- Email: [email protected]
Directly observed therapy for tuberculosis: history of an idea
Directly observed therapy for tuberculosis: history of an idea
Introduction
city with
Directly observed therapy has emerged as the standard of care in the treatment of tuberculosis in the USA. In response to the dismal record of assuring that those with tuberculosis complete their treatment, the problems of tuberculosis in persons with HIV infection, and the public alarm that attended the emergence of multidrug-resistant tuberculosis in New York, the Advisory Council for the Elimination of Tuberculosis (ACET) has recommended that directly observed therapy be considered for all patients in locales that do not achieve at least a 90% completion rate for treatment.’ What is so striking about these developments in public-health practice is that they were so long in coming. Indeed, the idea of using directly observed theapy for all, or virtually, all patients with tuberculosis emerged more than three decades ago as a result of work in Madras, and Hong Kong.
miles
Madras and
Hong Kong: lessons from the
East
The advent of chemotherapy in the late 1940s and early 1950s transformed the treatment of tuberculosis and hastened the demise of long-term hospitalisation as the standard management of the disease. In Africa and Asia, the disparity between the prevalence of tuberculosis and the availability of hospital beds2 made ambulatory care the only viable option. But how would such care compare to that which could be provided under the controlled conditions of the hospital? That was the central question posed by a British Medical Research Council (MRC) study in Madras, India, which sought to compare ambulatory and sanatorium-based drug therapy. In his first published analysis of the Madras study in 1958,Fox underscored the problem of achieving high rates of compliance with treatment among ambulatory patients. Despite intensive efforts to monitor the intake of aminosalicylic acid through urine testing, the counting of pills in the possession of patients at each clinic visit, and even through unannounced home visits, "Irregularity [had] been a problem throughout the course of treatments". Fox thus concluded in the very early days of the antibiotic treatment of tuberculosis that whereas the issue of which oral medications to use was important, it was "less fundamental" than the regularity with which patients would self-administer treatment over the long term. Given this situation, it was no surprise that Fox began an examination of the potential efficacy of supervised therapy in Madras. Despite the fact that the patients involved came from a poverty-stricken community in a Columbia University School of Public Health, 600 West 168th Street, New York, NY 10032, USA (Prof R Bayer PhD, D Wilkinson MB); and HIV Center for Clinical and Behavioural Studies, New York State Psychiatric Institute (Prof R Bayer)
Correspondence to: Prof Ronald Bayer
a poor transport system and that travel of up to 5 the clinics was necessary, it was possible to get patients to come to clinic 6 days a week for streptomycin injection and a supervised oral dose of pyrazinamide. The implications for poor as well as developed nations-a central concern of Fox was to draw lessons for the latter from his work in the former-was clear: "Long term daily supervised administration can be organized under special circumstances, even in developing countries".4 Equally importantly, Fox began in the early 1960s to explore the possibility of moving away from daily doses of medication to an intermittent regimen. Intermittent therapy was potentially a great advance because it made the supervision of treatment easier. However, such therapy made supervision all the more critical given the importance of taking every dose prescribed. A trial of intermittent therapy begun in Madras in 1961 found that an intermittent approach could indeed be effective.5 Paralleling the move toward directly observed therapy in Madras were the efforts undertaken in Hong Kong,.6 The prevailing situation in which 2% of the adult population had tuberculosis, dictated adoption of mass ambulatory care. Indeed, the first clinic for such care was opened in 1950, 8 years before the first reports of the Madras trials. By the early 1960s, the treatment regimen entailed direct supervision. For the first 25 weeks all patients were provided with injections of streptomycin and an oral dose of aminosalicylic acid and isoniazid. Although the daily injections required clinic visits, it was only on the suggestion of Fox that Moodie, the architect of Hong Kong’s ambulatory-care system, moved to supervision of oral medication during the first 6 months of treatment (Wallace Fox, personal communication). A central feature of the Hong Kong effort was to make the ambulatory clinics as convenient for patients as possible. Indeed, mirroring the experience of Madras and with important implications for the care of patients in wealthier industrialised nations, Moodie stressed that clinic organisation had to be determined according to the needs of patients and not the convenience of the staff. With this approach, 70% of patients completed therapy during an average of 2! months. Critical as were the insights gained in Madras and Hong Kong, they might well have been dismissed as relevant only for societies just emerging from, or still characterised by, colonialism, poverty, and illiteracy. However, the problems of compliance and the need to ensure that patients took their prescribed medication were not restricted to the developing countries. At about the same time that Fox and Moodie were beginning their pioneering work, Stradling and Poole of the Hammersmith Clinic, London, expressed their concern over the limits of self-medication by tuberculosis patients.7 Doubting the efficacy of "exhortations" for improving compliance and acknowledging that physicians knew too
to
1545
little
to be certain that patients were in fact taking their medication, they required that patients be treated six times a week with streptomycin injections at which time they were given an oral dose of isoniazid. But the demands of daily attendance imposed limits on the success of the therapeutic regimen established at the Hammersmith Clinic. Only 51 % of patients completed 18 months of streptomycin and isoniazid. It was these very limits that reinforced the case for development of an intermittent regimen that, if possible, was considerably briefer than the then prevailing standard of care. Thus, by the early 1960s, those concerned with tuberculosis control in places as diverse as Hong Kong, Madras, and London had concluded that effective treatment required direct supervision of therapy and that only such an approach could interrupt a general tendency-not restricted to those with tuberculosis-on the part of patients to cease taking medications when they no longer felt ill. Most importantly, this practice avoided the necessity of having to determine before the start of treatment which patients represented a higher risk for non-compliance. 8
