Controlling multidrug-resistant tuberculosis and access to expensive drugs: a rational framework
Abstract The emergence and spread of multidrug-resistant tuberculosis (MDR-TB), i.e. involving resistance to at least isoniazid and rifampicin, could threaten the control of TB globally. Controversy has emerged about the best way of confronting MDR-TB in settings with very limited resources. In 1999, the World Health Organization (WHO) created a working group on DOTS-Plus, an initiative exploring the programmatic feasibility and cost-effectiveness of treating MDR-TB in low-income and middle-income countries, in order to consider the management of MDR-TB under programme conditions. The challenges of implementation have proved more daunting than those of access to second-line drugs, the prices of which are dropping.
Using data from the WHO/International Union Against Tuberculosis and Lung Disease surveillance project, we have grouped countries according to the proportion of TB patients completing treatment successfully and the level of MDR-TB among previously untreated patients. The resulting matrix provides a reasonable framework for deciding whether to use second-line drugs in a national programme. Countries in which the treatment success rate, i.e. the proportion of new patients who complete the scheduled treatment, irrespective of whether bacteriological cure is documented, is below 70% should give the highest priority to introducing or improving DOTS, the five-point TB control strategy recommended by WHO and the International Union Against Tuberculosis and Lung Disease. A poorly functioning programme can create MDR-TB much faster than it can be treated, even if unlimited resources are available.
There is no single prescription for controlling MDR-TB but the various tools available should be applied wisely. Firstly, good DOTS and infection control; then appropriate use of second-line drug treatment. The interval between the two depends on the local context and resources. As funds are allocated to treat MDR-TB, human and financial resources should be increased to expand DOTS worldwide.
Keywords Tuberculosis, Multidrug-resistant/ drug therapy/epidemiology/history; Antitubercular agents/therapeutic use/economics; Treatment outcome; Developing countries (source: MeSH, NLM).
Mots clés Tuberculose résistante à la polychimiothérapie/chimiothérapie/épidémiologie/histoire; Antituberculeux/usage thérapeutique/économie; Evaluation résultats traitement; Pays en développement (source: MeSH, INSERM).
Palabras clave Tuberculosis resistente a multidrogas/quimioterapia/epidemiología/historia; Agentes antituberculosos/uso terapéutico/ economía; Resultado del tratamiento; Países en desarrollo (fuente: DeCS, BIREME).
The emergence and spread of multidrug-resistant tuberculosis (MDR-TB) could threaten global TB control. The treatment of patients with MDR-TB is prolonged, expensive and often unsuccessful (1, 2). Many experts assert that standard TB control prevents the emergence of MDR-TB in a cost-effective way (3). Others argue that it is unethical to abandon patients with MDR-TB and maintain that, if untreated, MDR-TB strains will become dominant and undermine TB control in future generations (4). These arguments are of particular consequence in settings where resources are scarce. While additional evidence would help to define the right point between efficiency and equity, we propose a preliminary rational framework for addressing the problem of MDR-TB in various circumstances.
Genesis and magnitude of multidrug-resistant TB
Treatment with only one effective drug, because of inappropriate prescription or poor adherence, suppresses the growth of organisms susceptible to it but permits the multiplication of isolated strains with spontaneous drug-resistance mutations. This phenomenon is called acquired drug resistance. Subsequent transmission leads to TB disease in new patients which is drug-resistant at the outset, a phenomenon known as primary resistance (5). Independent, cumulative events result in MDR-TB, defined as resistance to at least isoniazid and rifampicin. Both the creation and the transmission of drug resistance contribute to its incidence.
Resistance to TB drugs emerged soon after their introduction 50 years ago (6). A survey conducted by the International Union Against Tuberculosis and Lung Disease in 17 countries during the late 1950s found primary resistance of 3.7% for streptomycin, 3% for isoniazid, and 1% for both drugs together (7). Clinical outcomes were poorer with dual resistance (analogous to MDR-TB today), but the problem was deemed unimportant because it accounted for only a small proportion of treatment failures (8). Furthermore, clinical trials demonstrated that standard treatment without routine baseline testing for drug susceptibility produced outcomes similar to those obtained where such testing was applied and individualized treatment was given (9). The introduction of rifampicin in the early 1970s brought about ambulatory short-course chemotherapy, a regimen of three or four drugs including rifampicin for at least the first two months, given over six to nine months (10). This reinforced hopes for the elimination of TB.
