Rapid and inexpensive diagnostic tools and laboratory tests would greatly improve the clinician’s ability to determine when to initiate and how to monitor therapy, including making important decisions about the selection of and changes in drug regimens to avoid treatment failure. A better understanding of the impact of the nutritional status of patients on drug effectiveness and toxicity will be critical in populations plagued by chronic malnutrition and often by the lack of adequate quantities of food. The social and behavioral dimensions of ART scale-up are complex. Responding to these challenges will be greatly facilitated by a better understanding of the factors that improve

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities adherence to drug therapy, the most effective methods for reducing risk behaviors that contribute to HIV transmission, and effective measures for reducing stigma related to HIV/AIDS. Development and field evaluation of simple, rapid, inexpensive laboratory tests for diagnosing HIV infection and for monitoring therapeutic responses should be a high priority. The shortage of laboratories and laboratory technicians in resource-poor countries, together with the millions in need of HIV testing and treatment monitoring, underlies the priority of developing tests with these characteristics. In relatively well-resourced countries, critical monitoring for toxicity and viral response utilizes generally expensive assays, whose annual costs could themselves be comparable to those of the antiretroviral drugs 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. (Recommendation 6-3) Box ES-1 lists some priority topics for applied research to support ART scale-up initiatives. BOX ES-1 Some Applied Research Priorities for ART Scale-up Initiatives Simple, rapid, inexpensive laboratory tests for diagnosing and monitoring HIV/AIDS, to include the particular case of infants under 18 months of age. Culturally appropriate adherence interventions for both adult and pediatric populations. Randomized trials quantifying the effects of FDCs on health outcomes and adherence, along with relative benefits compared with blister packages and loose drugs, to better inform decisions about drug selection and delivery. The pharmacokinetics of ARVs in chronically malnourished populations and effects related to drug toxicity. The evidence-based development of pediatric ARV formulations. The optimal means of integrating ARV initiatives with other health services so as to minimize the negative collateral effects of these new large-scale programs.

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Scaling Up Treatment for the Global AIDS Pandemic: Challenges and Opportunities CONCLUSION Sustained action for scaling up treatment for the HIV epidemic presumes solutions to numerous scientific and management challenges. At the same time, as wealthy, middle-income, and poor nations join together 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 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. Even short-term interruptions in support could be clinically disastrous and ethically unconscionable 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 that will require vigilant and sustained support. REFERENCES Deeks SG, Barbour JD, Martin JN, Swanson MS, Grant RM. 2000. Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection . Journal of Infectious Diseases 181:946–953. Galvao J. 2002. Access to antiretroviral drugs in Brazil. Lancet 360(9348):1862–1865. Gray R, Wawer MJ, Brookmeyer R, Sewan Kambo NK, Serwadda D, Wabwire-Mangen F, Lutalo T, Li X, VanCott T, Quinn TC, Rakai Project Team. 2001. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1 discordant couples in Rakai, Uganda. Lancet 357:1149–1153. John GC, Nduati RW, Mbori-Ngacha DA, Richardson BA, Panteleeff D, Mwatha A, Overbaugh J, Bwayo J, Ndinya-Achola JO, Kreiss JK. 2001. Correlates of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission: Association with maternal plasma HIV-1 RNA load, genital HIV-1 DNA shedding, and breast infections. Journal of Infectious Diseases 183:206–212. Laniece I, Ciss M, Desclaux A, Diop K, Mbodj F, Ndiaye B, Sylla O, Delaporte E, Ndoye I. 2003. Adherence to HAART and its principle determinants in a cohort of Senegalese adults. AIDS 17:S103–S108. Nierengarten MB. 2003. Haiti’s HIV equity initiative, Lancet 3:266. Ometto L, Zanchetta M, Mainardi M, DeSalvo GL, Garcia-Rodriguez MC, Chieco-Bianchi L, Gray L, Newell ML, DeRossi A. 2000. Co-receptor usage of HIV-1 primary isolates, viral burden, and CCR5 genotype in mother-to-child HIV-1 transmission. AIDS 14: 1721–1729. Orrell C, Bangsberg DR, Badri M, Wood R. 2003. Adherence is not a barrier to successful antiretroviral therapy in South Africa. AIDS 17:1369–1375. Quinn TC, Wawer MJ, Sewankambo N, Serwadda D, Li C, Wabwire-Mangen F, Meehan MO, Lutalo T, Gray RH. 2000. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. New England Journal of Medicine 342:921–929.

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