Supervised therapy in the USA While the evidence from abroad suggested that a broad application of supervised therapy was necessary, tuberculosis-control efforts in the USA all but ignored the relevance of such findings and remained focused on what insights might be relied upon to predict patient behaviour and medication use, and on the importance of fashioning clinical structures and practices that would overcome noncompliance. Thus, in 1964 Curry9 described "problem patients" in San Francisco, who came from the "lowest socio-economic groups of all races". To enhance patient cooperation, "to protect the community, the patient and prevent the spread of resistant organisms", Curry believed it crucial to focus on the sociocultural context of missed clinic appointments. In 1966, Moulding of the National Jewish Hospital, Denver," emphasised the importance of educating patients to take their medication, of developing clinical approaches that met the needs of patients, of responding to the first indications of non-cooperation, and of employing surveillance through urine tests to detect the failure to take prescribed medication. Complete supervision was necessary, said Moulding, only for the unreliable or questionably reliable individuals. 10 Indeed, he described a pioneering programme initiated in Denver in 1965 that relied on twice-weekly supervised isoniazid and streptomycin for 21 uncooperative patients, only 1 of whom had been lost to contact. For those who were reliable-Moulding referred to them as the "equal or larger number who follow instructions quite faithfully"completely supervised therapy would be "unnecessary", a "diversion of resources". Sbarbaro and Johnson," whose work was influenced by Fox and Moodie, went on to provide greater detail of the trial of twice-weekly supervised treatment of unreliable patients in Denver. Among those included in the everexpanding trial were patients who admitted that they had failed to take their medication regularly, had demonstrated irregularity, or had a history of "sociopathic behavior" as evidenced by conflict with the law, jail missed clinic sentences, appointments, chronic treatment. In all, or failure of tuberculosis alcoholism, Sbarbaro noted that as many as 75% of patients treated at 1546
Denver General Hospital could be classified as unreliable. Sbarbaro’s ultimate embrace of supervised treatment for all patients put him at odds with virtually the entire tuberculosis-control establishment. Beginning in the late 1970s, Sbarbaro began a lonely but persistent campaign to transform the practice of outpatient care of tuberculosis patients. Central to his mission was an effort to characterise the problem of compliance with medical regimens as one that extended beyond the narrow class of "unreliable" patients. Taking a dim view of human nature and echoing the observations made by Fox almost two decades earlier, he asserted, "Unfortunately the health behavior of most people is unpredictable and does not conform with our expectation that patients will follow what their physicians recommend".’2 Sbarbaro thus broke with the long tradition of seeking to identify those characteristics that would be predictive of non-compliance. But direct supervision required that intermittent therapy replace daily doses of medication. Sbarbaro noted "there have been no reports of successful outpatient programs in which long term daily supervised treatment was the keystone of the therapeutic programme". 12 Sbarbaro’s arguments for and claims on behalf of supervised therapy formed the basis of the case for universal application of such care.13-15 To the obvious challenge that such an approach would impose unacceptable costs on local tuberculosis control programmes, he responded by presenting cost-benefit analyses that were the hallmark of his efforts. Against the costs associated with supervised treatment he compared the costs linked to the treatment of relapses and failures that might be anticipated with selfadministration. Despite the tenacity with which Sbarbaro pressed the case for directly observed therapy, practice in the USA continued to be centred on self-administration. Directly observed therapy remained the exception rather than the rule in the face of evidence to support this approach in problem patients,16,17 and recommendations from the Centers for Disease Control (CDC) and the American Thoracic Society that difficult patients be placed on twice weekly supervised therapy. 18 In addition, the CDC attempted to encourage use of supervised treatment with difficult patients as early as 1980 through grants to Miami, Los Angeles, and New York, and a report by the American Thoracic Society in 1985 concluded that unemployed alcoholic patients in inner cities should be
placed on supervised treatment.’9 Underscoring the extent of the gulf that existed between those who viewed directly observed therapy for most if not all patients as vital and the then standard practice even among difficult patients, were the notoriously low treatment-completion rates in New York City. In 1984-85 the New York City Department of Health identified 305 patients it deemed as meeting criteria for its supervised therapy programme-ie, frequently missed appointments, drug resistance, mental incompetence, chronic alcoholism, failure to respond to therapy, two hospital admissions for treatment of tuberculosis, and living conditions unconducive to compliance with ambulatory care. Only 114 were located and enrolled in the programme.20 As of December, 1986, 59 patients were treated under supervision.21 In 1988, 93 patients were under such care (New York City Department of Health, unpublished data). What accounted for the failure to use directly
