5

PEPFAR’s Treatment Category

Summary of Key Findings

  • PEPFAR narrowly defines treatment as antiretroviral therapy (ART) and includes in this category only activities that directly support the provision of ART. PEPFAR has supported rapid expansion of the availability of ART to people living with HIV infection. By September 2006, PEPFAR was supporting ART for 822,000 women, men, and children in the focus countries.

  • PEPFAR is supporting ART within national treatment plans that are consistent with the World Health Organization’s guidelines for ART in resource-constrained settings. However, PEPFAR has not always been able to support national plans for purchases of antiretroviral medications.

  • PEPFAR is supporting ART programs in addressing the critical issue of adherence to therapy, and limited observational studies show that adherence in the focus countries compares favorably with that observed earlier in Western Europe and North America. PEPFAR is also supporting sentinel surveillance to monitor for resistance.

  • Among people receiving ART supported by PEPFAR, 61 percent are women and 9 percent children. PEPFAR’s Pediatric Treatment Initiative is attempting to address real and perceived barriers to pediatric treatment.

  • The observed rapid clinical response to ART has, in a number of the programs the Committee visited, reportedly resulted in increased interest by people in obtaining HIV testing, followed by ART when indicated.

  • PEPFAR is supporting programs in addressing the rapid resurgence of tuberculosis in both child and adult populations throughout sub-Saharan Africa. This resurgence has been fueled by HIV-associated immunodeficiency. In some communities, as many as 80 percent of people newly diagnosed with active tuberculosis have concomitant HIV infection.

  • While the success of PEPFAR-supported roll-out of ART has been gratifying, many obstacles remain and will require continued concerted attention at all levels. These obstacles include shortages of trained medical and paramedical personnel, insufficient quantities of antiretroviral medications, difficulties in delivering ART in many rural districts, weak supply chains for antiretroviral medications and other commodities, and inadequate laboratory capacity.



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PEPFAR Implementation: Progress and Promise 5 PEPFAR’s Treatment Category Summary of Key Findings PEPFAR narrowly defines treatment as antiretroviral therapy (ART) and includes in this category only activities that directly support the provision of ART. PEPFAR has supported rapid expansion of the availability of ART to people living with HIV infection. By September 2006, PEPFAR was supporting ART for 822,000 women, men, and children in the focus countries. PEPFAR is supporting ART within national treatment plans that are consistent with the World Health Organization’s guidelines for ART in resource-constrained settings. However, PEPFAR has not always been able to support national plans for purchases of antiretroviral medications. PEPFAR is supporting ART programs in addressing the critical issue of adherence to therapy, and limited observational studies show that adherence in the focus countries compares favorably with that observed earlier in Western Europe and North America. PEPFAR is also supporting sentinel surveillance to monitor for resistance. Among people receiving ART supported by PEPFAR, 61 percent are women and 9 percent children. PEPFAR’s Pediatric Treatment Initiative is attempting to address real and perceived barriers to pediatric treatment. The observed rapid clinical response to ART has, in a number of the programs the Committee visited, reportedly resulted in increased interest by people in obtaining HIV testing, followed by ART when indicated. PEPFAR is supporting programs in addressing the rapid resurgence of tuberculosis in both child and adult populations throughout sub-Saharan Africa. This resurgence has been fueled by HIV-associated immunodeficiency. In some communities, as many as 80 percent of people newly diagnosed with active tuberculosis have concomitant HIV infection. While the success of PEPFAR-supported roll-out of ART has been gratifying, many obstacles remain and will require continued concerted attention at all levels. These obstacles include shortages of trained medical and paramedical personnel, insufficient quantities of antiretroviral medications, difficulties in delivering ART in many rural districts, weak supply chains for antiretroviral medications and other commodities, and inadequate laboratory capacity.

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PEPFAR Implementation: Progress and Promise Recommendations Discussed in This Chapter Recommendation 5-1: The U.S. Global AIDS Coordinator should ensure that adequate medications are available to place 2 million people on sustained antiretroviral therapy to achieve PEPFAR’s stated 5-year treatment target. To achieve this target, the Coordinator should also ensure that adequate linkages are established among prevention, treatment, and care programs and rapidly expand the availability of antiretroviral therapy to both children and adults. Recommendation 5-2: To support countries’ ownership of their responses to their HIV/AIDS epidemics, the U.S. Global AIDS Initiative should maintain its commitment to harmonization and participate fully in the development of harmonized procedures. To this end, the U.S. Global AIDS Coordinator should work to support World Health Organization (WHO) prequalification as the accepted global standard for assuring the quality of generic medications. Specifically, the Coordinator should provide an analysis of WHO prequalification that determines whether it can adequately assure the quality of generic antiretroviral medications for purchase under PEPFAR. If the analysis shows that WHO prequalification needs strengthening to provide a sufficient guarantee of quality for PEPFAR, the U.S. Global AIDS Initiative should work with other donors to support strengthening of the process, and work to transition from U.S. Food and Drug Administration approval to WHO prequalification as rapidly as feasible.

