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International Association of Physicians in AIDS Care, Journal: October - Volume 5, Number 10
José Zuniga
When the World Health Organization (WHO) reported in May 1999 that AIDS had become the world's most deadly infectious disease,1 it came as no surprise to Ugandan President Yoweri Museveni. He was struck by the ominous reality of AIDS in 1986 (soon after leading a successful miltary coup and becoming president). Cuban military authorities who were charged with training Ugandan troops, which included testing for HIV and other sexually transmitted infections (STIs), delivered news that up to 25 percent of the Ugandan military (including senior officers) might be HIV-infected. Exhausted from a civil war, struggling to consolidate a power base, and faced with the grim news about his troops, Museveni quickly established the nation's first AIDS control program.
In addition to an army whose power was hobbled by the specter of HIV, Museveni had to contend with the stress of his people coping with parallel epidemics of poverty and endemic diseases such as malaria and tuberculosis (TB), who now faced a third epidemic--HIV. For Uganda, the implications of HIV were grave. The infection rate in the general population was as high as 30 percent.2 Breadwinners were becoming chronically ill and unable to support their families. Their wives were also becoming infected and unable to care for their children, some of whom were also becoming infected. There would be countless children orphaned by the disease. The nation's fragile economy, already depressed by years of bloody civil war, a lack of foreign investment, and crippling debt, could not absorb additional losses resulting from the direct and indirect costs of HIV/AIDS.
More than ten years later, the incidence of AIDS in this central African country has decreased from 30 percent to about 14.5 percent3 in part as a result of actions taken by the Ugandan government in concert with international institutions. Although HIV prevention interventions, including the recent introduction of short-course antiretroviral (ARV) therapy to reduce mother-to-child transmission (MTCT) of the virus, have been swiftly implemented, parallel mechanisms for care and support of the general population infected with HIV have not been economically feasible. While the expanding armamentarium of sophisticated ARVs have transformed the lives and decreased the death rates of most of the HIV-infected in North America and Europe, access to these drugs by most of the estimated 930,000 Ugandans living with HIV/AIDS is unrealistic.4 In this resource-limited environment, most drugs including those efficacious in preventing and treating opportunistic infections (OIs) are often out of reach.5
The World Bank has used the standard of US$370 per capita in annual income, or about US$1 per day, as the threshold of extreme poverty.6 Based on this standard, the World Bank estimates that 30 percent of the population in developing countries--or some 1.3 billion people--live in extreme poverty.7 And the number of men, women, and children living in poverty is increasing.
It has been argued that the industrialized world has a strong moral obligation to respond to the human suffering caused by an epidemic of extreme poverty.8 An argument has also been made that fostering increased prosperity in less-industrialized nations would be in the economic and political self-interest of the industrialized nations. One might also posit that a closer connection between the people of all countries would result in the collective interests and values needed to manage poverty-related crises--not the least of which are endemic and epidemic diseases. The commonality of economic, political, and moral interests effected by globalization cannot be sustained in an environment marked by the degradation in human health that afflicts more than one billion people.
Source: World Health Organization/Action Programme on Essential Drugs, 1998. |
The United Nations Development Programme (UNDP) estimates that more than 880 million people worldwide lack access to any healthcare services.9 Estimates suggest that one-third of the world's population lacks access to drugs and vaccines defined by the WHO as "essential drugs." (Table 1)10 These drugs are not costly and their provision is a cost-effective intervention.10
Exacerbating the challenge of providing greater access to healthcare services and essential drugs in developing countries is a burgeoning HIV pandemic. WHO estimates that, at the end of 1997, 30.6 million people worldwide were living with HIV/AIDS, of whom 90 percent were in developing countries, two-thirds in sub-Saharan Africa.11
The highest HIV prevalences are seen among those who are poor, marginalized, and displaced which will further increase the gap between rich and poor.12 This widening gap in individual income coupled with scarcity of resources at the governmental level makes the issue of access to AIDS drugs and related healthcare services a dilemma. Most would concur that there is a moral and humanitarian obligation to provide whatever care, support, and assistance is appropriate or feasible for people living with and affected by HIV/AIDS.13 But with competing demands for fundamental human needs such as safe water, adequate nutrition, basic healthcare, and essential drugs, should expanding access to HIV/AIDS drugs and healthcare services be a priority? Is there some middle ground that can be achieved as governments and other bodies address human development issues--sanitation, water supplies, literacy--while stemming the human devastation wrought by competing epidemics including HIV disease?
Over several years, the international public health community has come to advocate a step-wise approach to the provision of HIV care, predicated on the financial and human resources available within a country. Several regional and international institutions, including the WHO, Joint United Nations Programme on HIV/AIDS (UNAIDS), Pan American Health Organization (PAHO), and International Association of Physicians in AIDS Care (IAPAC), endorse a general framework that emphasizes a three-tier approach: (1) a baseline level of core HIV services (ie, HIV testing, voluntary counseling, prevention interventions); (2) a middle level of support for the delivery of enhanced basic healthcare services (ie, improved resources for primary healthcare, clinical guidelines, palliative care); and (3) a final level involving the delivery of specialist HIV/AIDS care for OIs and the provision of ARV drugs.14
The argument follows that within the hierarchy of care levels in resource-poor settings, a minimum level of care can be defined which even the poorest health service should aim to provide and which needs to be in place if any effective care for HIV/AIDS is to be delivered.15 Certainly, countries such as Uganda, where the government spends 1.6 percent of its annual budget on the provision of healthcare services and essential drugs,9 this hierarchy provides an opportunity of improving care and support services within very limited budgets, with the knowledge that these services can be expanded as more resources become available (Tables 2, 3, 4).
| HIV testing1 | 3.1 |
| Prevention2 | 7.6 - 15.3 |
| Support and counselling3 | 9.4 |
| Information and education on care and support | Insufficient data |
| Training for health of staff | Insufficient data |
| Access to groups of people living with HIV/AIDS | Insufficient data |
| Total | 20.1 - 27.8 |
| 1. Assumes 20 percent of those infected will be tested each year and that the same number of people who are sero negative will also be tested. Test costs are based on those for Uganda in 1977, ie, US$6.