supervised therapy despite the fact that at least 20-30% of patients throughout the USA failed to complete treatment within 24 months? Many health departments believed that requiring individuals to take their medication in the presence of a responsible party would entail unacceptable assumptions about the prospect of the future behaviour of those under care. Rather than a service, directly observed therapy was often viewed as an imposition that could be justified only in the presence of evidence that the patient would behave in a way that posed a threat to the public health. At a later date, some argued that widespread application of directly observed therapy entailed an inversion of a basic human right by treating tuberculosis patients as guilty until proven innocent. But the most important factor was the assumption that the widescale use of supervised therapy would entail an extraordinary and unjustifiable expense. Certainly questions of cost and limitations on available resources were among the factors that played a part in the failure of the CDC to press publicly for the wider adoption of directly observed therapy as a practice even when some believed such a move would have salutory consequences. (D Snyder, severe
CDC, personal communication.) There were, however, examples of successful application of directly observed therapy in the 1980s. Not surprisingly, in Denver, Sbarbaro’s home base, an average of 60% of tuberculosis
patients treated between 1973 and 1983 were supervised. More striking, there were a few locales where directly observed therapy was adopted as a universal or near universal approach in tuberculosisIn Baltimore, Glasser, the treatment programmes. Commissioner of Health, introduced directly observed therapy to a city that had long been known for its high rates of tuberculosis. Glasser, who was influenced by the work of the International Union Against Tuberculosis and by Moodie, began his efforts with noncompliant patients but rapidly moved to include all patients treated by the city’s tuberculosis programme (privately treated patients were not included). In Mississippi, directly observed therapy began with non-compliant patients in the early 1980s in one region. By the decade’s end, the programme had extended to the entire state.22 In the early 1990s, 98% of tuberculosis patients were treated by directly observed therapy. Finally, in Tarrant County, Texas,23 after an outbreak of multidrug-resistant tuberculosis in the mid1980s, the Director of Public Health started a programme in consultation with Sbarbaro of directly observed therapy for all publicly treated patients (S E Weis, Tarrant County Health Department, personal communication). This initiative was undertaken without additional funds. That these developments occurred despite limited support from federal authorities makes clear the fact that resource constraints explained only a part of the resistance in the USA to directly observed therapy. Where there was a political commitment to instituting such an approach to tuberculosis contol it was possible to make substantial changes. Such commitment also required a cultural climate within which supervision of all, or nearly all, patients was not offensive. Certainly the cultural climate in Texas and Mississippi was very different from that in northern states, making possible tuberculosiscontrol initiatives that might otherwise have been viewed as unacceptably authoritarian. The availability of resources and the political and cultural climate surrounding tuberculosis control underwent a radical transformation in the early 1990s as a
result of a rising number of cases, an increase in drugresistance disease, and nosocomial outbreaks in hospitals. As a result of the fear that what had been a treatable disease might become an untreatable danger to middleclass populations that had in recent years been spared the threat of tuberculosis, concern took hold about the rate at which patients failed to complete their tuberculosis therapy in cities such as New York, Chicago, Newark, and Washington. Public concern and a demand for remedial action provoked Congress to greatly increase funding for tuberculosis-control efforts. In all, the money available to CDC for tuberculosis control rose from$25 million in 1991 to$104 million in 1993 (CDC, unpublished data). Central to the new commitment was a striking determination to place directly observed therapy for most if not all patients at the centre of public-health efforts. When in 1993, the ACET made directly observed therapy the standard of care, as a matter of federal policy,’1 it turned from the decades-long efforts to identify individuals at high risk for non-compliance and more recent attempts to designate groups as being at high risk for failure to complete their tuberculosis treatment. The council stated that "Directly observed therapy should be considered for all patients because of the difficulty in predicting which patients will adhere to a prescribed regimen. Decisions regarding the use of expanded or universal directly observed therapy should be based on a quantitative evaluation of local treatment completion rates". In a compromise dictated by those who viewed universal directly observed therapy as unnecessary, where other approaches had proven effective, the ACET stipulated that universal directly observed therapy be relied upon in those locales where treatment completion rates fell below 90%. But even in settings where treatment completion exceeded 90%, it urged that "consideration should be given to extending the use of directly observed therapy to [further] increase treatment-completion rates". The recommendations of the ACET were reflected in the CDC’s standards for cooperative agreement applications from state and local health departments seeking funds for tuberculosis elimination. The transformation of federal policy has been reflected at the local level as state, county, and municipal health departments shape their tuberculosis policies and practices. In Chicago, since June 1, 1993, all newly diagnosed tuberculosis cases treated in health department clinics have been placed on directly observed therapy (Chicago Department of Health, unpublished data). In Rhode Island, in response to 9 cases of multidrugresistant tuberculosis and a number of patients deemed to be at high risk for non-adherence, the health department increased availability of directly observed therapy in mid1993. In the 6 months before June, 1993, 34% of cases were placed on directly observed therapy; this figure had risen to 80% by the last 6 months of the year (Rhode Island Department of Health, unpublished data). But most remarkable has been the changes in outlook and practice in New York City, which has embarked on a massive expansion of directly observed therapy, although mandatory measures have been rejected. In December, 1991, New York had 137 people on directly observed therapy; by the end of 1993 the number had risen to 1282 (New York City Department of Health, unpublished data). When the number of new tuberculosis cases in 1993 in New York declined for the first time in 15 years, the reversal was attributed to the enhanced role of directly 1547