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PEPFAR Implementation: Progress and Promise 5 PEPFAR’s Treatment Category CATEGORY, TARGET, AND RESULTS The Treatment Category The President’s Emergency Plan for AIDS Relief (PEPFAR) defines treatment narrowly as antiretroviral therapy (ART), and for purposes of budgeting and performance targets, ART is categorized separately from all other related care services. PEPFAR’s treatment category includes only activities that directly or indirectly support the provision of ART, including procurement of antiretroviral medications (ARVs), essential laboratory monitoring, equipment and training of personnel for the provision of ART and laboratory monitoring, development of adequate laboratory infrastructure, and support for supply chain management systems for ARVs and related commodities. For purposes of budgeting, complying with budget allocations, and counting progress toward targets, PEPFAR categorizes other services in the care continuum under its other categories. For example, PEPFAR includes most treatment for the prevention of mother-to-child transmission in its prevention category1 (see Chapter 4), and therapy for coinfections such as tuberculosis and malaria, as well as nonclinical care, in its care category (see Chapter 6). The consequences of this definition and categorization are discussed further in this chapter and in Chapter 8 in the section 1 Only services in which the mother is receiving ART (termed prevention of mother-to-child transmission plus) are included under the treatment category. Provision of ARVs solely to prevent transmission of HIV from mother to infant is included under the prevention category.

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PEPFAR Implementation: Progress and Promise on integration. Funding for PEPFAR-supported treatment activities includes ART and laboratory infrastructure and has roughly tripled from 2004 to 2006 (see Chapter 3). Target PEPFAR’s 5-year treatment target, as described in the program’s authorizing legislation, is to support the focus countries in providing ART to 2 million people. This target represents a count of the number of people receiving ART that is supported directly or indirectly by PEPFAR, and is a globally accepted and widely used early indicator of program implementation. This count provides limited information and does not indicate how well people receiving ART are doing or how the availability of ART affects a country and its HIV/AIDS epidemic. Challenges to obtaining this count are discussed in this chapter; measures of treatment success are addressed in the discussion of impact evaluation in Chapter 8. Similar to other donor programs, PEPFAR has had to balance its need to be accountable to the U.S. Congress with its accountability to the people of the focus countries within the framework of harmonization. The program has faced the dilemma of needing information that is not readily or routinely available from clinics or ministries of health, and has imposed unprecedented reporting requirements on both urban and rural treatment centers that often have severe shortages of personnel at all levels. At the global level, PEPFAR requirements for monitoring the number of people receiving ART are reasonably well harmonized with the recommended indicators of the World Health Organization (WHO) and their definitions. PEPFAR generally supports the WHO-recommended tools, including patient records and ART registers, for monitoring and evaluating ART. Information systems in the focus countries are generally in need of substantial development and strengthening, and PEPFAR is supporting improved HIV-related information systems from the level of rural clinics to that of ministries of health. Although PEPFAR is supporting some innovative information system projects, paper-based records and limited computer access are still the prevailing norm in the focus countries. Provision of even basic monitoring data therefore remains a challenge in most of the countries. PEPFAR has had to work closely with host countries and other donors to determine which people on ART it can fairly count as having received its support. Host countries are understandably sensitive to donors appearing to take credit for the country’s accomplishments, and it is important at both the country and global levels to avoid double-counting if an accurate accounting of the proportion of eligible patients who are receiving ART is to be obtained. Initially, PEPFAR did create ill will in a few focus countries

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PEPFAR Implementation: Progress and Promise by appearing to take credit for the country’s accomplishments. The program has since endeavored to be clear in its reporting that it is claiming credit for having provided some measure of support for a person’s ART rather than exclusively and directly providing the treatment. PEPFAR has also been working closely with the Global Fund, as well as with each focus country, to avoid overlaps in attribution. The Committee encourages PEPFAR to continue in this vein, participating in joint attribution and enhancing coordination among all donors and with the host countries. PEPFAR’s strategy for achieving its treatment target includes Rapidly scaling up treatment availability using a network model. Building capacity for long-term sustainability of quality HIV/AIDS treatment programs. Collecting strategic information with which to monitor and evaluate progress and ensure compliance with PEPFAR and national policies and strategies (OGAC, 2004). To achieve the treatment target, PEPFAR’s approach to implementation is to assist countries in the “development of appropriate treatment protocols and policies to ensure safe and effective treatment services, drug supply, and equitable distribution of health resources,” and to work with existing clinical programs and develop additional infrastructure, staff, and technical capacity, as needed, to provide “long-term, widespread, high-quality, safe, and essential services to the maximum number of people in need” (OGAC, 2004, p. 11). Results According to the Office of the U.S. Global AIDS Coordinator (OGAC), 822,000 people were receiving PEPFAR-supported ART in the focus countries by the end of September 2006, as compared with 155,000 in fiscal year 2004. Approximately 61 percent of this total were women and 9 percent children (OGAC, 2007). These proportions for women and children compare favorably with global averages (WHO and UNAIDS, 2006; UNAIDS, 2006), but may need to increase to reflect actual needs. Recent data indicate that women are disproportionately represented among people living with HIV/AIDS and among the newly infected, particularly in resource-constrained countries, and that children accounted for more than 13 percent of AIDS deaths in 2005 (GAA, 2006; UNAIDS, 2006; WHO and UNAIDS, 2006). PEPFAR has also supported training in the provision of ART for more than 100,000 health workers and training for more than 17,000 laboratory personnel, as well as significant expansion in the number of ART delivery