2. Cost for Africa as a whole estimated at US$225 millions to US$435 millions (Broomberg and Schopper, 1996), equivalent to US$0.4 to US$0.8 per person. Range for Uganda is given by its population multiplied by 0.4 and 0.8 respectively. 3. Assumes pre-test and post test counselling for all those tested and four counselling sessions per year for 50 percent of those infected. The figure of US$3 is used for the cost of a counselling session, since recent data (unpublished) from TASO in Uganda indicate that this is a more realistic figure than the US$12 quoted in the summary cost data table. Adapted from Table 12. Care and Support for People with HIV/AIDS in Resource-Poor Settings, Department for International Development, UK. 1998.13 |
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| Restructured TB control1 | 3.0 - 7.8 |
| Hospital services with capacity to cope with increased caseload in equitable fashion2 | 22.2 |
| Improved primary healthcare services to include specific HIV/AIDS care packages | Insufficient data |
| Home-based care3 | 0.1 - 0.3 |
| Support for restructuring of TB services | Likely to be relatively small and one-off costs |
| Total | 25.3 - 30.3 |
| 1. Assumes only extra costs associated with higher caseload are drugs and laboratory tests. Hence the low estimate is the low estimate from Table 2, which assumed 5 percent of those infected develop TB each year; the high estimate assumes 13 percent develop TB each year.
2. Assumes low-cost estimate from Table 2. 3. Range reflects high and low-cost estimate of per person home-based care costs from Zambia and Zimbabwe, ie, 52 per year in Zambia to approximately 170 per year in Zimbabwe (assuming four visits per year). The numbers eligible are assumed to equate to the numbers of AIDS cases. Adapted from Table 13. Care and Support for People with HIV/AIDS in Resource-Poor Settings, Department for International Development, UK. 1998.13 |
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| AZT for people with AIDS1 | 7.0 |
| Cost of AZT for people with AIDS as % health expenditure | 4.8 |
| Cost of triple-combination therapy for all those with HIV infection | 11,409 - 16,695 |
| Cost of triple-combination therapy for all those with HIV infection as % health expenditure | 7,857 - 11,498 |
| 1. Based on estimate per person annual costs recently estimated for provision of AZT and triple-combination therapy (Floyd and Gilks, 1997) and on (a) the numbers with AIDS and (b) the numbers with AIDS and those with HIV infection pre-AIDS quoted in earlier tables. Insufficient data to cost provision of interventions for opportunistic infections.
Adapted from Table 14. Care and Support for People with HIV/AIDS in Resource-Poor Settings, Department for International Development, UK. 1998.13 |
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Upon what foundation of principles would this hierarchal framework be constructed? The PAHO, WHO, UNAIDS, and IAPAC, at a Consultation on Standards of Care for People with HIV/AIDS in 1998 agreed upon the following principles to meet the physical, social, and economic needs of people living with HIV/AIDS:14
Respect: regard for human rights and individual dignity.
Accessibility and availability: appropriate care provided at the local level.
Equity: provision of care to all persons living with HIV/AIDS regardless of gender, age, race, ethnicity, sexual identity, income, and place of residence.
Coordination and integration: to ensure a continuum of care across providers and levels of care.
Efficiency and effectiveness: efficacious care provided at reasonable societal costs as demonstrated through ongoing monitoring and evaluation.
Contentious debates around expanding access to ARVs and OI drugs in resource-poor countries beg an important question: are there any points of consensus? In fact, there is an emerging consensus on several fronts:16,17
With specific regard to expanding access to ARVs, the WHO articulated minimum requirements that healthcare systems must meet before the introduction of ARV treatments:17,18
With an emerging consensus on the drug access issue, UNAIDS devised a multi-pronged HIV drug access initiative during an unprecedented three-day meeting in June 1997 between pharmaceutical industry representatives and government officials, including health ministers, from the four developing countries selected to pilot the initiative--Chile, Côte d'Ivoire, Uganda, and Viet Nam. The result of this meeting was the launch of the UNAIDS HIV Drug Access Initiative in November 1997.
UNAIDS defined the initiative's purpose as creating the proper environment and inducing relevant changes in healthcare delivery systems to improve access to HIV/AIDS and related drugs at all levels of provision of healthcare services. At the launch press conference, the initiative's coordinator, Joseph Saba, MD, a clinical research specialist at UNAIDS, explained: "This program will provide the information we need to determine whether HIV/ AIDS-related drugs can be obtained and distributed effectively in developing countries. Armed with this information, countries will then be able to mobilize the necessary resources to treat infected individuals, and to help control the global epidemic."19
The initiative was geared to proceed over a four- to five-year period in two phases. Phase I, meant to last two to three years, was designed to develop, implement, and test a model to successfully expand access to HIV-related drugs on a small, sustainable scale in developing countries. In Phase II of the initiative, UNAIDS plans to apply lessons learned and adapt the model for wider application in other developing countries. Chile, Côte d'Ivoire, Uganda, and Viet Nam were chosen to participate in Phase I based on the following criteria:
Specifically, the initiative's objectives included:
The launch of this ambitious experiment required the support of pharmaceutical and diagnostics manufacturers to provide price discounts that were reasonable enough for an increased number of people with HIV/AIDS in the participating countries to afford the drugs and technologies. UNAIDS hoped that the companies participating in the initiative would make a range available of HIV-related drugs, including ARVs, antimicrobials, and antibiotics. In addition, diagnostic companies were asked to provide discounted virological tests and services for patient monitoring.