By the early 1990s the incidence of TB had increased in the USA (11), following reductions in control programmes associated with the HIV epidemic, growing poverty, and homelessness (12). Poor adherence to recommended treatment regimens by doctors and patients fostered high levels of MDR-TB (13). MDR-TB came to widespread attention with the occurrence of nosocomial and prison outbreaks (14). High case-fatality rates (15) and cases of MDR-TB among health care workers and others (16) led to an increase in public concern (17). WHO declared TB a global emergency in 1993, focusing on developing countries where 95% of cases occurred (18).
Although MDR-TB was one of many concerns in global TB control, there were no data on the magnitude of the problem. For this reason, WHO and the International Union Against Tuberculosis and Lung Disease began the Global Project on Anti-tuberculosis Drug Resistance Surveillance in 1994. A network of supranational reference laboratories provided quality control for drug susceptibility-testing (19). It emerged that the prevalence of multidrug resistance among new patients was generally low, the median value being 1%, especially in Africa. However, several hot spots, i.e. countries or regions where the prevalence of multidrug resistance among new TB patients exceeded 3%, were identified, particularly in the former Soviet Union (20). Drug resistance was found in all 72 countries surveyed by 2000 (21).
International response to growing problem of multidrug-resistant TB
Because of the low prevalence of multidrug resistance in most countries, WHO stressed basic TB control as the priority for the prevention of MDR-TB in low-income countries (20). The world body did not advocate treatment against MDR-TB on a large scale but recommended that individual patients with MDR-TB be referred to clinical experts (22). The reasons for these recommendations included: i) uncertainties about the risk posed by MDR-TB and the rapidity of its spread; ii) the high costs and poor results of treatment in patients with chronic MDR-TB before the 1990s (23); and iii) the potential diversion of resources to MDR-TB instead of expanding the DOTS strategy (the TB control strategy recommended by WHO and the International Union Against Tuberculosis and Lung Disease) (24).
The scenario changed in the second half of the 1990s. In New York City, individualized chemotherapy based on drug susceptibility-testing became nearly as effective in new patients with MDR-TB as in those with drug-susceptible TB (25) and the number of MDR-TB cases decreased by more than 90% during the decade (26). The relatively large number of cases in rich countries made second-line drugs (amikacin, kanamycin, capreomycin, cycloserine, para-aminosalicylic acid (PAS), ethionamide, and the fluoroquinolones) more available and affordable. Yet questions remained about which interventions had led to New York City's success, and about the need, feasibility and cost-effectiveness of this approach in countries with fewer resources.
A pilot project involving community-based treatment of MDR-TB in northern Lima, Peru, challenged the status quo (27): it was shown that it was possible to cure MDR-TB on an outpatient basis in a country where TB was endemic. Advocates of individualized treatment for the control of MDR-TB argued that empirical short-course chemotherapy regimes could amplify the problem of MDR-TB in patients already infected with strains resistant to one or more drugs (27). The human rights of patients dying with MDR-TB in Russian prisons were highlighted (28). The spectre of an explosive, transnational epidemic of MDR-TB was raised, and the price of inaction became a subject of intense debate.
In 1999, WHO created a working group on "DOTS-Plus for multidrug-resistant tuberculosis" to address the management of MDR-TB under programme conditions (29). This initiative seeks to assess the feasibility and cost-effectiveness of treating MDR-TB in low-income and middle-income countries (30). Several pilot projects, using different management and therapeutic strategies, are under way (31). DOTS-Plus has already successfully negotiated a 90% price reduction for selected projects with the pharmaceutical industry (32).
Significance of multidrug-resistant TB
MDR-TB is still infrequent in most countries. Its global prevalence in new patients remains below 2% (20, 21), decades after the introduction of tuberculosis drugs. Increases, although rapid in outbreak settings with immunocompromised people, e.g. those affected by AIDS or malnutrition, have generally been gradual (21). On the other hand, in hot spots in Eastern Europe and elsewhere the levels of MDR-TB are alarming (20, 21).
While some strains of MDR-TB have caused large outbreaks, recent analyses based on molecular epidemiology suggest that they are, on average, less infectious than drug- susceptible organisms (33, 34). Genetic mutations that confer a survival advantage in the presence of an environmental factor may become a functional burden in the absence of such selective pressure (35). The selection factor for MDR-TB is inadequate drug treatment (12), which is prevented by directly observed therapy (36). Thus, even in the absence of widespread treatment of MDR-TB, the prevalence of the latter does not necessarily increase (37).
After TB control was strengthened in New York City the number of MDR-TB cases fell much faster than the total number of TB cases (26). Similarly, during the 1960s in Kolin, then in Czechoslovakia, the number of chronic cases fell ten times faster than new TB cases (38). While second-line drugs were used in those instances, strains that were virtually pan-resistant also disappeared and declines in MDR-TB were achieved with standard short-course chemotherapy (39). With DOTS in place, curing MDR-TB appears to accelerate such trends, with a time-limited increase in costs.