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PEPFAR Implementation: Progress and Promise TABLE 5-1 PEPFAR Treatment Results by Fiscal Year, 2004–2006 Subcategory Fiscal Year 2004 Fiscal Year 2005 Fiscal Year 2006 ART       Number of people receiving ART supported by PEPFAR 155,000 401,000 822,000 Number of ART sites supported by PEPFAR* 300 800 1,912 Number of health workers trained with PEPFAR support in the provision of treatment according to national and/or international standards 12,200 36,500 52,000 Laboratory Infrastructure       Number of laboratories supported by PEPFAR with the capacity to perform (1) HIV tests and (2) CD4 tests and/or lymphocyte tests Not available 900 958 Number of people trained with PEPFAR support in the provision of laboratory-related services 3,100 5,700 8,300 *Includes both ART and prevention of mother-to-child transmission plus sites. SOURCE: OGAC, 2005a, 2006a, 2007. sites and laboratories that can provide the needed support (see Table 5-1). In addition, PEPFAR has provided funding and technical assistance to strengthen laboratory infrastructure and national procurement and supply chain systems. REVIEW OF PROGRESS TO DATE Support for National Programs to Follow the World Health Organization’s Guidelines Nearly all of the focus countries have developed treatment targets and published plans for scaling up ART to meet those targets. While each focus country has a program tailored to its particular circumstances, all the programs are based on WHO’s recommendations for delivery of ART in resource-limited settings. PEPFAR has both supported the development of national treatment plans and endeavored to program its activities within the parameters of these national plans and the WHO guidelines. Although concerns have been expressed by several focus countries about the lack of consultation with local authorities during the initial development of PEPFAR treatment programs, and there has been widespread frustration with PEPFAR limits on the procurement of ARVs, PEPFAR’s support for ART appears to be generally consistent with national plans in the focus countries.

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PEPFAR Implementation: Progress and Promise The 2003 revision of the WHO guidelines is intended to support and facilitate the proper management and scale-up of ART by promoting a public health approach that includes the following elements: Scaling up ART, with the objective of universal access. Standardizing and simplifying antiretroviral regimens to support efficient implementation of treatment programs in resource-limited settings. Ensuring a scientific evidence base for ART programs so as to avoid the use of subpar treatment protocols that could compromise the treatment outcomes of individual patients and create the potential for the emergence of widespread drug resistance. The WHO guidelines emphasize consideration of the challenges to ART programs posed by working in resource-limited settings, including human resources, health system infrastructure, and socioeconomic conditions. The guidelines include recommendations for when to start ART and with which antiretroviral regimens, reasons for changing the treatment, and what regimens to use if such change is necessary. They also address how treatment should be monitored, with specific reference to the side effects of ART, and make recommendations for particular patient subgroups (WHO, 2006a). PEPFAR recommends that ART include the following elements (OGAC, 2005a): Uninterrupted supply of appropriate ARVs General clinical support for patients, including other medications and diagnostics Training and support for health care providers Infrastructure (clinics, counseling rooms, laboratories, distribution and logistics systems) Monitoring and reporting systems Appropriate referrals At the same time, PEPFAR officials have recognized that each nation’s needs are unique, and that each nation is therefore in the best position to tailor its plans to fit its particular circumstances. Thus the approach to ART varies considerably among the focus countries. One important factor in this variation is differences in the prevalence of HIV infection; the national HIV prevalence varies more than 20-fold among the 15 focus countries (see Chapter 2). A second salient factor is wide variation in the health care systems already in place. Several countries have well-established medical, nursing, and paramedical education programs, while a few have neither medical nor nursing schools. Access to basic medical services is also highly variable, although most of the focus countries have developed plans for

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PEPFAR Implementation: Progress and Promise improving access to medical care as an essential element of national policy. In those nations with strong publicly financed health systems, government-supported hospitals were generally able to assume major responsibilities for the initial roll-out of ART, while in others, the process was more dependent on nongovernmental organizations, often faith-based organizations, which provide the majority of health care services in many of the focus countries (GHC, 2005). Integration of those organizations into the national system also varies considerably from country to country. Diagnosis and Evaluation As seen among the ART programs the Committee visited, patients diagnosed as HIV-positive are usually scheduled to receive clinical and laboratory evaluation by a health care worker to determine whether they require initiation of ART. Clinical evaluation is uniformly based on the WHO clinical criteria; availability of appropriate laboratory evaluation is variable, however. Eligibility for ART Eligibility for ART is determined by country treatment guidelines, which are generally based on the WHO 2006 Recommendations for Antiretroviral Therapy in Adults and Adolescents in Resource-Limited Settings. As recommended by WHO, focus country guidelines utilize WHO clinical staging and, when available, CD4 cell count to determine eligibility for ART. Patients with severe HIV-associated clinical disease (WHO clinical stage 4) and those with WHO clinical stage 3 disease with associated tuberculosis or severe bacterial infections are eligible for ART, as are all patients with CD4 counts below 200 cells/mm3, regardless of WHO clinical stage. In all focus countries visited, the great majority of patients receiving ART have WHO clinical stage 4 disease or clinical stage 3 complicated by major opportunistic infections (usually tuberculosis or severe bacterial disease) or unexplained severe malnutrition. Eligibility criteria for infants and young children are different and are discussed in the section below on treatment of HIV/AIDS in children. Preparation for ART Most of the focus countries have developed readiness programs to enhance adherence of eligible patients to ART. Although these programs vary, many are based on the “buddy” concept, by which each patient is required to bring a friend (a family member if possible) to one or more meetings with an adherence counselor prior to the initiation of ART. An essential part of such programs is discussing with the patient and buddy what side