When the initiative officially began in Côte d'Ivoire in July 1998, the previous months of negotiations at the country level had yielded discounts ranging from 40 percent to 60 percent from a half dozen pharmaceutical companies. Two diagnostics manufacturers had agreed to discount their technologies. Start-up capital and in-kind drug was contributed by the first three pharmaceutical companies to sign on to the initiative--Bristol-Myers Squibb, Glaxo Wellcome, and Roche Laboratories. UNAIDS also contributed more than US$1 million to support national advisory boards as well as evaluation components in the four participating countries.
UNAIDS stressed the importance of country participation from beginning to end of the pilot phase of the drug access initiative. To guarantee active participation at the local level, all parties agreed to the formation of national advisory boards tasked with coordinating national policies for the provision of HIV-related drugs, drafting treatment guidelines for physicians prescribing drugs through the initiative, and setting criteria for the selection of patients and participation of primary and referring health centers. These national advisory boards were established under the aegis of the Ministry of Health and comprised of representatives of the local medical, public health, and HIV/AIDS communities.
The parties also agreed to establish a non-profit company in each country tasked with managing ARV drug procurement and distribution to reduce the risks of interruption of therapy that are often a consequence of erratic drug procurement and unreliable distribution systems.
The final component of the drug access model was the critical evaluation mechanism. The organizers agreed on including several review areas in the evaluation of the pilot phase: economics, pharmacoeconomics, financing mechanisms, clinical management, epidemiology, social and behavioral science, logistics, and patient selection. The US Centers for Disease Control and Prevention (CDC) and the French Agence Nationale de Recherches sur le SIDA (ANRS) were assigned the evaluation role. IAPAC was subsequently approved by UNAIDS as an independent observer to chronicle the initiative's evolution and progress, as well as to comment on opportunities to maximize the value of the drug access initiative in each of the four countries.
Commonly referred to as "The Pearl of Africa," an epithet originally coined by Winston Churchill, Uganda is largely an agricultural country struggling to grow its economy and improve the quality of life of its 20 million plus citizens. The country has much to overcome, including a life expectancy of 39.6 years at birth, an infant mortality rate of 86 per 1000 live births, and an adult literacy rate of 36 percent.9 Twenty-nine percent of the population lack access to any healthcare, and 54 percent lack access to safe water.9 Economically, external debt of US$3.7 million20 and a lack of significant private investment has crippled the government's ability to provide its citizens with little more than the commitment to extend basic services to a greater number of people as resources permit. Thus, public health expenditure on health as a percentage of gross domestic product (GDP) is a paltry 1.6 percent, whereas payment on debt and interest represents 3 percent of GDP.9
Uganda, like most resource-limited countries in sub-Saharan Africa, is forced to make very difficult decisions on the allocation of scarce resources.21 It has also been forced to rely on assistance from bilateral institutions and nongovernmental organizations (NGOs) in other countries to address the numerous social challenges facings its population. These institutions and organizations have achieved many significant successes. One example is the measles immunization initiative spearheaded by the WHO, United Nations Children's Fund (UNICEF), and other like-minded organizations which resulted in 60 percent of Ugandan 1-year-olds being fully immunized against measles.9 Still, the remaining challenges are daunting, especially when compounded by the HIV pandemic.
Museveni's swift action in 1986, Minister of Health Crispus Kiyonga's implementation of a national AIDS plan, and community mobilization have provided an extraordinary example and model for other African countries facing similar challenges. In August 1999, newly appointed South African Minister of Health Manto Tshabalala-Msimang headed a delegation to Uganda to learn lessons that might benefit her nation's struggle against the ravages of AIDS.22 Yet despite an unwavering government commitment to people infected with and affected by HIV disease and the implementation of effective prevention interventions, addressing the broader, more complex issue of HIV care was beyond the scope of Uganda's structural and financial capacity.
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Uganda joined the UNAIDS HIV Drug Access Initiative in March 1998 when Museveni's presidential cabinet approved the Ugandan health minister's proposal to implement the initiative as a means of proving that ARVs could be introduced into a resource-poor setting while providing clinical benefit for an increased number of people with HIV/AIDS. Kiyonga appointed the 15-member National Advisory Board as well as a national coordinator for the initiative--Dorothy Ochola, MD, MPH, a former Ugandan health ministry official with a wealth of field experience in Uganda's remote healthcare facilities.
Appointed to the advisory board were representatives from the Ugandan ministries of health, planning and finance, defense, and gender; representatives from the Ugandan AIDS Commission; NGO representatives; the national AIDS program coordinator; clinicians; public health experts; and representatives from patient advocacy groups. Three subcommittees of the advisory board were tasked with implementation and oversight responsibilities:
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| In industrialized countries, clinical care is dominated by late-stage disease and AIDS. In poor communities in resource-poor developing countries, early disease tends to dominate clinical care.