observed
therapy. The
when in March, tuberculosis cases was
same was true
in
1995, a further decline announced.24 The embrace of the principle of universal or nearuniversal directly observed therapy by federal, state, and local health departments, has, not surprisingly, provoked opposition from some public-health officials, who believe that their own programmes were effective without the need to devote resources to so labour-intensive an effort. More striking has been the criticism from those for whom civil liberties are of pre-eminent importance. Such criticisms have not opposed the universal offer of directly observed therapy, making it available to all patients as a service. Nor have they opposed the imposition of directly observed therapy by court order after patients have shown that they cannot adhere to the prescribed treatment regimen. What civil liberties groups have found appalling-a violation of the constitutional requirement that the state use the least restrictive alternative in pursuit of public-health goals-is the notion that all or nearly all patients, irrespective of behaviour, should be required to ingest their medication in the presence of an observer.25 The designation of classes of patients-the poor, the homeless, drug users-as being at high risk for noncompliance and as requiring directly observed therapy, was viewed as particularly offensive.26 Despite such objections we believe that the weight of historical evidence and recent experience make the move to directly observed therapy as a standard of care crucial to the prevention of drug resistance. The insights gained into the epidemiology of tuberculosis through molecular techniques can only reinforce the case for the reliance on directly observed therapy from the start of treatment. In San Francisco, restriction fragment length polymorphism studies suggested that 40% of cases diagnosed in 1991 and 1992 were the result of recent transmission and indicated that individual noncompliant patients were responsible for sizeable clusters of disease. 1 noncompliant patient accounted for 6% of all the cases evaluated.27 As directly observed therapy programmes are started or expanded, it will be necessary to determine the appropriate mix of clinic-based care and care provided by community-based outreach workers; the need for provision of housing for homeless patients; the need for drug and alcohol abuse treatment, and psychiatric services for those who are impaired; the part to be played by financial inducements for remaining in care; and the functions of court mandates and the ultimate threat of compulsory hospitalisation for those who refuse to remain in treatment until cured. In short, it will be necessary to examine carefully the role of enablers and incentives.28 None of these studies will be simple or cheap, and all will require that resources for tuberculosis-control remain adequate, even if the number of new cases declines. Recognising the centrality of directly observed therapy is thus just the beginning of the challenge posed by tuberculosis. RB was supported by the Robert Wood Johnson Foundation, by center grant P50-MH43520 from NIMH, Dr Anke A Ehrhardt, principal investigator, HIV Center for Clinical and Behavioural Studies, New York
1548
State Psychiatric Institute, and by the Health Services Improvement Fund of Empire Blue Cross/Blue Shield of Greater New York. DW was supported by Fogarty International Center Grant [NIH] 5D43#TWOO231.
References
Advisory Council for the Elimination of Tuberculosis. Initial therapy for tuberculosis in the era of multidrug resistance: recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR
1
1993; 42: RR/7. Tuberculosis chemotherapy centre, Madras. A concurrent comparison of home and sanitorium treatment of pulmonary tuberculosis in South India. Bull World Health Organ 1959; 21: 51-144. 3 Fox W. The problem of self-administration of drugs; with particular reference to pulmonary tuberculosis. Tubercle 1958; 39: 269-74. 4 Fox W. Self-administration of medicaments: a review of published work and a study of the problems. Bull Int Union Tuberc 1962; 32: 307-31. 5 Tuberculosis chemotherapy centre, Madras. A concurrent comparison of intermittent (twice weekly) isoniazid plus streptomycin and daily isoniazid plus PAS in the domiciliary treatment of pulmonary tuberculosis. Bull World Health Organ 1964; 31: 247-71. 6 Moodie AS. Mass ambulatory chemotherapy in the treatment of tuberculosis in a predominantly urban community. Am Rev Respir Dis
2
1967; 95: 384-97. Stradling P, Poole G. Self-medication in tuberculosis. Lancet 1958; ii:
7
1066-67. Poole G. Towards foolproof chemotherapy for tuberculosis. Tubercle 1963; 44: 71-75. 9 Curry F. District clinics for out patient treatment of tuberculosis problem patients. Br J Dis Chest 1964; 46: 524-30. 10 Moulding T. New responsibilities for health departments and public health nurses in tuberculosis-keeping the outpatient on therapy. Am J Public Health 1966; 56: 416-27. 11 Sbarbaro JA, Johnson S. Tuberculous chemotherapy for recalcitrant outpatients administered directly twice weekly. Am Rev Respir Dis 1968; 97: 895-903. 12 Sbarbaro JA. Public health aspects of tuberculosis: supervision of therapy. Clin Chest Med 1980; 1: 253-63. 13 Sbarbaro JA. Compliance: inducements and enforcements. Chest 1979; 6 (suppl): 750-56. 14 Sbarbaro JA. The nature of man and physician. Am Rev Respir Dis 8
Stradling P,
1981; 123: 247. 15 Sbarbaro JA. All patients should receive directly observed therapy in tuberculosis. Am Rev Respir Dis 1988; 138: 1075-76. 16 McDonald RJ, Memon AM, Reichman LB. Successful supervised ambulatory management of tuberculosis treatment failures. Ann Intern Med 1982; 96: 297-302. 17 Committee on non-drug issues in chemotherapy. Non-drug issues related to the treatment of tuberculosis. Chest 1985; 87: 125-27S. 18 American Thoracic Society. Guidelines for short-course tuberculosis chemotherapy. Am Rev Respir Dis 1980; 212: 611-14. 19 American Thoracic Society. Standard therapy for tuberculosis 1985.