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PEPFAR Implementation: Progress and Promise effects may be experienced with ART, which of those side effects may be self-limited, and which dictate prompt discontinuation of ART (Nachega et al., 2006). Overall, this approach appears to be working well, but is difficult to accomplish in instances in which access to ART is limited to centers at considerable distances from where patients live. ART Initiation Following diagnosis, evaluation, and readiness training, the patient begins ART, usually involving one of the three-drug, first-line regimens recommended by WHO (Gilks et al., 2006). None of the WHO-recommended first-line regimens for adults require refrigeration, and all are now produced in generic form by one or more pharmaceutical companies (FDA, 2006). Although the ART guidelines in all the focus countries are based on the ARV regimens recommended by WHO, other three-drug regimens may be used at the discretion of the supervising physician in some tertiary treatment sites. Follow-up of Patients Receiving ART Follow-up is arranged at intervals recommended by WHO and is often reinforced by providing ARVs sufficient to last until the next essential follow-up visit. Most programs visited by the Committee use additional techniques to support adherence during the first few weeks of ART. In some sites, weekly visits to patients’ dwellings by an outreach worker are arranged for 4 to 6 weeks after initiation of treatment. In other cases, assigned “buddies,” who have received adherence training along with the patients, provide similar support. Although not universal, such techniques for enhancing adherence are employed in the majority of treatment sites. At follow-up visits, the patient is asked about side effects and difficulties with adherence. Continued close adherence to the prescribed regimen is emphasized by the health care worker. If stated adherence is good but improved strength and well-being have not been achieved, potential underlying problems (for example, inadequate caloric intake or concomitant tuberculosis infection, both discussed below) are investigated, and appropriate adjuvant therapy, insofar as possible, is arranged. Adherence to Therapy Based on limited observational studies, short-term adherence to ARV regimens in the focus countries appears to be as good as or better than that observed earlier in Western Europe and North America (Farmer et al., 2001; Mills et al., 2006; Nachega et al., 2006; Stringer et al., 2006). As PEPFAR progresses with rapid scale-up and outreach to previously

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PEPFAR Implementation: Progress and Promise neglected communities, a continued strong emphasis on adherence to therapy is essential. Substantial lack of adherence would not only result in treatment failure, but also would contribute to widespread resistance of the virus to therapy. Failure to adhere would thus not only be harmful to individual patients, but would also necessitate even greater investments of human and financial resources to overcome the resulting resistance problems (IOM, 2005). PEPFAR does not routinely report on adherence as part of its ongoing program monitoring. However, some relevant data have been obtained from independent observational cohort studies in the focus countries, several of which have reported encouraging levels of adherence (Spacek et al., 2005; Calmy et al., 2006; Stringer et al., 2006; Wools-Kaloustian et al., 2006). Continued support for such evaluations will be critical for determining program effectiveness. Relatively short breaks in adherence (2 to 4 weeks) or repeated breaks for shorter intervals can result in viral resistance to two of the three components of recommended first-line ARV regimens. And a single resistance mutation (K103N) to the non-nucleoside component (either nevirapine or efavirenz) renders the virus resistant to the entire class of non-nucleoside reverse transcriptase inhibitor drugs. The consequence of such resistance patterns is that patients require drugs of a different class—protease inhibitors (Hirsch et al., 2003). The protease inhibitors not only cause more frequent undesirable side effects, but are several-fold more expensive than the WHO-recommended first-line drugs. Few protease inhibitors are now available as generics, and the complexity of their production may cause them to remain relatively expensive for the indefinite future. Stigma Reduction Clinicians visited by the Committee reported that the excellent clinical response to ART has in many areas led people in the surrounding communities to be more receptive to obtaining HIV testing and, when appropriate, therapy. This same phenomenon has been reported in other settings as well, including South Africa and Haiti (Castro and Farmer, 2005; Nachega et al., 2006). It appears that a benefit of the response to therapy may be a reduction in stigma associated with HIV testing. Recognition that people receiving effective ART rapidly gain weight and strength and do not suffer from recurrent opportunistic infections reportedly has greatly enhanced the perceived value of the PEPFAR program in the focus countries. Resistance Monitoring A previous Institute of Medicine report concluded that general screening for resistance to ARVs was not recommended because the prevalence

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PEPFAR Implementation: Progress and Promise of resistance in HIV-infected individuals not previously exposed to ART was expected to be very low. However, the report did recommend that coordinated, systematic testing for resistance to ARVs should be conducted among a subset of patients failing treatment (IOM, 2005). The results of testing such patients would aid in determining whether and when routine population-based resistance testing might prove effective. PEPFAR provides support for resistance monitoring; selected examples of such activities in are presented in Box 5-1. Women as a Proportion of Those Receiving PEPFAR-Supported ART To ensure that women benefit from equitable access to ARVs and other HIV-related treatments, PEPFAR is working to support treatment programs in addressing the many barriers faced disproportionately by women and girls in accessing health care. Approaches to this end include efforts to shorten waiting times, to provide appropriate appointment schedules and increased numbers of female health workers, and to ensure privacy and confidentiality. These efforts appear to be yielding positive results, and OGAC reported that 61 percent of those receiving PEPFAR-supported ART are women and girls. BOX 5-1 Selected Examples of PEPFAR-Supported Resistance Monitoring Activities In Mozambique, PEPFAR is supporting a combined tuberculosis/HIV prevalence and drug resistance study. In Namibia, PEPFAR is providing technical assistance and funding for resistance testing for surveillance purposes, and is planning to gradually build local capacity to perform resistance testing in the country over the next 3 to 4 years. In Rwanda, PEPFAR is providing technical assistance and training to laboratory professionals in molecular virology techniques, as well as the development of a quality assurance/quality control program for the HIV drug resistance surveillance program. In South Africa, PEPFAR is supporting surveillance to detect resistant virus in pregnant women. In Vietnam, PEPFAR supported the establishment of a surveillance system for ARV resistance focused on strengthening national collaboration and partnerships for ARV resistance monitoring and assisting in the development of national guidelines for such efforts. SOURCE: OGAC, 2005b.