Source: Care and Support for People with HIV/AIDS in Resource-Poor Settings, Department for International Development, UK. 1998.13 |
The National Medical Stores (NMS) in Uganda was established in 1993 as an autonomous drug supply system. There were financing troubles in the beginning, as the government gave the start-up money directly to 27 of the 39 health districts that were being decentralized, making it impossible for the NMS to stock an adequate supply of drugs.23 As a result, some districts were forced to buy drugs from the private sector at higher prices. Corruption charges a year before the initiative's launch in Uganda did little to allay the fears of UNAIDS and participating pharmaceutical companies that drug procurement and distribution might be erratic and, thus, jeopardize the health of patients accessing HIV-related drugs through the initiative.24 To address these concerns, the Ugandan government agreed to facilitate the establishment of Medical Access (U) Ltd., a non-profit company tasked with procuring and, subsequently, distributing ARVs through the initiative. Since its establishment in May 1998, Medical Access, which is administered and staffed by registered Ugandan pharmacist Sowedi Muyiengo, has:
Medical Access's negotiations with the participating pharmaceutical companies, which were strongly aided by UNAIDS, succeeded in reducing the cost of double ARV therapy from an average of US$600 to US$250 per month. The cost of triple ARV therapy was reduced from US$1000 to between US$500 and US$600 per month. These prices were for drugs manufactured by Abbott Laboratories, Bristol-Myers Squibb, DuPont Pharma, Glaxo Wellcome, Merck & Co., and Roche Laboratories, all of which are now partners on the initiative. As of May 1999, Organon Teknika and Virco pledged discounted prices for viral load and CD4 count technologies through the initiative. Negotiations are ongoing with Becton Dickinson to reduce the cost of its diagnostic technology.
Drug prices negotiated by Medical Access are indexed in US dollars. This indexing has diminished the value of the discounts as consecutive depreciations of the Ugandan shilling against the US dollar resulted in several revisions in the price charged to patients for their drugs. Sudden, unannounced increases in drug prices resulting from these currency fluctuations have forced some patients on triple ARV therapy who could not afford to pay the higher prices to either switch to double-therapy or obtain drugs from sources outside of the initiative that are less affected by the immediate impact of currency fluctuations. Medical Access and UNAIDS are discussing the establishment of a contingency fund to better sustain currency fluctuations by ensuring a transition period of one to three months between price increases.
As currently configured, once Medical Access secures a discount commitment (again, indexed in US dollars) from a participating pharmaceutical company and agrees upon a payment schedule, drug supplies are shipped to the JMS, which receives a fee for storing the drugs in their facilities. Supplies are then shipped to the dispensaries at the participating clinics in accordance with needs expressed by the clinic directors. Medical Access is tasked with maintaining tight control of the drug supply to avoid price gouging or other abuse at the dispensary or clinic levels. The dispensaries charge patients the discounted prices for their particular ARV therapy variation and, after taking a two to five percent administrative mark-up, reimburse Medical Access in Ugandan shillings for drugs purchased through the initiative. Closing the loop, Medical Access pays the agreed upon discounted price to participating pharmaceutical companies in US dollars (Figure 2).
The General Principles of ARV Therapy: Summary Guidelines, finalized by the Subcommittee on Care and Practice in April 1999, identified two aims for ARV therapy in Uganda: the reduction of patient viral load to undetectable levels, and the reduction of viral mutations to prevent and reduce the emergence of resistant viral strains.
ARV therapy presents several challenges to HIV-infected Ugandans and their healthcare providers: (1) patients are responsible for purchasing their ARV therapy; (2) many patients present with advanced stage disease (severe immunodepression, multiple life-threatening OIs, and HIV- associated malignancies); and (3) many clinics lack laboratory services to monitor immunological and virological response to ARV therapy. In acknowledging these challenges in the summary guidelines, the subcommittee established recommendations for the use of ARV therapy which, if accepted and appropriately dealt with by the physicians participating in the drug access initiative, could reduce the consequences resulting from poor compliance with ARV regimens.
The use of ARV therapy is recommended for post-exposure prophylaxis; HIV-infected pregnant women to prevent MTCT transmission; treatment of acute HIV infection; and treatment of established HIV infection (both symptomatic and asymptomatic).
Occupational post-exposure prophylaxis. The recommendation for occupational HIV exposure for which there is a recognized transmission risk (ie, needle stick that did not contain visible blood but which was used in an HIV-infected individual) is a four-week course of zidovudine (ZDV) and lamivudine (3TC). For occupational exposure posing a greater risk of transmission (ie, laceration sustained from a broken blood specimen bottle), the recommended course is four weeks of ZDV and 3TC plus either indinavir or nelfinavir.
ARVs and pregnancy. The subcommittee suggests that HIV-infected women already on ARV therapy may elect to halt ARV treatment before getting pregnant and resume treatment at the commencement of the second trimester. The initiation of ARV therapy for maternal health reasons is considered optional if CD4 count is more than 500 cells/mm3 and plasma HIV RNA is less than 10,000 copies/ml. The minimum recommended regimen is ZDV monotherapy during the second and third trimesters.
Acute HIV infection. Since many people with HIV or other diseases rarely go to physicians unless they have symptoms that demand immediate attention, the subcommittee did not stress recommendations for ARV therapy in acute HIV infection, but made the following observation: "The diagnosis of acute HIV infection is rarely made in our population probably because the symptoms are confused with other common disorders like malaria and other common viral diseases.... most authorities would use aggressive therapy (otherwise referred to as "standard therapy") when faced with patients who have confirmed acute HIV infection."
Established HIV infection. Although recognizing the benefit of ARV therapy for patients with asymptomatic chronic infection, the subcommittee also weighed the risks posed by an expensive regimen that presents serious compliance challenges because of the complexity of dosing schedules and side effects of ARV therapy. Thus, the subcommittee recommends delaying therapy where viral load is low (less than 10,000 copies/ml) and CD4 count is high (above 500 cells/mm3). Indications to initiate ARV therapy include rising viral loads to more than 10,000 copies/ml or doubling of the viral load in three months and/or falling CD4 counts to below 500 cells/mm3.