Chest 1985; 87: 177-24S. 20 New York Lung Association. Tuberculosis in New York City 1984-85. New York: New York Lung Association, 1987. 21 New York Lung Association. Tuberculosis in New York City 1986. New York: New York Lung Association, 1988. 22 Hotchkiss RL. Directly observed treatment of tuberculosis. N Engl J Med 1993; 329: 135. 23 Weis SE, Clocum PC, Blais FX, et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994; 330: 1179-84. 24 Jones C. Tuberculosis cases decline second year in a row, city says. New York Times 1995; March 14; p B1. 25 Annas G. Control of tuberculous: the law and the public health. N Engl
J Med 1993; 328: 585-88. 26 Gostin LO. Controlling the resurgent tuberculosis epidemic. JAMA 1993; 269: 255-61. 27 Small PM, Hopewell PC, Singh SP, et al. The epidemiology of tuberculosis in San Francisco: a population-study using conventional and molecular methods. N Engl J Med 1994; 330: 1703-09. 28 Bloch AB, Sumartojo E, Castro KG, Centers for Disease Control and Prevention. Directly observed therapy for tuberculosis in New York City. JAMA 1994; 262: 436.
Introduction
city with
Directly observed therapy has emerged as the standard of care in the treatment of tuberculosis in the USA. In response to the dismal record of assuring that those with tuberculosis complete their treatment, the problems of tuberculosis in persons with HIV infection, and the public alarm that attended the emergence of multidrug-resistant tuberculosis in New York, the Advisory Council for the Elimination of Tuberculosis (ACET) has recommended that directly observed therapy be considered for all patients in locales that do not achieve at least a 90% completion rate for treatment.’ What is so striking about these developments in public-health practice is that they were so long in coming. Indeed, the idea of using directly observed theapy for all, or virtually, all patients with tuberculosis emerged more than three decades ago as a result of work in Madras, and Hong Kong.
miles
Madras and
Hong Kong: lessons from the
East
The advent of chemotherapy in the late 1940s and early 1950s transformed the treatment of tuberculosis and hastened the demise of long-term hospitalisation as the standard management of the disease. In Africa and Asia, the disparity between the prevalence of tuberculosis and the availability of hospital beds2 made ambulatory care the only viable option. But how would such care compare to that which could be provided under the controlled conditions of the hospital? That was the central question posed by a British Medical Research Council (MRC) study in Madras, India, which sought to compare ambulatory and sanatorium-based drug therapy. In his first published analysis of the Madras study in 1958,Fox underscored the problem of achieving high rates of compliance with treatment among ambulatory patients. Despite intensive efforts to monitor the intake of aminosalicylic acid through urine testing, the counting of pills in the possession of patients at each clinic visit, and even through unannounced home visits, "Irregularity [had] been a problem throughout the course of treatments". Fox thus concluded in the very early days of the antibiotic treatment of tuberculosis that whereas the issue of which oral medications to use was important, it was "less fundamental" than the regularity with which patients would self-administer treatment over the long term. Given this situation, it was no surprise that Fox began an examination of the potential efficacy of supervised therapy in Madras. Despite the fact that the patients involved came from a poverty-stricken community in a Columbia University School of Public Health, 600 West 168th Street, New York, NY 10032, USA (Prof R Bayer PhD, D Wilkinson MB); and HIV Center for Clinical and Behavioural Studies, New York State Psychiatric Institute (Prof R Bayer)
Correspondence to: Prof Ronald Bayer
a poor transport system and that travel of up to 5 the clinics was necessary, it was possible to get patients to come to clinic 6 days a week for streptomycin injection and a supervised oral dose of pyrazinamide. The implications for poor as well as developed nations-a central concern of Fox was to draw lessons for the latter from his work in the former-was clear: "Long term daily supervised administration can be organized under special circumstances, even in developing countries".4 Equally importantly, Fox began in the early 1960s to explore the possibility of moving away from daily doses of medication to an intermittent regimen. Intermittent therapy was potentially a great advance because it made the supervision of treatment easier. However, such therapy made supervision all the more critical given the importance of taking every dose prescribed. A trial of intermittent therapy begun in Madras in 1961 found that an intermittent approach could indeed be effective.5 Paralleling the move toward directly observed therapy in Madras were the efforts undertaken in Hong Kong,.6 The prevailing situation in which 2% of the adult population had tuberculosis, dictated adoption of mass ambulatory care. Indeed, the first clinic for such care was opened in 1950, 8 years before the first reports of the Madras trials. By the early 1960s, the treatment regimen entailed direct supervision. For the first 25 weeks all patients were provided with injections of streptomycin and an oral dose of aminosalicylic acid and isoniazid. Although the daily injections required clinic visits, it was only on the suggestion of Fox that Moodie, the architect of Hong Kong’s ambulatory-care system, moved to supervision of oral medication during the first 6 months of treatment (Wallace Fox, personal communication). A central feature of the Hong Kong effort was to make the ambulatory clinics as convenient for patients as possible. Indeed, mirroring the experience of Madras and with important implications for the care of patients in wealthier industrialised nations, Moodie stressed that clinic organisation had to be determined according to the needs of patients and not the convenience of the staff. With this approach, 70% of patients completed therapy during an average of 2! months. Critical as were the insights gained in Madras and Hong Kong, they might well have been dismissed as relevant only for societies just emerging from, or still characterised by, colonialism, poverty, and illiteracy. However, the problems of compliance and the need to ensure that patients took their prescribed medication were not restricted to the developing countries. At about the same time that Fox and Moodie were beginning their pioneering work, Stradling and Poole of the Hammersmith Clinic, London, expressed their concern over the limits of self-medication by tuberculosis patients.7 Doubting the efficacy of "exhortations" for improving compliance and acknowledging that physicians knew too