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PEPFAR Implementation: Progress and Promise to pregnant and lactating women living with HIV/AIDS (OGAC, 2006b). Both the 2005 and 2006 Country Operational Plans describe ongoing and planned nutritional support activities, including collaborations with other, non-PEPFAR U.S. government food funding sources (see Box 5-3). Need to Harmonize PEPFAR’s ARV Purchase Requirements with National Plans PEPFAR has a stated goal of supporting rapid scale-up of ART and is “committed to funding the purchase of the lowest-cost ARVs from any source, regardless of origin, whether copies, generic, or branded, as long as those drugs are proven safe, effective, and of high quality, and their purchase is consistent with international law” (OGAC, 2006a, p. 47). However, PEPFAR’s quality assurance requirement has prevented the program from being fully harmonized with the ART programs of the focus countries and thus has limited PEPFAR’s ability to support the purchase of the focus countries’ first-choice ARVs. When PEPFAR was initiated, the U.S. Global AIDS Coordinator determined that FDA approval would be the standard for assuring the quality of PEPFAR-provided ARVs. This standard differs from that of other donors—the Global Fund, the World Bank, and the agencies of the United Nations—as well as that of national HIV/AIDS programs, including those BOX 5-3 Selected Examples of PEPFAR-Supported Nutritional Support Activities In Kenya, PEPFAR is supporting a demonstration/training farm that fills food prescriptions for eligible patients. The initiative is a public–private partnership between U.S. and Kenyan organizations that involves several comprehensive HIV care clinics in urban and rural centers in western Kenya with close to 4,000 patients on ART. In Ethiopia, PEPFAR coordinates with the U.S. Department of Agriculture food aid program. Funding is managed by USAID and is used to complement care programs for orphans and vulnerable children and people living with HIV/AIDS. In Haiti, PEPFAR coordinates with other U.S. food assistance programs for the nutritional support of orphans. In Mozambique, PEPFAR is supporting HIV-specific nutritional training for improved immune system response in people who are HIV-positive, as well as training on home garden food production specifically for resource-poor households to improve food security for those on ART.

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PEPFAR Implementation: Progress and Promise in the focus countries, all of which rely on the WHO Prequalification of Medicines Project to assure the quality of ARVs for purchase under their programs (see Box 5-4). The majority of the focus countries have chosen to use generic versions of ARVs in their national programs, and a number of generic ARVs have been prequalified by WHO. When PEPFAR started, however, no generic ARVs had FDA approval, and thus the focus countries were unable to use PEPFAR funds to support their purchase—particularly first-line ARVs and medications that combine two or three ARVs into one pill, known as fixed-dose combinations. Consequently, focus countries whose plans called for generic ARVs made arrangements, whenever possible, to use other sources of funding to purchase the desired generics, and used PEPFAR funds for the purchase of ARVs for which no generic version was available—primarily second-line and pediatric formulations. Subsequently, the Coordinator supported an expedited FDA review process for generic ARVs (DHHS, 2004; DHHS et al., 2006), and since December 2004 when the first such drug was approved, more than 30 generic versions of first-line ARVs have been FDA-approved for purchase by PEPFAR, including several of the two- and three-drug fixed-dosed combinations suitable for adults as well as several pediatric formulations (FDA, 2006; OGAC, 2007). However, some of the fixed-dose combination ARVs most desired by the focus countries were approved by the FDA only within the past year (FDA, 2006). Moreover, because some focus countries rely on WHO prequalification, they require it in addition to FDA approval. To partly address this problem, the FDA has agreed to share its drug files BOX 5-4 The WHO Prequalification of Medicines Project The WHO Prequalification of Medicines Project started in 2001 with the mission of facilitating access to medicines that meet unified standards of quality, safety, and efficacy for HIV/AIDS, malaria, and tuberculosis. The United Nations and the World Bank support WHO prequalification as a key contribution to the United Nations’ priority goal of addressing widespread diseases in countries with limited access to quality medicines. Prequalification evaluates products submitted by companies around the world according to WHO standards of quality, safety, and efficacy. When products are found to meet those standards, they are added to a list accessible to United Nations organizations, countries, and procurement agencies. SOURCE: WHO, 2006b.