"In managing symptomatic disease," the subcommittee recommends, "special considerations for therapy in patients with advanced stage disease will usually be necessary as most of the patients in Uganda present late." Specifically, the subcommittee stresses the evaluation for and management of OIs. The concern is that patients with advanced HIV disease and subclinical OIs such as cytomegalovirus (CMV) infection may develop a new immunologic response to HIV resulting in new symptoms which could be misinterpreted as treatment failure. According to the summary guidelines, newly presented OIs should be treated appropriately while maintaining patients on ARV therapy.
Standard ARV therapy is defined as a three-drug combination that includes a protease inhibitor (PI) plus two nucleoside reverse transcriptase inhibitors (NRTIs). (Table 5) The subcommittee further identifies alternative potentially efficacious regimens (nevirapine, delavirdine, efavirenz, and abacavir in combination with 2 NRTIs) and cost-effective regimens (an NRTI plus two PIs or an NRTI plus a PI plus hydroxyurea [HU]). The subcommittee str ongly advises that physicians should start their patients on the most potent regimen whenever possible and aim at maintaining undetectable viral load with that same regimen for as long as possible.
| Column A | Column B |
| indinavir | didanosine (ddI) |
| nelfinavir | lamivudine (3TC) |
| ritonavir | stavudine (d4T) |
| saquinavir (Invirase) | zalcitabine (ddC) |
| amprenavir | zidovudine (AZT) |
| Source: General Principles of ARV Therapy: Summary Guidelines, 1999. | |
Should the need arise to interrupt ARV therapy, the subcommittee advises physicians and patients discuss resistance issues and the "theoretical advantage of stopping all ARV therapy simultaneously rather than continuing one or two agents." As for criteria for changing therapy, physicians are advised that a change in regimen because of treatment failure should involve the replacement of the regimen with a new regimen of drugs to which the patient is naive. In a clinically stable patient with detectable viremia, the subcommittee suggests it may be more prudent to delay any change in therapy.
In another reflection of the economic pressures faced by Ugandans with HIV/AIDS, the subcommittee articulated a partial viral suppression strategy aimed at lowering viral load (not necessarily to undetectable levels) to the l evel necessary to alleviate the patient's symptoms. ".... [P]artial suppression is superior to no suppression of virus. This is the argument that underlies the use of two-drug regimens." Partial suppression regimens include two NRTIs; one NRTI plus one NNRTI; or the addition of HU (ie, ddI plus HU; ddI plus d4T plus HU; ddI plus PI plus HU).
Discouraged are monotherapies (except as an MTCT intervention or in post-exposure prophylaxis). The subcommittee also discouraged the following combinations: d4T plus ZDV; ddC plus ddI; ddC plus d4T; and ddC plus 3TC.
The subcommittee strongly emphasizes the need for clinical follow-up and laboratory tests, including viral load, CD4 counts, and complete blood counts (CBC). For humanitarian reasons the subcommittee emphasized identifying treatment failure over simply determining clinical efficacy to determine when ARVs should be stopped or changed, "as continued administration where [ARVs] have failed is not only useless but is unnecessarily wasteful of the patient's resources...."
As of May 1999, five referral hospitals in Kampala--Joint Clinical Research Center (JCRC), Mengo Hospital, Mildmay Center, Mulago Hospital, and Nsambya Hospital--were offering access to ARVs to 825 patients, a more than 50 percent increase from the 400 patients who had access to ARVs before the UNAIDS initiative was launched in Uganda a year earlier. (Pre-initiative, ARVs were obtained primarily through a private clinical setting, although donations from family members and a thriving black market also offered unchecked access to these sophisticated treatments.)25 Viral load and CD4 count analyses are provided at a cost through JCRC, Case Western Collaboration Laboratory at Mulago Hospital, and Ebenezer Clinical Laboratory.
A lack of HIV clinical management skills outside of the JCRC (the one clinic in Kampala prescribing ARV therapy before the UNAIDS initiative) required the establishment of a rigorous educational component. To date, educational programs have been conducted in collaboration with the Ugandan Ministry of Health's STI/AIDS Control Program. Two symposia have been conducted with support from Roche Products Ltd. and Merck Sharpe & Dohme. While focusing primarily on physicians, training activities have also involved pharmacists, counselors, nurses, lab technologists, and social workers. The finalization and subsequent distribution of ARV treatment guidelines further promotes a rationale use of sophisticated AIDS treatments.
Educational efforts and the promotion of clinical standards have resulted in adequate clinical management practices at the four participating centers. A wide range of drug combinations, mostly two-drug combinations, are in use through the UNAIDS initiative. Approximately 75 percent of patients are on double therapy versus 25 percent on triple therapy--all combinations in line with the clinical guidelines articulated by the Subcommittee on Care and Practice.
A site visit to Mildmay Center, a private clinic financed and run by the UK-based non-profit Mildmay International, provided an example of an ideal clinical setting into which ARVs could be introduced. Mildmay counts on a medical staff fully versed in clinical management guidelines and running a state-of-the-art clinic with the needs of its patients in mind. A review of patient medical records revealed impressive results with ARV therapies, including a general maintenance of low viral load and high CD4 counts.26 The exception to the ideal clinical management situation is the large number of switches from three-drug to two-drug combinations linked with the depreciation of the Ugandan shilling. Notable, however, is that of 31 Mildmay patients on ARV therapy, only two have failed therapy and died of AIDS-related complications (both presented with late stage HIV disease and severely compromised immune systems).
Certainly not unique to Uganda, despite educational efforts and the promotion of clinical guidelines, UNAIDS program evaluators have noted only a few instances of HIV monotherapy outside of the accepted norm. During IAPAC's visit to Uganda in May 1999, three cases of monotherapy were noted at Nsyambya Hospital. Uganda initiative coordinator Ochola has called for expanded educational efforts to ensure that all physicians and healthcare professionals participating in the initiative follow established clinical management guidelines.
