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HEALTH POLICY AND ETHICS |
Moïse Desvarieux is with the Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY. Roland Landman is with the Service de Maladies Infectieuses, Centre Hospitalier Universitaire, Bichat Claude Bernard, Université de Paris, Paris, France, and the Institut de Médecine et d’Épidémiologie Appliquée (IMEA), Paris. Bernard Liautaud is with the Hôspital de Jour en Maladies Infectieuses, Centre Hospitalier Universitaire de Fort-de-France, Fort-de-France, Martinique, and Groupe Haitien d’Études du Sarcome de Kaposi et des Infections Opportunistes, Port-au-Prince, Haiti. Pierre-Marie Girard is with the Service de Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire de Saint-Antoine, Université de Paris, Paris, and the Institut de Médecine et d’Épidémiologie Appliquée, Paris.
Correspondence: Requests for reprints should be sent to Moïse Desvarieux, MD, PhD, Department of Epidemiology, Mailman School of Public Health, 722 W 168th St, New York, NY 10032 (e-mail: md108{at}columbia.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPOPULATION OBJECTIVES OF ARV...PROPOSAL FOR A NEW...CONCLUSIONSReferences |
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The prospects for antiretroviral therapy in resource-poor settings have changed recently and considerably with the availability of generic drugs, the drastic price reduction of brand-name drugs, and the simplification of treatment. However, such cost reductions, although allowing the implementation of large-scale donor programs, have yet to render treatment accessible and possible in the general population.
Successfully providing HIV treatment in high-prevalence/high-caseload countries may require that we redefine the problem as a public health mass therapy program rather than a multiplication of clinical situations. The public health goal cannot simply be the reduction of morbidity and mortality for those treated but must be the reduction in morbidity and mortality for the many, that is, at a population level.
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INTRODUCTION |
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However, often overlooked is the fact that such reductions in costs, if they allow the implementation of large-scale donor programs, have yet to render treatment economically accessible to or possible for the general population. Indeed, even with these substantial cost reductions, like those negotiated via the United Nations Global Fund,2 the US president’s initiative,3 and the Clinton Foundation, or even the advent of generics, treatment remains beyond the reach of all but the upper classes in numerous countries.4 It is indeed the paradox of lower ARV therapy costs that these reductions brought with them a cortege of pressures that must be recognized with wide-open eyes. In order for lower ARV therapy costs to truly usher in the era of "global treatment" beyond pilot or research programs, a realistic discussion of attainable goals of ARV treatment in resource-poor countries is necessary.5
The debate is peculiar in that the necessity of making ARV therapy available in resource-poor countries has been justified for its population benefits (namely, maintenance of economic capacity, distributive justice, and curbing of the HIV epidemic) as much as for the immediate public health goals of reduced morbidity and mortality. As a consequence, these larger population benefits are sometimes seen as primary, with the public health objectives considered a vehicle toward accomplishing these larger goals. But are those goals always in harmony? Or might some of those goals be better attained in other ways? If so, which objectives are the most important?
We review the population goals implicit in ARV treatment programs, assess their feasibility, and contrast them with the vehicle that is supposed to bring them to fruition—access to ARV care for the many—before proposing a paradigm shift anchored in today’s reality.
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POPULATION OBJECTIVES OF ARV DRUG THERAPY PROGRAMS |
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Of course these observations ignore the intangible economic impact of the patients’ lost contributions to society and those of family members drawn to their care. Nevertheless, immediate economic gains would be better guaranteed in settings where patients would have received a certain level of care leading to prolonged life and its attendant hospitalization costs. Thus, at a population level, economic stability is likely to be a benefit of untargeted treatment only if the HIV prevalence cuts across social groups to such an extent that a substantial portion of the productive workforce is affected and if the population reached by treatment is large enough to encompass a significant portion of the untargeted workforce. Conversely, a siphoning of resources from other health priorities may increase economic instability: for example, if malaria mortality or morbidity were to increase as an unintended result of increased attention to HIV/AIDS, the impact across social classes might be greater. In the end, the long-term economic (and social) impact of raising generations of orphans may be the most staggering, albeit delayed, draw on resources.
Nevertheless, the strict goals of economic benefits might be more surely attained with targeted treatment of the critical workforce rather than the general population; this possibly conflicts with the larger public health goals.
Objective 2: Achieving Distributive Justice
The issue of distributive justice between rich and poor countries often obscures the fact that distributive injustices within a country may be compounded by the availability of treatments to only the privileged segments of resource-poor countries. Also—and this is often overlooked—distributive justice encompasses the reciprocal obligation between neighboring countries to ensure that drug resistance emergence is minimized. This illustrates the difficulty of having neighboring countries with and without access to ARV therapy and the disjunction in responsibility that ensues. This is also true for prevention efforts; for example, an excellent Population Services International social marketing program promoting Kapot Pantè (a condom brand) in Haiti but not in the Dominican Republic led to substantial trans-border transportation of condoms, draining condoms away from the intended Haitian population, and Population Services International recently had to launch a new distribution program in the Dominican Republic. This could again happen with ARV therapy, because drugs are presently more widely accessible in Haiti than in the Dominican Republic. Thus, the availability of ARV therapy might paradoxically further the injustices within and across resource-poor countries.