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PEPFAR Implementation: Progress and Promise with WHO to expedite the drugs’ addition to WHO’s list of prequalified medicines. Nonetheless, PEPFAR’s requirement for FDA approval rather than the globally accepted WHO prequalification was the most often-cited impediment to coordination and harmonization during the Committee’s visits to the focus countries, and continues to limit harmonization and rapid availability of PEPFAR-supported first-line ARVs. OGAC reported that only 10 percent of all PEPFAR-supported ARV purchases were for FDA-approved generics in fiscal year 2005, increasing to 27 percent in 2006 (OGAC, 2006f, 2007). Across the focus countries in 2006, the proportion of PEPFAR-supported ARV purchases for FDA-approved generics ranged from 0 to 87 percent (OGAC, 2007). A previous IOM Committee strongly endorsed “a rigorous, standardized international mechanism to support national quality assurance programs for antiretroviral drugs” (IOM, 2005, p. 8). The Coordinator has not yet determined whether WHO prequalification provides such a mechanism and can adequately assure the quality of generic ARVs for purchase under PEPFAR. U.S. participation in such a mechanism would improve both coordination at the global level and harmonization at the country level, and facilitate more rapid availability of ARVs. Recommendation 5-2: To support countries’ ownership of their responses to their HIV/AIDS epidemics, the U.S. Global AIDS Initiative should maintain its commitment to harmonization and participate fully in the development of harmonized procedures. To this end, the U.S. Global AIDS Coordinator should work to support World Health Organization (WHO) prequalification as the accepted global standard for assuring the quality of generic medications. Specifically, the Coordinator should provide an analysis of WHO prequalification that determines whether it can adequately assure the quality of generic antiretroviral medications for purchase under PEPFAR. If the analysis shows that WHO prequalification needs strengthening to provide a sufficient guarantee of quality for PEPFAR, the U.S. Global AIDS Initiative should work with other donors to support strengthening of the process, and work to transition from U.S. Food and Drug Administration approval to WHO prequalification as rapidly as feasible. Human Resource Limitations Although PEPFAR has supported the training of large numbers of health and laboratory workers, the human resource limitations facing treatment facilities are increasingly felt as treatment expands. A full discussion of human resource issues and the Committee’s related recommendation can be found in Chapter 8.

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PEPFAR Implementation: Progress and Promise Limited Laboratory Services The focus countries have generally accepted the WHO guidelines on minimal basic laboratory requirements for initiating and monitoring ART (Gilks et al., 2006; WHO, 2006d). All focus countries have at least one functioning laboratory that can provide these essential services in a tertiary site. However, these services are not uniformly available in secondary treatment sites (provincial medical centers), are seldom available in primary sites (district medical centers), and are generally lacking in outlying rural areas in every focus country. This situation further limits the achievement of PEPFAR’s treatment goals. PEPFAR’s stated goal for laboratory activities and infrastructure is to establish and support national quality-assured networks of tiered laboratory services that provide clear lines of authority and organization for the development of national laboratory policies, quality assurance programs, and standardized training and testing. PEPFAR’s approach is to promote the early establishment and regular reinforcement of local referral networks both within and among implementing partners. According to 2007 PEPFAR planning direction (OGAC, 2006e), the laboratory components of Country Operational Plans should emphasize implementing partner efforts to Standardize laboratory best practices and provide related training. Provide for uniform quality assurance measures among laboratories. Provide for common equipment and supportive maintenance testing. Support a unified approach to procurement and distribution of laboratory commodities. A previous Institute of Medicine committee recommended that donors and program managers plan and budget for laboratory activities that can foster more accurate and effective HIV diagnosis and management, using WHO’s 2003 guidelines as the initial template (IOM, 2005). PEPFAR’s Adult Treatment Technical Working Group advised that the focus of PEPFAR-funded laboratory services should be to support ART, and that funding and activities for laboratory services should therefore be related primarily to supporting patients at sites where they are treated. In addition, the working group advised that laboratory services should demonstrate the adequacy of physical infrastructure, trained staff, equipment, supplies, reagents, and quality assurance for diagnosing and treating HIV and opportunistic infections and evaluating drug toxicities. The working group recommended that PEPFAR promote and support a tiered, public health–focused laboratory network as part of the national laboratory strategy (OGAC, 2006h).

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PEPFAR Implementation: Progress and Promise Strengthening the Supply Chain Both the Leadership Act and the PEPFAR strategy recognized the life-threatening consequences of any interruption to the supply of ARVs, as well as the need to avoid waste and to address such issues as diversion and counterfeiting. During the Committee’s visits, the many challenges to securing a reliable supply of ARVs and other HIV/AIDS commodities were evident across all of the focus countries, as were considerable efforts to overcome those challenges, many supported by PEPFAR. Officials in most of the countries visited reported that their ability to predict and maintain supplies had improved, often with assistance from PEPFAR. Some reported past examples of dangerous stock-outs, and all cited the difficulty of obtaining certain drugs or formulations and ongoing concern about maintaining adequate supplies. PEPFAR has supported the strengthening of supply chain systems and initially planned to support a central supply chain management system (OGAC, 2004, 2005b, 2006b). In late 2005, PEPFAR established the Partnership for Supply Chain Management, a consortium of 17 companies (including those that had previously been providing procurement and logistical support in the focus countries) that is managed under a contract with the U.S. Agency for International Development (USAID) (see Box 5-5). The stated goal of the partnership is to support the provision of an uninterrupted supply of HIV/AIDS commodities flowing through an accountable system. OGAC funds the central operations of the Partnership for Supply Chain Management from its budget ($15 million for the first year, which includes funds to provide technical assistance to the focus countries in planning for their supply chain needs). The rest of the partnership’s funding comes from country budgets and depends on which services the Country Teams opt to purchase. OGAC reported that at the end of 2006, funding from focus country prevention, treatment, and care budgets totaled $94 million (OGAC, 2007). The contract for the Partnership for Supply Chain Management began in October 2005—too late for the 2006 planning cycle; thus its activities would, at the earliest, be part of the 2007 Country Operational Plans. However, Partnership for Supply Chain Management officials told the Committee that all 15 focus countries had opted to work with the partnership to some degree, ranging from procurement of a limited range of ARVs or laboratory supplies to procurement of almost all PEPFAR-funded commodities. Further, officials of the partnership have made initial visits to all focus countries and opened 10 country offices (OGAC, 2007). Also, as part of its effort to collaborate with other global procurement and distribution systems, the Partnership for Supply Chain Management is serving as the technical secretariat of a World Bank, Global Fund, and PEPFAR working group for joint procurement planning.