Ochola and UNAIDS's Saba have implemented a new policy aimed at patients who secure ARVs outside of the UNAIDS initiative--either through donations from family members or through the black market. To ensure supervised use of the drugs and reduce the likelihood of resistance, participating centers are now advised to provide clinical services to individuals outside of the initiative.
In addition to the five referral clinics in Kampala, the advisory board selected 12 follow-up clinics and 90 peripheral centers to participate in the initiative. During the pilot phase of the initiative, Ochola, colleagues from UNAIDS, and program evaluators from France and the US have visited many of these centers to assess:
The ambitious goal of including so many follow-up clinics and peripheral centers in the initiative was set by the advisory board in an effort to address some of the most pressing issues affecting Uganda's poorer, and geographically remote health districts. IAPAC site visits to four distinct health provision centers in the Kabale and Masaka districts provided a clearer view of the challenges facing Uganda's medical infrastructure outside of the nation's capital.
Rubanda Clinic. The Rubanda Clinic is a Catholic Mission-managed peripheral health clinic with an annual caseload of more than 26,000 patients, mostly women and their children. Located more than five miles up a mountain, Rubanda Clinic provides basic healthcare services, vaccinations, and, through the World Bank's STI Project, access to STI drugs. Three nurses triage and care for patients within a [number]-mile radius just miles from the Uganda-Rwanda border. Patients must trek up the mountain burdened with pots, pans, firewood and food stuffs, since the clinic is unable to provide much more than bread and water. The sickest patients are transported to the clinic in specially designed litters, carried by up to 30 Ugandan men who take the day off work to assist a neighbor in need (see August 1999 Journal). Laboratory resources are non-existent, with a syndromic approach guiding diagnosis of most illnesses, including TB. Universal precautions are observed when latex gloves are available. Disposable syringes are reused after a thorough washing with soapy water--more as a result of an administrative misunderstanding of procurement procedures than a supply issue.
Kabale Regional Hospital. At this 250-bed government district health hospital, a physician and his senior nurse oversee a smooth running medical institution complete with a rigorous training program that includes a basic HIV and OI management component, and high standards of patient care as seen by the attention paid to the patient living quarters. There have been shortages in essential drugs including those for TB prophylaxis--the last gap in drug supply lasted one week and required the clinic purchase TB drugs off the open market at steeper prices. Laboratory services are directed by a Kampala-trained lab technologist and include malaria and TB test analyses, as well as HIV rapid testing. Except for the sporadic lapses in drug supplies, the hospital functions at the level of any one of the referral centers in Kampala. Yet, expanding access to ARVs is not on the wish list of this clinic director who defines the hospital's needs as expanding access to essential drugs, including malaria treatment, to more patients and ensuring uninterrupted OI drug availability.
Buhinda Health Center. One physician and two nurses run a resource-limited health center under often very trying conditions, providing basic healthcare services to an average 20 patients a week in this remote part of the Kabale District. The clinic has no laboratory facilities. There are shortages of some essential drugs, including malaria and TB treatments. Because of its remote location, there is little contact with the District Medical Officer's (DMOs) office, which may explain many of the shortages. STI drugs are available through the World Bank's STI Project, but the clinic's physician could not remember the last time a World Bank representative visited the clinic to evaluate the ongoing STI Project activities.
Masaka District Hospital. Masaka District Hospital, with a staff of more than 20 physicians and other healthcare professionals, manages an annual caseload of more than 50,000 patients. Because of its proximity to the DMO's office, the 330-bed hospital counts on adequate laboratory services and has not experienced a shortage of essential drugs since the decentralization of the Ugandan healthcare infrastructure. The hospital supervisor maintains a rigorous medical educational program which includes basic OI clinical management. However, training in OI management is based on clinical guidelines developed before 1993. As with the other centers IAPAC visited, neither the hospital supervisor nor the physicians interviewed at Masaka District Hospital were aware of the Subcommittee on Care and Practice's General Principles of ARV Therapy: Summary Guidelines, which include OI management recommendations.
Throughout IAPAC's visits to health centers and other clinical settings, Ugandan physicians and other healthcare professionals, some of whom were not participating in the drug access initiative, articulated their frustration that patients present with severe immunodepression and OI manifestations either beyond the physician's scope of medical expertise or beyond the scope of care services and drugs available to manage OIs. This is especially troubling because in areas where there is inadequate clinical care, people die with early HIV disease before AIDS has developed. Thus, in many cases early death is occurring relatively few years into the natural history and course of disease.27 Higher exposure to virulent OIs and poor and inadequate healthcare for the first serious HIV-related disease is the main reason for this early death.28
The majority of adults in developing countries, and certainly in Uganda, are infected with M. tuberculosis. HIV infection provides the strongest known risk for the development of TB disease.29,30 It is, therefore, not surprising that TB is the most common OI in developing countries such as Uganda.31 Other commonly seen OI manifestations in Uganda are candidiasis, herpes zoster, cryptococcal meningitis, HIV-related cancers, microsporidiosis, toxoplasmosis, Pneumocystis carinii pneumonia (PCP), and CMV infection.
Although there is general concurrence of front-line physicians in the Ugandan referral hospitals and peripheral centers that more effective OI management is needed where the burden of HIV and related diseases continues to expand, applying effective management is made difficult by the lack of laboratory facilities, without which precise diagnosis is often impossible, and the prohibitive cost of treatment of many OIs.31 An additional challenge that was identified in the IAPAC observation is the lack of consensus around specific clinical management practices. In Uganda, for example, there is no consensus around TB prophylaxis and no official recommendations regarding the use of cotrimoxazole or isoniazid (INH) as prophylactic treatments. These are daunting challenges, but challenges that must be met when 65 percent of HIV-infected patients present with TB.28
In addition to expanding access to ARVs, another of the UNAIDS initiative's defined goals was to address the challenges presented by OI prevention and treatment. While the initiative has successfully advanced the expansion of access to ARVs in participating referral centers, as per the Ugandan advisory board's direction, a result of this single focus has been a delay in efforts to improve OI management in participating district hospitals and peripheral centers.