to
1545
little
to be certain that patients were in fact taking their medication, they required that patients be treated six times a week with streptomycin injections at which time they were given an oral dose of isoniazid. But the demands of daily attendance imposed limits on the success of the therapeutic regimen established at the Hammersmith Clinic. Only 51 % of patients completed 18 months of streptomycin and isoniazid. It was these very limits that reinforced the case for development of an intermittent regimen that, if possible, was considerably briefer than the then prevailing standard of care. Thus, by the early 1960s, those concerned with tuberculosis control in places as diverse as Hong Kong, Madras, and London had concluded that effective treatment required direct supervision of therapy and that only such an approach could interrupt a general tendency-not restricted to those with tuberculosis-on the part of patients to cease taking medications when they no longer felt ill. Most importantly, this practice avoided the necessity of having to determine before the start of treatment which patients represented a higher risk for non-compliance. 8
Supervised therapy in the USA While the evidence from abroad suggested that a broad application of supervised therapy was necessary, tuberculosis-control efforts in the USA all but ignored the relevance of such findings and remained focused on what insights might be relied upon to predict patient behaviour and medication use, and on the importance of fashioning clinical structures and practices that would overcome noncompliance. Thus, in 1964 Curry9 described "problem patients" in San Francisco, who came from the "lowest socio-economic groups of all races". To enhance patient cooperation, "to protect the community, the patient and prevent the spread of resistant organisms", Curry believed it crucial to focus on the sociocultural context of missed clinic appointments. In 1966, Moulding of the National Jewish Hospital, Denver," emphasised the importance of educating patients to take their medication, of developing clinical approaches that met the needs of patients, of responding to the first indications of non-cooperation, and of employing surveillance through urine tests to detect the failure to take prescribed medication. Complete supervision was necessary, said Moulding, only for the unreliable or questionably reliable individuals. 10 Indeed, he described a pioneering programme initiated in Denver in 1965 that relied on twice-weekly supervised isoniazid and streptomycin for 21 uncooperative patients, only 1 of whom had been lost to contact. For those who were reliable-Moulding referred to them as the "equal or larger number who follow instructions quite faithfully"completely supervised therapy would be "unnecessary", a "diversion of resources". Sbarbaro and Johnson," whose work was influenced by Fox and Moodie, went on to provide greater detail of the trial of twice-weekly supervised treatment of unreliable patients in Denver. Among those included in the everexpanding trial were patients who admitted that they had failed to take their medication regularly, had demonstrated irregularity, or had a history of "sociopathic behavior" as evidenced by conflict with the law, jail missed clinic sentences, appointments, chronic treatment. In all, or failure of tuberculosis alcoholism, Sbarbaro noted that as many as 75% of patients treated at 1546
Denver General Hospital could be classified as unreliable. Sbarbaro’s ultimate embrace of supervised treatment for all patients put him at odds with virtually the entire tuberculosis-control establishment. Beginning in the late 1970s, Sbarbaro began a lonely but persistent campaign to transform the practice of outpatient care of tuberculosis patients. Central to his mission was an effort to characterise the problem of compliance with medical regimens as one that extended beyond the narrow class of "unreliable" patients. Taking a dim view of human nature and echoing the observations made by Fox almost two decades earlier, he asserted, "Unfortunately the health behavior of most people is unpredictable and does not conform with our expectation that patients will follow what their physicians recommend".’2 Sbarbaro thus broke with the long tradition of seeking to identify those characteristics that would be predictive of non-compliance. But direct supervision required that intermittent therapy replace daily doses of medication. Sbarbaro noted "there have been no reports of successful outpatient programs in which long term daily supervised treatment was the keystone of the therapeutic programme". 12 Sbarbaro’s arguments for and claims on behalf of supervised therapy formed the basis of the case for universal application of such care.13-15 To the obvious challenge that such an approach would impose unacceptable costs on local tuberculosis control programmes, he responded by presenting cost-benefit analyses that were the hallmark of his efforts. Against the costs associated with supervised treatment he compared the costs linked to the treatment of relapses and failures that might be anticipated with selfadministration. Despite the tenacity with which Sbarbaro pressed the case for directly observed therapy, practice in the USA continued to be centred on self-administration. Directly observed therapy remained the exception rather than the rule in the face of evidence to support this approach in problem patients,16,17 and recommendations from the Centers for Disease Control (CDC) and the American Thoracic Society that difficult patients be placed on twice weekly supervised therapy. 18 In addition, the CDC attempted to encourage use of supervised treatment with difficult patients as early as 1980 through grants to Miami, Los Angeles, and New York, and a report by the American Thoracic Society in 1985 concluded that unemployed alcoholic patients in inner cities should be