Globally, an estimated 20% of patients with TB default or fail to respond to therapy (40) but less than 2% have MDR- TB. The vast majority of patients who are not successfully treated do not have MDR-TB (Fig. 1), even in hot spots, indicating failure to ensure that drugs are taken properly. This represents inadequacy in the implementation of basic DOTS programmes more than failure in the drugs themselves.
Furthermore, a poorly functioning programme can create MDR-TB much faster than it can be treated, even if unlimited resources are available. MDR-TB results from poor TB management, i.e. inadequate drug treatment followed by lapses in infection control (41), and its prevalence is up to ten times higher in previously treated patients than in new patients (20). The highest priority in stopping MDR-TB must therefore be its prevention. The establishment of DOTS programmes has been shown to reduce the development of MDR-TB in addition to cutting TB mortality by 70% (42).
The programme benefits of treatment against MDR-TB are being evaluated. The costs are substantial. Such treatment requires the administration of drugs that are more toxic and less effective and are given for at least three times as long and at 100 times the cost of basic short-course chemotherapy regimens (22). TB control programmes could spend over 30% of their budgets on less than 3% of their cases. Cost-effectiveness analyses are needed before treatment against MDR-TB is implemented in national programmes.
Susceptibility-testing for second-line anti-TB drugs has not been standardized and has yet to be systematically evaluated for individual clinical management in developing countries. In a community with a true prevalence of MDR-TB of 3%, a laboratory with an average drug susceptibility-testing specificity for rifampicin of 98% and a sensitivity of 96% would report a prevalence of 4.8%, but one-third of patients reported as having MDR-TB would not have it. Widespread testing and treatment of MDR-TB might subject some patients without it to unnecessary expense and toxicity.
The DOTS strategy, developed and field-tested during the 1970s and 1980s, was not designed to cure patients with MDR-TB, especially those with chronic disease (2). However, DOTS can prevent MDR-TB from becoming a serious problem in a population. This has been demonstrated in Benin, Cuba, the Czech Republic, and Kenya, where MDR-TB is virtually non-existent (20). It is also possible that DOTS can reduce MDR-TB once it has occurred; in Burkina Faso (39), Hong Kong (China) (37), Chile, Sierra Leone, and Uruguay, MDR-TB is rare and decreasing (21).
Worldwide, less than one-third of patients with TB are treated in DOTS programmes (40). At most, half the estimated number of patients with TB are officially detected and barely 60% of these complete treatment (40). From a global public health perspective, therefore, the top priority should be the expansion of DOTS. In individual countries or parts of countries, however, additional strategies may be appropriate. In settings where there are large outbreaks of MDR-TB an intensive approach, including infection control, is essential.
Rational strategy for controlling multidrug- resistant TB
On the basis of data from the WHO/International Union Against Tuberculosis and Lung Disease surveillance project (21), Fig. 2 groups countries according to the proportion of TB patients completing treatment successfully and the level of MDR-TB among previously untreated patients. Specific cut-points for what constitutes good clinical outcomes and high levels of MDR-TB have not been empirically validated (43). The resulting matrix provides a reasonable framework for deciding whether to implement treatment against MDR-TB. Since approximately 70% of new cases of MDR-TB occur in only 10 countries a global strategy could emerge while individual countries take appropriate action.
Countries in which the treatment success rate, i.e. the proportion of new patients who complete the scheduled treatment whether bacteriological cure is documented or not, is less than 70% (Fig. 2, quadrants a, b, and c) should give top priority to the introduction or improvement of the DOTS programme. Second-line drugs should not be widely available in such settings. Similarly, in countries with multidrug resistance levels below 1.5% (c, f, i) the treatment of MDR-TB is not a priority, although it could be undertaken on individual clinical grounds with appropriate laboratory support. This category would include most African countries, where it is more important to expand DOTS and to consider interventions to limit the impact of HIV on TB.
Notably, quadrant g is empty: almost no country with treatment success above 85% has a rate of primary MDR-TB above 5%. Countries in quadrant h with intermediate levels of multidrug resistance and achieving more than 85% treatment success, generally countries where DOTS has been well implemented in recent years, are prime locations for DOTS-Plus programmes. A good laboratory and directly observed therapy are essential for the avoidance of patient misclassification and the selection of resistance to second-line drugs. In these few countries, resource mobilization and international assistance for the treatment of MDR-TB is justified.