Objective 3: Curbing the HIV Epidemic
Treatment of severely symptomatic patients, as currently recommended in resource-poor countries, is unlikely to affect the epidemic transmission significantly, because most transmission occurs via patients with high viremia who are well enough to engage in sexual activities.1 The latter generally represent the larger pool, especially in countries where survival is limited once AIDS is diagnosed. Curbing the epidemic would thus entail treatment of most HIV patients, including the asymptomatic ones with a high viral load, thereby shifting the incidence and seroprevalence curve to lesser values.5 This naturally presupposes effective large-scale screening and individualized CD4 count and viral load assessments to select those asymptomatic people eligible for treatment. This approach would be most similar to that used in resource-rich countries where all at-risk individuals are encouraged to be tested. Even in these countries, however, this strategy is only marginally successful in identifying eligible patients. Thus, although laudable, this objective is realistically unattainable in most resource-poor countries for the foreseeable future.
Therefore, to summarize the 3 objectives mentioned previously, the population goal of economic stability might be more immediately achieved through targeted treatment of the privileged or productive workforce. The quest for distributive justice might paradoxically lead to a furthering of the gap within and across resource-poor countries, and epidemic containment is unattainable in most settings. Thus, these population objectives should not be seen as primary, because they may indeed conflict with the immediate public health goal of reduced morbidity and mortality for the many; this goal must stand on its own as a primary objective rather than as a vehicle to other goals.
Objective 4: Reducing Morbidity and Mortality
At an individual level, the objectives of reduced morbidity and mortality are naturally the ones directly sought when ARV treatment is initiated. These individual objectives entail an eminently clinicobiological approach to care that originated in resource-rich countries, with the consecrated mainstays of treatment initiation: CD4 counts and the viral load. It has now become clear that viral load assessment is not necessary to initiate treatment,8,9 as reflected in World Health Organization guidelines.9 However, the CD4 count guidelines of resource-rich countries remain a prominent goal.10 In an attempt to replicate resource-rich countries’ treatment guidelines, efforts have been directed toward greater availability or affordability of CD4 counts, cheaper ways to determine viral loads, or substitutes for CD4 counts.11,12
At a population level, however, the goal of reduced morbidity and mortality can be achieved only if a large number of patients receive care. In the collective attempt to do so, HIV health providers have struggled to transpose an individualized, highly biological approach to care onto a massive public health problem. We have ourselves experimented with these approaches in countries with varied seroprevalence rates, for example, in Senegal, Côte d’Ivoire, or Haiti. Indeed, it is the difficulties we have encountered in these various seroprevalence settings that have led us to realize that current approaches, based on model transposition, neglect one singularly important factor: the actual patient load. For example, HIV seroprevalence rates in the United States and in France are estimated to be around 0.25%, leading to a national caseload of 800 000 (Centers for Disease Control and Prevention) to 950 00013 in the United States and 150 000 in France.13 As a comparison, an estimated 250 000 to 400 000 people live with HIV/AIDS in Haiti, a larger patient load than in France, where the population is nearly 8 times larger. India, with the largest number of people living with HIV outside South Africa, has 5.1 million seropositive people,13 and Nigeria, with a relatively low HIV seroprevalence of 5.8%, still yields a caseload of 7 million, nearly 10 times the number of seropositive people in the entire United States.13
A 5% to 10% HIV seroprevalence in the United States or France would translate to a 20-to 40-fold increase in current caseloads. Because of this reality, it is extremely doubtful that current extensive biological monitoring approaches would be either used or simply feasible, even within the United States or France, given the multifold increase in labor, personnel, and infrastructure that such approaches require. As an example, Cohen et al.14 projected that 5.1 million additional patient visits per year would be required to provide routine HIV care in western Kenya alone with the current treatment paradigms. Thus, in spite of improvements in cost and technical requirements for CD4 counts,15,16 replicating the individual monitoring of resource-rich countries remains illusory. It is not simply a matter of cost.
Therefore, addressing the global problem of HIV treatment in high-prevalence/high-caseload (HPHC) countries may require that health decisionmakers first specifically recognize that the public health goal cannot simply be the reduction of morbidity and mortality for those treated but must be the reduction in morbidity and mortality for the many, that is, at a population level. Once that goal is clearly stated, the HIV seroprevalence or caseload constitutes the major operational factor, necessitating that we redefine the problem in the most affected regions as a public health mass therapy program rather than simply a multiplication of clinical situations. Therefore there is a need for a paradigm shift in delivering, monitoring, and assessing success of ARV therapy programs in HPHC settings.