placed on supervised treatment.’9 Underscoring the extent of the gulf that existed between those who viewed directly observed therapy for most if not all patients as vital and the then standard practice even among difficult patients, were the notoriously low treatment-completion rates in New York City. In 1984-85 the New York City Department of Health identified 305 patients it deemed as meeting criteria for its supervised therapy programme-ie, frequently missed appointments, drug resistance, mental incompetence, chronic alcoholism, failure to respond to therapy, two hospital admissions for treatment of tuberculosis, and living conditions unconducive to compliance with ambulatory care. Only 114 were located and enrolled in the programme.20 As of December, 1986, 59 patients were treated under supervision.21 In 1988, 93 patients were under such care (New York City Department of Health, unpublished data). What accounted for the failure to use directly
supervised therapy despite the fact that at least 20-30% of patients throughout the USA failed to complete treatment within 24 months? Many health departments believed that requiring individuals to take their medication in the presence of a responsible party would entail unacceptable assumptions about the prospect of the future behaviour of those under care. Rather than a service, directly observed therapy was often viewed as an imposition that could be justified only in the presence of evidence that the patient would behave in a way that posed a threat to the public health. At a later date, some argued that widespread application of directly observed therapy entailed an inversion of a basic human right by treating tuberculosis patients as guilty until proven innocent. But the most important factor was the assumption that the widescale use of supervised therapy would entail an extraordinary and unjustifiable expense. Certainly questions of cost and limitations on available resources were among the factors that played a part in the failure of the CDC to press publicly for the wider adoption of directly observed therapy as a practice even when some believed such a move would have salutory consequences. (D Snyder, severe
CDC, personal communication.) There were, however, examples of successful application of directly observed therapy in the 1980s. Not surprisingly, in Denver, Sbarbaro’s home base, an average of 60% of tuberculosis
patients treated between 1973 and 1983 were supervised. More striking, there were a few locales where directly observed therapy was adopted as a universal or near universal approach in tuberculosisIn Baltimore, Glasser, the treatment programmes. Commissioner of Health, introduced directly observed therapy to a city that had long been known for its high rates of tuberculosis. Glasser, who was influenced by the work of the International Union Against Tuberculosis and by Moodie, began his efforts with noncompliant patients but rapidly moved to include all patients treated by the city’s tuberculosis programme (privately treated patients were not included). In Mississippi, directly observed therapy began with non-compliant patients in the early 1980s in one region. By the decade’s end, the programme had extended to the entire state.22 In the early 1990s, 98% of tuberculosis patients were treated by directly observed therapy. Finally, in Tarrant County, Texas,23 after an outbreak of multidrug-resistant tuberculosis in the mid1980s, the Director of Public Health started a programme in consultation with Sbarbaro of directly observed therapy for all publicly treated patients (S E Weis, Tarrant County Health Department, personal communication). This initiative was undertaken without additional funds. That these developments occurred despite limited support from federal authorities makes clear the fact that resource constraints explained only a part of the resistance in the USA to directly observed therapy. Where there was a political commitment to instituting such an approach to tuberculosis contol it was possible to make substantial changes. Such commitment also required a cultural climate within which supervision of all, or nearly all, patients was not offensive. Certainly the cultural climate in Texas and Mississippi was very different from that in northern states, making possible tuberculosiscontrol initiatives that might otherwise have been viewed as unacceptably authoritarian. The availability of resources and the political and cultural climate surrounding tuberculosis control underwent a radical transformation in the early 1990s as a
result of a rising number of cases, an increase in drugresistance disease, and nosocomial outbreaks in hospitals. As a result of the fear that what had been a treatable disease might become an untreatable danger to middleclass populations that had in recent years been spared the threat of tuberculosis, concern took hold about the rate at which patients failed to complete their tuberculosis therapy in cities such as New York, Chicago, Newark, and Washington. Public concern and a demand for remedial action provoked Congress to greatly increase funding for tuberculosis-control efforts. In all, the money available to CDC for tuberculosis control rose from$25 million in 1991 to$104 million in 1993 (CDC, unpublished data). Central to the new commitment was a striking determination to place directly observed therapy for most if not all patients at the centre of public-health efforts. When in 1993, the ACET made directly observed therapy the standard of care, as a matter of federal policy,’1 