UNAIDS's Saba hopes to fast-track the implementation of the initiative's OI component by building on what has been done--training symposia in several districts on OI management and palliative care, and the development of OI management guidelines--and forging partnerships with the World Bank's STI Project and the WHO's Tuberculosis Programme to ensure broader access to OI drugs at the peripheral clinics. According to Saba, although many of the drugs needed to prevent and/or treat OIs are available in medical stores in large quantities, the peripheral delivery system is inadequate to ensure drug distribution to those who need them most.
Differences in the relative prevalences of OIs mean that guidelines for appropriate presumptive treatment and prophylaxis for HIV-infected individuals should be region-specific.32 The Subcommittee on Care and Practice articulated the following recommendations for OI management in its April 1999 General Principles of ARV Therapy: Summary Guidelines:
TB. A four-drug regimen is recommended for initial treatment, preferably under directly observed treatment short-course (DOTS) strategy. The regimen includes ethambutol, streptomycin, isoniazid, rifampicin/rifabutin, and pyramzinamide. For suspected multiple drug resistant (MDR) strains of TB, in addition to consulting a TB expert, the subcommittee advises treatment with the four standard drug regimen as sensitivity tests, and eventually the addition of three drugs to which the MDR strain may be susceptible, including ethionamide, capreomycin, ciprofloxacin, and cycloserin. During pregnancy, the subcommittee recommends the use of INH, rifampicin/rifabutin, and ethambutol, and avoidance of streptomycin and pyrazinamide because of their toxicity and teratogenicity on the fetus. Because rifampicin/rifabutin decrease PI serum levels, the subcommittee advises that for concomitant therapy with ARVs, rifampicin should be replaced with a reduced dose of rifabutin and an increased dosage of the PI.
PCP. The subcommittee identified trimethroprim-sulfumethoxazole (TMP-SMX), dapsone, and aerosolized pentamidine as established agents for PCP prophylaxis. For established PCP infection, recommended treatment is TMP-SMX. The recommendation for treating patients with moderately severe to severe PCP is the use of the corticosteroid prednisolone.
Cryptococcosis. Cryptococcosis without meningitis is managed with fluconazole. In cryptococcal meningitis, amphotericin B is the preferred initial treatment, followed by a course of treatment with fluconazole. The subcommittee recommended that intraconazole may be used instead of fluconazole, but not for maintenance therapy. In addition, the summary guidelines indicate that fluconazole is acceptable as initial treatment of cryptococcal meningitis in patients with normal mental status.
Toxoplasmosis. According to the subcommittee, efficacy for toxoplasmosis prophylaxis is established for TMP-SMX and dapsone plus pyrimethamine. For acute infection with toxoplasma enchephalitis, the preferred treatment is pyrimethamine plus sulfadiazine plus folinic acid. This same regimen, in a different dosage, is recommended for lifelong suppressive therapy.
CMV infection. Preferred treatment is gancyclovir or foscarnet. In addition, the subcommittee commented that prophylaxis for patients with CD4 counts of less than 50 cells/mm3 has been attempted with oral gancyclovir, but the drug is expensive and has not proved clinical benefit.
Herpes zoster. The subcommittee recommends that treatment with acyclovir commence within 24 hours of the appearance of lesions.
Herpes simplex. Preferred treatment is with acyclovir for ten days or until lesions crust.
Candida. Preferred treatment for thrush is with nyastatin, with alternatives including clotrimazole, ketoconazole, fluconazole, and itraconazole.
Diarrhea. Because chronic diarrhea is a common complication of advanced HIV disease and poses problems in drug administration, the subcommittee recommends aggressive treatment, including rehydration and parenteral or enteral feeding, if available. Additionally, the subcommittee strongly encourages evaluation for and appropriate treatment of salmonella, shigella, microsporidia, cryptosporidia, entamoeba histolitica, and giardia.
Malignant tumors (Kaposi's sarcoma, non-Hodgkins Lymphoma). The subcommittee recommends performing a biopsy where possible and referral of the patient to the Uganda Cancer Institute in Kampala.
The UNAIDS HIV Drug Access Initiative was launched with two primary goals: (1) expanding access to ARVs in four resource-limited countries, and (2) implementing and/or improving mechanisms for access to other HIV-related care and drugs. If evaluated by these two objectives, alone, the initiative has achieved half of its objective in its first year in Uganda. ARV access has been expanded in a population of Ugandans who can afford to purchase at least some variation of discounted ARV therapy. Less progress was observed in addressing the challenges of access to appropriate management of the high incidence of OIs.
However, from its outset, the initiative has been about much more than these two goals. Year One of the initiative in Uganda has provided valuable lessons that should guide decision-making for other newly launched initiatives as well as future drug access and other healthcare endeavors to improve healthcare provision in the developing world. This is why model programs are launched. If looked at through this prism, the UNAIDS initiative in Uganda has been a resounding success, providing a wealth of valuable experience upon which public health specialists can build:
There remain pressing questions. Why promote more costly therapeutic combinations when more cost-effective, alternative therapies may assist patients in better meeting the challenge of paying for drugs and diagnostics? While acknowledging a narrow focus on ARVs in Year One is important, what concrete steps will be taken to integrate targeted OI management into the initiative, thus benefiting tens of thousands of patients? What steps will be taken to address the issue of sustainability? How to continue building on a successful model when the pilot's initial objectives are met? What happens to the 700-plus patients currently on ARV therapy? Will the pharmaceutical and diagnostic technology companies maintain price discounts after the pilot phase of the initiative? If not, will the Ugandan government be in a better position to subsidize sophisticated HIV drugs and care services?