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PROPOSAL FOR A NEW PROGRAM-BASED STRATEGY |
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Initially, from a pragmatic point of view, programs need to be implemented around existing centers (generally, but not always, urban centers because seroprevalence is generally higher in urban centers, populations are more accessible and have more access to care, and tailored training is easier) and radiate outward. In this programmatic approach, extensive evaluation would move away from the individual but would utilize the population as the unit of analysis. Such a programmatic approach implies a small number of specific requirements.
Immediate Planning of First- (ARV) and Second-line (ARV-plus) Drug Supply
Unlike tuberculosis therapy, in which programs have been built largely on first-line treatments, with second-line treatments (directly observed therapy [DOT]-plus) recommended only in settings with established DOT programs,23 ARV-plus programs would need to be planned concurrently because, at a population level, HIV develops resistance to ARV drugs faster than tuberculosis bacilli do to antibiotics.
Program Evaluation in Concordance with the Principles of Mass Therapy
We should abandon individual efficacy in favor of population efficiency as tenets of program success. We propose the following criteria for annual or semiannual population-based evaluation of program success: (1) death rate (overall and HIV-related); (2) incidence of major opportunistic infections, for example, tuberculosis; (3) magnitude of CD4 changes among a sample of treated individuals; (4) proportion of patients with undetectable viral loads among a sample of treated individuals; (5) rates of drug resistance among a sample of treated individuals; and (6) rates of drug resistance among a sample of untreated individuals to estimate the diffusion in the population. Sequential data on CD4 counts, viral loads, and drug resistance, collected on a representative sample of the population, would thus assess treatment efficiency at the population level and inform changes in recommended regional or national treatment guidelines. This is somewhat similar to tuberculosis and malaria therapy, in which treatment guidelines are informed by prevalent drug resistance rates in several countries that do not actually have the effective capacity for individual drug susceptibility testing.
The annual rates of HIV infection among women with first pregnancies also may be incorporated to monitor the continuation of prevention in a comprehensive program.24 Well-integrated prevention programs may benefit from the availability of ARV therapy. Like the "combination prevention" advocated by the Gates Foundation,25 "combination outcomes" should primarily measure program success. Utilizing—and adapting—these proposed criteria across countries and regions should allow more direct comparisons and improve experience sharing.
Simple Schemes for Community-Level HIV Treatment
In a second phase, treatment should move from hospital- and clinic-based to community-based programs with staff at each level trained for appropriate referral dictated by clinical worsening or side effects. This approach would differ from that of resource-rich countries. Moving from well-equipped health care centers in urban sites to ill-equipped suburban or rural areas is an undeniable challenge in HIV care. All personnel should be trained in recognizing adverse outcomes and among them those requiring treatment interruption. Clear referral guidelines should be created and taught.
We must state candidly that in advocating this approach, we recognize that treatment may not be as effective for every patient as that provided by the biological approach. However, this public health approach recognizes reality. Indeed, we wonder whether the difficulties in adapting to the reality dictated by high caseloads are a remnant of the exceptionalism that has historically characterized policy in resource-rich countries, wherein HIV was exempted from traditional public health practices such as contact tracing and partner notification.26 To be frank, in the context of resource-poor countries, this reluctance to implement public heath measures is compounded by the fear of being accused of advocating a 2-tiered system, lesser for the poor and disenfranchised. This fear clouds the reality that even the scaling up of facilities and staff will not change the impossibility of meeting the challenges with the traditional approach.
However, we do advocate scaling up. First, 1 central national or regional reference laboratory must be improved for population-based evaluation of program success (CD4 levels, viral loads, drug-resistance). Second, general laboratories must be improved for individual monitoring of toxicity that will impact overall public health. HIV programs should therefore be linked to primary care,25,27,28 including existing mother–infant programs as well as tuberculosis programs. More specialized treatment can be only at the tertiary care level with training at these levels done accordingly. The demise of exceptionalism can be a good thing.26–28 Naturally, improvements in laboratory techniques and logistics (including personnel training) should be monitored for adaptation of the population-based/individual-based ratio of laboratory tests.