it turned from the decades-long efforts to identify individuals at high risk for non-compliance and more recent attempts to designate groups as being at high risk for failure to complete their tuberculosis treatment. The council stated that "Directly observed therapy should be considered for all patients because of the difficulty in predicting which patients will adhere to a prescribed regimen. Decisions regarding the use of expanded or universal directly observed therapy should be based on a quantitative evaluation of local treatment completion rates". In a compromise dictated by those who viewed universal directly observed therapy as unnecessary, where other approaches had proven effective, the ACET stipulated that universal directly observed therapy be relied upon in those locales where treatment completion rates fell below 90%. But even in settings where treatment completion exceeded 90%, it urged that "consideration should be given to extending the use of directly observed therapy to [further] increase treatment-completion rates". The recommendations of the ACET were reflected in the CDC’s standards for cooperative agreement applications from state and local health departments seeking funds for tuberculosis elimination. The transformation of federal policy has been reflected at the local level as state, county, and municipal health departments shape their tuberculosis policies and practices. In Chicago, since June 1, 1993, all newly diagnosed tuberculosis cases treated in health department clinics have been placed on directly observed therapy (Chicago Department of Health, unpublished data). In Rhode Island, in response to 9 cases of multidrugresistant tuberculosis and a number of patients deemed to be at high risk for non-adherence, the health department increased availability of directly observed therapy in mid1993. In the 6 months before June, 1993, 34% of cases were placed on directly observed therapy; this figure had risen to 80% by the last 6 months of the year (Rhode Island Department of Health, unpublished data). But most remarkable has been the changes in outlook and practice in New York City, which has embarked on a massive expansion of directly observed therapy, although mandatory measures have been rejected. In December, 1991, New York had 137 people on directly observed therapy; by the end of 1993 the number had risen to 1282 (New York City Department of Health, unpublished data). When the number of new tuberculosis cases in 1993 in New York declined for the first time in 15 years, the reversal was attributed to the enhanced role of directly 1547
observed
therapy. The
when in March, tuberculosis cases was
same was true
in
1995, a further decline announced.24 The embrace of the principle of universal or nearuniversal directly observed therapy by federal, state, and local health departments, has, not surprisingly, provoked opposition from some public-health officials, who believe that their own programmes were effective without the need to devote resources to so labour-intensive an effort. More striking has been the criticism from those for whom civil liberties are of pre-eminent importance. Such criticisms have not opposed the universal offer of directly observed therapy, making it available to all patients as a service. Nor have they opposed the imposition of directly observed therapy by court order after patients have shown that they cannot adhere to the prescribed treatment regimen. What civil liberties groups have found appalling-a violation of the constitutional requirement that the state use the least restrictive alternative in pursuit of public-health goals-is the notion that all or nearly all patients, irrespective of behaviour, should be required to ingest their medication in the presence of an observer.25 The designation of classes of patients-the poor, the homeless, drug users-as being at high risk for noncompliance and as requiring directly observed therapy, was viewed as particularly offensive.26 Despite such objections we believe that the weight of historical evidence and recent experience make the move to directly observed therapy as a standard of care crucial to the prevention of drug resistance. The insights gained into the epidemiology of tuberculosis through molecular techniques can only reinforce the case for the reliance on directly observed therapy from the start of treatment. In San Francisco, restriction fragment length polymorphism studies suggested that 40% of cases diagnosed in 1991 and 1992 were the result of recent transmission and indicated that individual noncompliant patients were responsible for sizeable clusters of disease. 1 noncompliant patient accounted for 6% of all the cases evaluated.27 As directly observed therapy programmes are started or expanded, it will be necessary to determine the appropriate mix of clinic-based care and care provided by community-based outreach workers; the need for provision of housing for homeless patients; the need for drug and alcohol abuse treatment, and psychiatric services for those who are impaired; the part to be played by financial inducements for remaining in care; and the functions of court mandates and the ultimate threat of compulsory hospitalisation for those who refuse to remain in treatment until cured. In short, it will be necessary to examine carefully the role of enablers and incentives.28 None of these studies will be simple or cheap, and all will require that resources for tuberculosis-control remain adequate, even if the number of new cases declines. Recognising the centrality of directly observed therapy is thus just the beginning of the challenge posed by tuberculosis. RB was supported by the Robert Wood Johnson Foundation, by center grant P50-MH43520 from NIMH, Dr Anke A Ehrhardt, principal investigator, HIV Center for Clinical and Behavioural Studies, New York
1548
State Psychiatric Institute, and by the Health Services Improvement Fund of Empire Blue Cross/Blue Shield of Greater New York. DW was supported by Fogarty International Center Grant [NIH] 5D43#TWOO231.
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