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PEPFAR Implementation: Progress and Promise BOX 5-5 Institutions Comprising the Partnership for Supply Chain Management Affordable Medicines for Africa (AMFA)—Johannesburg, South Africa AMFA Foundation—St. Charles, Illinois, USA Booz Allen Hamilton—McLean, Virginia, USA Crown Agents Consultancy, Inc.—Washington, DC, USA Fuel Logistics Group (Pty) Ltd.—Sandton, South Africa International Dispensary Association—Amsterdam, Nether lands JSI Research & Training Institute, Inc.—Boston, Massachusetts, USA Management Sciences for Health, Inc.—Boston, Massachusetts, USA The Manoff Group, Inc.—Washington, DC, USA MAP Inter national—Brunswick, Georgia, USA Net1 UEPS Technologies, Inc.—Rosebank, South Africa The North-West University—Potchefstroom, South Africa Northrop Grumman Information Technology—McLean, Virginia, USA Program for Appropriate Technology in Health (PATH)—Seattle, Washington, USA UPS Supply Chain SolutionsSM—Atlanta, Georgia, USA Voxiva, Inc.—Washington, DC, USA 3i Infotech, Inc.—Edison, New Jersey, USA SOURCE: OGAC, 2007. The Partnership for Supply Chain Management was established too recently for the Committee to be able to judge its performance fairly. However, the Committee shares a number of concerns that have been raised by various stakeholders and urges OGAC to monitor the partnership’s implementation carefully to ensure that any problems that develop are addressed immediately. One concern relates to PEPFAR’s requirement for FDA approval of medications purchased under the program, discussed elsewhere in this chapter. The Partnership for Supply Chain Management is subject to this requirement, which will likely limit its usefulness to many of the focus countries, its efficiency, and its ability to offer medications at the lowest possible cost. The Committee also shares the concern expressed by stakeholders such as the advocacy group Health GAP and the Ecumenical Pharmaceutical Network—a broadly based international organization that includes many of the faith-based organizations supported by PEPFAR—that the Partnership for Supply Chain Management could undermine country capacity by creating a parallel system, and thus destabilizing rather than strengthening existing systems; having a brain drain effect by taking personnel from

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PEPFAR Implementation: Progress and Promise existing systems to work for the partnership; lacking adequate transparency in sharing plans for an exit strategy; and lacking long-term plans for sustainability (Health GAP, 2005; EPN, 2004, 2006). The Partnership for Supply Chain Management has articulated plans to address each of these concerns (Partnership for Supply Chain Management, 2006; OGAC, 2007), but it is too soon to determine how effectively it is carrying out these plans. The Committee believes it is critical that the Partnership for Supply Chain Management not create a parallel, U.S.-controlled system, but rather strengthen existing local, national, and regional systems, as well as facilitate technology transfer and regional harmonization to ensure sustainability well beyond the life of PEPFAR. To this end, the partnership requires the ability to respond genuinely to local priorities and needs rather than imposing a uniform solution. Evaluating the effectiveness of the partnership in these terms would encourage it to operate in this manner (see Chapter 8). CONCLUSION PEPFAR has supported a rapid and substantial expansion of the availability of ART to men, women, and children in the focus countries and has provided support to strengthen the associated workforce, laboratory, procurement, and supply chain systems. The primary early accomplishment of the U.S. Global AIDS Initiative has been to demonstrate that HIV/AIDS services, particularly treatment, can be rapidly scaled up in resource-constrained and otherwise severely challenged environments such as those existing in the focus countries—something many had doubted could be done (UNAIDS, 2001; WHO, 2003a,b; IOM, 2005). But the impact of the expanded availability of ART on the countries’ epidemics remains to be demonstrated, and further expansion of treatment and strengthening of related systems are needed. Meeting these needs will continue to be challenging, and continued support from the U.S. Global AIDS Initiative, with the improvements suggested by the Committee, will be necessary to assist the focus countries in sustaining and expanding the gains made against their HIV/AIDS epidemics. REFERENCES Aaron, L., D. Saadoun, I. Calatroni, O. Launay, N. Memain, V. Vincent, G. Marchal, B. Dupont, O. Bouchaud, D. Valeyre, and O. Lortholary. 2004. Tuberculosis in HIV-infected patients: A comprehensive review. Clinical Microbiology and Infection 10:388–398. Calmy, A., L. Pinoges, E. Szumilin, R. Zachariah, and N. L. Ford. 2006. Generic fixed-dose combination antiretroviral treatment in resource-poor settings: Multicentric observational cohort. AIDS 20(8):1163–1169. Castro, A., and P. Farmer. 2005. Understanding and addressing AIDS-related stigma: From anthropological theory to clinical practice in Haiti. American Journal of Public Health 95:53–59.