A Plan for Adherence Monitoring
Preliminary data17–19,29 show adherence to be high in several African settings. Careful monitoring of clinic visits to replenish drug supplies, questioning by friendly staff, and validated clinical signs and symptoms might be acceptable surrogate markers of adherence. Regions should be able to reasonably tailor adherence monitoring to their reality with supervision from funding agencies and health authorities. Is universal DOT necessary? In spite of the attractiveness of DOT for ARV therapies, it seems doubtful that in HPHC settings, strict DOT will be practical or possible.30 It would entail the lifelong mobilization of huge numbers of "accompagnateurs" if one were to replicate the successful program of Farmer et al.22 in central Haiti or those of Médecins sans Frontières.31 However, programs should clearly define and integrate their plans for treatment adherence monitoring at the time of initiation of therapy, and funding agencies should insist on those plans and link continued funding to their effective implementation. Black markets for ARV therapies as well as counterfeit drugs are major concerns in countries with poor capacity for pharmacological control, and specific policies must be in place. From a programmatic standpoint, investing in such efforts seems more efficient than investing in large-scale individual immunologic monitoring.
Finally, public health principles require donor agencies to ensure that drugs are not simply delivered to countries and allowed to disappear into the local distribution system. Donor agencies that engage solely in ARV distribution must guard against the illusion of a policy of treatment. Without programs, a narrow policy of drug distribution may simply lead to a policy of drug disappearance masquerading as a policy of treatment. Now that drugs are being made available to countries, both recipients and donors have new responsibilities. Some would argue that a program of drug delivery is better than no program at all. They might further argue that our position of requiring an effective program of drug treatment is equal to advocating that drugs not be delivered at all. This point of view clouds the debate. From a population perspective, if it is morally untenable that drugs be withheld from those regions most in need to prevent resistance in those regions least in need, it is equally ethically impermissible to abdicate the dual responsibility of ensuring that the drugs reach the intended patients and of protecting the efficacy of these drugs. An example of the potentially deleterious effects of unbridled drug delivery without this assurance is provided by nevirapine, distributed largely to pregnant women in certain areas; its use has even been advocated for all women in highly HIV endemic countries.32 Even the brief use of nevirapine in mother-to-child transmission prevention leads to increased resistance to the entire class of drugs, possibly erasing the efficacy of 1 of the 3 major drug classes available for HIV treatment.33 Therefore, preserving the future for both local populations and neighboring countries should be a primary objective.
ARV Therapy Deliverers as Primary Care Deliverers
The dual role of ARV deliverer and primary care deliverer will reduce the stigmatization of HIV and minimize resources and personnel drain. This principle also recognizes reality: a public health problem affecting a substantial number of the population is a primary care issue. The appellation "HIV doctors" should be discouraged.
Of course, easier treatments, with fewer side effects, would make things simpler. We still need the innovation of pharmaceutical companies to develop these better treatments, as much as we needed generic drugs to render the current debate even possible. The superb advocacy of individuals and groups like Médecins Sans Frontières, the Clinton Foundation, or the United Nations, as well as the availability of generic drugs, clearly has to be credited for persuading the pharmaceutical companies to lower their prices. Delaporte’s recent evaluation of a fixed-drug combination pill,34 regrouping generic ARV drugs from different manufacturers, may be seen as a telling illustration of the cooperation that is both possible and needed. However, contrary to popular belief, generic drugs are not always cheaper than patented drugs.35 Therefore, the debate should not be cast in terms of good versus evil, in spite of the obvious temptation to do so.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONPOPULATION OBJECTIVES OF ARV...PROPOSAL FOR A NEW...CONCLUSIONSReferences |
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The urgency of the need to rush HIV treatment to resource-poor countries underscores a true public health emergency, and the achievement of public health goals requires access to the many. However, the understandable fear of rushing in with eyes shut may now lead to the pursuit of laudable yet disproportional responses to an outsized reality. Only a public health approach will allow a timely and proportional impact, with eyes wide open to the dangers and to the responsibilities of all health providers and decisionmakers.
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Acknowledgments |
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Members of the International Training and Research Program in Infectious Disease Epidemiology (INTREPIDE) include Olivier Bouchaud, MD, Anke Bourgeois, MD, Marc Brodin, MD, Jean-Pierre Coulaud, MD, Eric Delaporte, MD, Philippe Deloron, PhD, Moïse Desvarieux, MD, PhD, Arnaud Fontanet, MD, DrPH, Pierre-Marie Girard, MD, Roland Landman, MD, Bernard Larouzé, MD, Jacques Lebras, PhD, Bernard Liautaud, MD, and Sophie Matheron, MD, from the Université de Paris, the Université de Montpellier, the Institut Pasteur de Paris, the Centre Hospitalo-Universitaire de Martinique.
This article is dedicated to Professor Jean-Pierre Coulaud, who in 1997 chaired the first international meeting Guidelines in the Use of Antiretroviral Drugs in Africa in Dakar, Senegal, and remains a fervent advocate for, and an inspiration to, many.
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Footnotes |
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Contributors
M. Desvarieux and P.-M. Girard wrote the original article with substantial input and editing from R. Landman and B. Liautaud.
Accepted for publication December 14, 2004.
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References |
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