Countries or regions in the middle of the grid (quadrant e) would benefit from additional evidence. Resource-rich countries in this category would generally offer treatment for patients with MDR-TB. In resource-poor countries, where national programmes can barely afford DOTS, nongovernmental organizations could provide assistance in the implementation and evaluation of DOTS-Plus pilot projects.
The hot spots with multidrug resistance levels above 5% (a, d) represent international public health emergencies. The countries concerned cannot administer individualized treatment against MDR-TB without creating even more drug resistance. If a programme cannot deliver two to four non-toxic drugs for six to nine months after sputum smear microscopy has been performed, the delivery of five to eight drugs that are often toxic for 18 - 30 months with culture and first-line and second-line drug susceptibility-testing is nearly impossible. Such settings require a complete overhaul of control activities and outbreak control operations, and coordinated, intensive and sustained international assistance.
The importance of infection control practices should be emphasized (44). Outbreaks in crowded settings such as hospitals, shelters or prisons, particularly among immunocompromised individuals (with AIDS or malnutrition), are a common denominator in MDR-TB hot spots. Ending such outbreaks was vital in turning the tide of MDR-TB in New York City (45) and Milan (46). No single intervention can control MDR-TB but the various tools available should be applied wisely: firstly, good DOTS and infection control; then second-line drug treatment. The interval between the two depends on the local context and resources.
At present, most national TB programmes do not need to introduce second-line anti-TB therapy in order to control the disease. Access, in this case, is a secondary question. First-line DOTS remains one of the most cost-effective of all public health strategies (47). Relatively simple, standardized short-course chemotherapy regimens can cure more than 90% of new TB patients and prevent transmission of the disease (24).
The emergence and spread of MDR-TB is a symptom of poor programme performance. In the absence of an effective TB control programme, a narrow focus on MDR-TB therapy could, paradoxically, make a bad situation worse. In countries where TB is endemic, resources spent curing a single case of MDR-TB could be used to treat 100 new TB patients. Many lives could thus be saved and the development of new MDR-TB cases could be reduced. This would be fundamentally in keeping with human rights and public health principles. Drug resistance is ubiquitous, but primary MDR-TB is still infrequent after decades of drug treatment. However, the several hot spots that have emerged require urgent attention.
The framework that we propose for dealing with MDR-TB highlights important differences in various programmes. Countries differ not only in their resources but also in matters of epidemiology and health care. The differences may determine which strategy is most appropriate for preventing and controlling TB and MDR-TB. Formal modelling and cost-effectiveness analyses are needed in order to refine the framework, as is research on the transmissibility and overall impact of MDR-TB under programme conditions (43). As a recent paper put it, "the future may not be so dark" (48).
The DOTS-Plus initiative has led to dramatic reductions in the prices of second-line drugs. Pilot projects around the world have qualified for implementation (49) and can be expected to provide important guidance on the evidence-based expansion of treatment against MDR-TB. As funds are allocated for the treatment of MDR-TB in hot spots it is essential to increase human and financial resources for the expansion of DOTS worldwide. The top priority should continue to be the improvement of basic treatment programmes in order to prevent the emergence of MDR-TB. For treatment to be undertaken on a large scale it is important to reduce further the cost of second-line drugs, implement outbreak control, maintain surveillance, improve diagnostic testing, and develop new anti-TB drugs. Only a comprehensive approach, tailored to local conditions, can be expected to prevent a global epidemic of MDR-TB (50).
The authors thank Mario Raviglione, Marcos Espinal and Chris Dye for valuable comments and suggestions on an earlier version of the manuscript. The Rockefeller Foundation has provided funding for WHO's DOTS-Plus initiative. Dr Pablos-Méndez is a member of the Board of Directors of the non-profit Global Alliance for Tuberculosis Drug Development.
Conflicts of interest: none declared.
Lutte contre la tuberculose multirésistante et accès aux médicaments coûteux : un cadre rationnel
L'émergence et la propagation de la tuberculose multirésistante, c'est-à-dire présentant une résistance à au moins l'isoniazide et la rifampicine, pourrait menacer la lutte antituberculeuse dans le monde entier. La conduite à tenir face à la tuberculose multirésistante dans des contextes de ressources limitées est controversée. En 1999, l'OMS a créé un groupe de travail sur le DOTS-Plus, une initiative explorant la faisabilité programmatique et le rapport coût-efficacité du traitement de la tuberculose multirésistante dans les pays de revenu faible à moyen, afin d'examiner la prise en charge de cette affection dans les conditions de mise en œuvre du programme. En fait, les problèmes de cette mise en œuvre se sont avérés plus ardus que ceux posés par l'accès à des médicaments de deuxième intention, dont les prix ont commencé à baisser.