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PEPFAR Implementation: Progress and Promise DHHS (Department of Health and Human Services), FDA (U.S. Food and Drug Administration), and CDER (Center for Drug Evaluation and Research). 2004. Guidance for industry: Fixed dose combination and co-packaged drug products for treatment of HIV. Washington, DC: DHHS. DHHS, FDA, and CDER. 2006. Guidance for industry: Fixed dose combinations, co-packaged drug products, and single-entity versions of previously approved antiretrovirals for the treatment of HIV. Washington, DC: DHHS. EPN (Ecumenical Pharmaceutical Network). 2004. A statement of the Ecumenical Pharmaceutical Network (EPN) on the President’s Emergency Plan for AIDS Relief (PEPFAR). http://www.healthgap.org/press_releases/04/100704_EPN_PEPFAR_statement.html (accessed October 2, 2006). EPN. 2006. Annual report, 2005. Kenya: EPN Publications. Elliott, A. M., B. Halwiindr, R. J. Hayes, N. Luo, G. Tembo, L. Machiels, C. Bem, G. Steenbergen, J. O. Pobee, and P. P. Nunn. 1993. The impact of human immunodeficiency virus on presentation and diagnosis of tuberculosis in a cohort study in Zambia. The Journal of Tropical Medicine and Hygiene 96:1–11. Farmer, P., F. Leandre, J. Mukherjee, R. Gupta, L. Tarter, and J. Y. Kim. 2001. Community-based treatment of advanced HIV disease: Introducing DOT-HAART (directly observed therapy with highly active antiretroviral therapy). Bulletin of the World Health Organization 79:1145–1151. Geneva, Switzerland: World Health Organization. FDA (Food and Drug Administration). 2006. President’s Emergency Plan for AIDS Relief approved and tentatively approved antiretrovirals in association with the President’s Emergency Plan. http://www.fda.gov/oia/pepfar.htm (accessed October 26, 2006). GAA (Global AIDS Alliance). 2006. Children left out: Global community failing to scale up the prevention and treatment of pediatric HIV/AIDS. Washington, DC: GAA. GHC (Global Health Council). 2005. Faith in action: Examining the role of faith-based organizations in addressing HIV/AIDS: A multi-country, key informant survey. Washington, DC: GHC. Gilks, C. F., S. Crowley, R. Ekpini, S. Gove, J. Perriens, Y. Souteyrand, D. Sutherland, M. Vitoria, T. Guerma, and K. De Cock. 2006. The WHO public-health approach to antiretroviral treatment against HIV in resource-limited settings. Lancet 368(9534):505–510. Harries, A. D., N. J. Hargreaves, J. Kemp, A. Jindani, D. A. Enarson, D. Maher, and F. M. Salaniponi. 2001. Deaths from tuberculosis in sub-Saharan African countries with a high prevalence of HIV-1. Lancet 357:1519–1523. Health GAP (Global Access Project). 2005. Analysis of the U.S. Global AIDS Program and the PEPFAR Supply Chain Management System (SCMS). http://www.pepfarwatch.org (accessed February 18, 2007). Hirsch, M., F. Brun-Vezinet, B. Clotet, B. Conway, D. R. Kuritzkes, R. T. D’Aquila, L. M. Demeter, S. M. Hammer, V. A. Johnson, C. Loveday, J. W. Mellors, D. M. Jacobsen, and D. D. Richman. 2003. Antiviral drug resistance testing in adults infected with human immunodeficiency virus, type 1: Recommendations of an International AIDS Society-USA Panel. Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America 37:113–128. IOM (Institute of Medicine). 2005. Scaling up treatment for the global AIDS pandemic: Challenges and opportunities. Washington, DC: The National Academies Press. Lawn, S. D., L. Myer, L. G. Bekker, and R. Wood. 2006. Burden of tuberculosis in an antiretroviral treatment programme in sub-Saharan Africa: Impact on treatment outcomes and implications for tuberculosis control. AIDS 20:1605–1612. Mills, E. J., J. B. Nachega, I. Buchan, J. Orbinski, A. Attaran, S. Singh, B. Rachlis, P. Wu, C. Cooper, L. Thabane, K. Wilson, G. H. Guyatt, and D. R. Bangsberg. 2006. Adherence to antiretroviral therapy in sub-Saharan Africa and North America: A meta-analysis. JAMA: The Journal of the American Medical Association 296:679–690.

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PEPFAR Implementation: Progress and Promise WHO. 2006c. Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach, 2006 revision. Geneva, Switzerland: WHO. WHO. 2006d. Patient monitoring guidelines for HIV and antiretroviral therapy (ART). Geneva, Switzerland: WHO. WHO and UNAIDS (2006). Progress in scaling up access to HIV treatment in low- and middle-income countries, June 2006. Fact Sheet. Geneva, Switzerland: WHO and UNAIDS Wools-Kaloustian, K., S. Kimaiyo, and L. Diero. 2006. Viability and effectiveness of large-scale HIV treatment initiatives in sub-Saharan Africa: Experience from western Kenya. AIDS 20:41–48.

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