As Uganda begins Year Two of the UNAIDS HIV Drug Access Initiative, there is much experience and, indeed, there are many successes upon which to build. By the same token there are just as many issues that must be satisfactorily resolved if Ugandans living with HIV/AIDS and, ultimately, Uganda's healthcare infrastructure are to benefit from this bold experiment. ARV drugs have proven to be a clinical model enabling hundreds of Ugandans with HIV/AIDS to live more productive and meaningful lives. Lower drug prices and the resourcefulness with which the Ugandan people overcome great adversity has proven to be a social model which also contributes to increased survival. As in Uganda, success in mitigating the human devastation wrought by intersecting epidemics of poverty and disease will require the marriage of these interdependent clinical and social models so that people in the developing world share with the developed world a commonality of opportunity.
1. Press release issued by the World Health Organization (WHO), Geneva, Switzerland, May 11, 1999.
2. Armstrong J. Uganda's AIDS Crisis: Its Implications for Development. World Bank Discussion Series. 1995: No. 298.
3. Ainsworth M and Over M. Confronting AIDS: Public Priorities in a Global Epidemic. New York, NY: Oxford University Press; 1997.
4. Epidemiological Fact Sheet on HIV/AIDS and Sexually Transmitted Disease--Uganda. UNAIDS/WHO; June 1998.
5. Access to Treatment Satellite Meeting during the 3rd International Conference on Home and Community Care for People Living with HIV/AIDS. Hosted by GNP+. Amsterdam, The Netherlands, May 10, 1997.
6. World Development Report 1998. The World Bank; 1998
7. Poverty Reduction and the World Bank: Progress in Fiscal 1998. World Bank; 1999.
8. Shaping the 21st Century: The Contribution of Development Cooperation (a report by the Organization for Economic Cooperation and Development), May 1996.
9. Human Development Report 1999. United Nations Development Programme. New York, NY: Oxford University Press; 1999.
10. Removing Obstacles to Healthy Development: WHO Report on Infectious Diseases. World Health Organization. May 1999.
11. World AIDS Report. WHO; 1999.
12. Report on Global HIV/AIDS Epidemic. UNAIDS/WHO; June 1998.
13. Gilks CF et al. Care and Support for People with HIV/AIDS in Resource-Poor Settings Health and Population. Occasional Paper. Department for International Development, UK. 1998.
14. Building Blocks: Guidelines for Providing Comprehensive Care to Persons Living with HIV/AIDS in the Americas. Consultation by Pan American Health Organization/World Health Organization in Collaboration with UNAIDS and IAPAC. Cancún, Mexico: November 1998.
15. Gilks CF et al. The challenge of providing effective care for HIV/AIDS in Africa. AIDS. 1997; 11: S99-S106.
16. van Praag E et al. The Implications of Antiretroviral Treatments. WHO/ASD; 1997.
17. Technical Guidelines for the Introduction of Antiretroviral Treatments into National Health Systems. WHO/ASD; 1998.
18. Floyd K and Gilks CF. Cost and Financing Aspects of Providing Antiretroviral Therapy: The Implications of Antiretroviral Treatments. WHO; 1997.
19. UNAIDS launches initiative to help bridge gap in access to HIV/AIDS-related drugs in developing world. Press release. Joint United Nations Programme on HIV/AIDS (UNAIDS), Geneva, Switzerland, Nov. 5, 1997.
20. Organization for Economic Cooperation and Development (http://www.oecd.org). 1998.
21. De Cock KM et al. Clinical research, prophylaxis, therapy, and care for HIV disease in Africa. Am J Public Health. 1993; 83:1385-1389.
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24. Interview with John Rwomushana, PhD, Director-General, Ugandan AIDS Commission, Kampala, Uganda (conducted May 1999).
25. Interview with Dorothy Ochola, MD, MPH, Uganda HIV Drug Access Initiative Coordinator, Kampala, Uganda (conducted May 1999).
26. Interview with Badara Samb, MD, National Institute of Health and Medical Research, Hopital National de Sainte-Maurice, Paris, France; and Veronica Moss, MD, Group Medical Director, Mildmay International-Africa, Kampala, Uganda (conducted May 1999).
27. Morgan D et al. Early manifestations (pre-AIDS) of HIV-1 infection in Uganda. AIDS. 1998; 12:591-596.
28. Gilks CF. The clinical challenge of the HIV epidemic in the developing world. Lancet. 1993; 342:1037-1039.
29. Allen S et al. Two-year incidence of tuberculosis in cohorts of HIV-infected and uninfected urban Rwandan women. Am Rev Respir Dis. 1992; 146:1439-1444.
30. Selwyn PA et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med. 1989; 320:545-550.
31. Grant AD, De Cock KM. The growing challenge of HIV/AIDS in Developing Countries. British Medical Bulletin. 1998; 54 (No. 2): 369-381.
32. Kaplan JE et al. Preventing opportunistic infections in human immunodeficiency virus-infected persons: implications for the developing world. Am J Trop Med Hyg. 1996; 55:1-11.
José Zuniga is Executive Director of IAPAC
Editor's note: Following is the first in a series of reports by IAPAC Executive Director José Zuniga in his role as an Independent Observer of the UNAIDS HIV Drug Access Initiative in Chile, Côte d'Ivoire, Uganda, and Viet Nam. "Out of Africa: Uganda and UNAIDS Advance a Bold Experiment" provides Zuniga's perspective on the Uganda component of the initiative after a nine-day visit to the central African country in May 1999.
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