A partir de données du projet de surveillance OMS/Union internationale contre la Tuberculose et les Maladies respiratoires, nous avons groupé les pays selon la proportion de malades tuberculeux ayant achevé leur traitement avec succès et la proportion de cas de tuberculose multirésistante parmi les patients n'ayant encore jamais été traités. La matrice ainsi obtenue fournit un cadre permettant de décider d'utiliser ou non des médicaments de deuxième intention dans un programme national. Les pays dans lesquels le taux de réussite du traitement - c'est-à-dire la proportion de nouveaux malades qui vont jusqu'au bout du traitement prévu, que la guérison bactériologique soit documentée ou non - est inférieur à 70 % devraient donner la priorité à l'introduction ou à l'amélioration du DOTS, la stratégie de lutte antituberculeuse en cinq points recommandée par l'OMS et l'Union internationale contre la Tuberculose et les Maladies respiratoires. Un programme défectueux peut générer une multirésistance plus vite qu'il n'est capable de la traiter, même en disposant de ressources illimitées.
Il n'existe pas de recette unique pour lutter contre la Tuberculose Multirésistante sinon une utilisation judicieuse des divers outils disponibles : tout d'abord un DOTS correctement appliqué et des pratiques de lutte contre l'infection, et ensuite le recours approprié à des médicaments de deuxième intention. L'intervalle entre ces deux phases dépendra du contexte et des ressources locaux. Lorsque des fonds sont alloués pour le traitement de la tuberculose multirésistante, il est nécessaire d'augmenter les ressources humaines et financières pour étendre l'utilisation du DOTS dans le monde.
Control de la tuberculosis polifarmacorresistente y acceso a medicamentos costosos: un marco racional
La aparición y propagación de la tuberculosis polifarmacorresistente - es decir, la caracterizada por la resistencia a por lo menos la isoniazida y la rifampicina - podría poner en peligro el control de la tuberculosis a nivel mundial. Hay opiniones discrepantes respecto a la mejor manera de hacer frente a la tuberculosis polifarmacorresistente en los entornos con recursos muy limitados. En 1999 la OMS creó un grupo de trabajo sobre la DOTS-Plus, una iniciativa que analiza la viabilidad programática y la costoeficacia del tratamiento de la tuberculosis polifarmacorresistente en los países de ingresos bajos y de ingresos medios, a fin de considerar el tratamiento de la tuberculosis polifarmacorresistente en el marco de las condiciones de los programas. Los problemas de ejecución han resultado ser más desalentadores que los asociados al acceso a los medicamentos de segunda línea, cuyos precios están disminuyendo.
Usando datos del proyecto de vigilancia de la OMS/Unión Internacional Contra la Tuberculosis y las Enfermedades Pulmonares, hemos agrupado a los países según la proporción de enfermos tuberculosos que terminan el tratamiento con éxito y según el nivel de tuberculosis polifarmacorresistente entre los pacientes no tratados con anterioridad. La matriz resultante brinda un marco razonable para decidir si conviene usar medicamentos de segunda línea en un programa nacional. Los países en los que la tasa de éxito terapéutico - esto es, la proporción de nuevos pacientes que terminan el tratamiento previsto, esté o no documentada la curación bacteriológica - es inferior al 70% deberían asignar la máxima prioridad a la introducción o la mejora de la DOTS, la estrategia de cinco puntos para el control de la tuberculosis recomendada por la OMS y la Unión Internacional contra la Tuberculosis y las Enfermedades Pulmonares. Un programa mal ejecutado puede generar tuberculosis polifarmacorresistente a un ritmo muy superior al de su tratamiento, aun con recursos ilimitados.
No hay una receta única para combatir la tuberculosis polifarmacorresistente, pero es preciso aplicar juiciosamente las diversas herramientas disponibles. En primer lugar, hay que aplicar bien el DOTS para controlar la infección; y a continuación debe aplicarse debidamente el tratamiento farmacológico de segunda línea. El intervalo entre los dos dependerá del contexto y de los recursos locales. Al tiempo que se asignen fondos para tratar la tuberculosis polifarmacorresistente, deberán aumentarse los recursos humanos y financieros para ampliar la estrategia DOTS a nivel mundial.
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▲ College of Physicians and Surgeons, Columbia University, New York, USA.
▲ The Rockefeller Foundation, New York, USA. Correspondence should be addressed to Dr Pablos-Méndez, The Rockefeller Foundation, 420 Fifth Avenue, 21st Floor, New York, NY 10018, USA (email: firstname.lastname@example.org).
▲ Department of Health, New York City, USA.
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