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W2328779957 abstract "Introduction Directly observed therapy (DOT) for tuberculosis (TB) is widely recommended by experts (6,20,50,67,71,100) and has been endorsed by local (12,21,42,99), national (17), and international (104–5) health authorities as the “standard of care” for TB treatment, yet it remains controversial in some quarters. Critics have questioned the appropriateness and net effectiveness of “universal” DOT on pragmatic, scientific, and ethical grounds (4,6,25,47,96–7,108). They suggest that DOT may be poorly accepted and hence fail to improve outcome in some settings, that it may consume scarce resources better directed elsewhere, and that concurrent improvements in other aspects of previously ineffective TB programs, in accordance with the “DOTS strategy” of the World Health Organization (WHO) (105), may actually account for much of DOT’s alleged benefit (6,45,47,72,96–7,108). Skeptics may also cite the lack of critically designed trials and question the cost-effectiveness of building an infrastructure for DOT in districts that already achieve good results with unsupervised therapy (however, these often resort to selective DOT) (6,45,72,87,96). Thus an evidence-based review published in June 2001 rated the DOT option as having “unknown effectiveness” (47). Modern chemotherapy of TB is highly successful provided a well-designed drug regimen is taken as planned. Even effective TB programs, however, fail to achieve long-term cure in a small minority of fully treated patients (typically 1%–5%) (40,48), and completion rates can fall below 50% when there are major impediments to “case-holding” (keeping patients engaged in treatment until they complete their designated drug regimen) (9,11,30,82). A poor treatment outcome may occur for behavioral reasons on the part of the patient (missed doses) or the program staff (faulty selection and dosing of drugs; ineffective case-holding due to administrative inconveniences, lax follow-up, nonsupportive interactions with patients, etc.) Other potential reasons are biologic in nature: impaired drug bioavailability related to enteric malabsorption (55) or pill formulation (92), poor penetration of circulating drug or drugs into infected sites (34), deletion of a key drug or drugs due to an adverse effect or acquired drug resistance, and—possibly—inadequate host defences (2,51,78). In addition, reinfection by a new strain of Mycobacterium tuberculosis during or after treatment (83,94), if it manifests clinically, is likely to be misinterpreted as a failure to eradicate the initial strain. To clarify DOT’s actual “track record” we review the published treatment outcomes of contemporary (human immunodeficiency virus [HIV] era) DOT cohorts. We examine how often and why TB treatment was unsuccessful despite DOT, focusing on 2 critical outcome measures, treatment failure and posttreatment relapse (29,40,48). Given that faulty adherence to pill-taking is regarded worldwide as the foremost cause of poor outcome (13,19,40,62,72,74,91), DOT, if successfully implemented, should yield measurable reductions in failure and relapse in a variety of settings. We reasoned that the consistent application of DOT removes nonadherence from consideration: any remaining failures of a first-line regimen could then be attributed to biologic, not behavioral, problems. Methods Cohorts were identified by manual search of relevant studies, reviews, and journals and by a computerized literature search (MEDLINE, National Library of Medicine, Bethesda, MD) combining text word sets: 1) tuberculosis and 2) DOT or supervised therapy crossmatched with 3) cohort, outcome, failure, or relapse. We arbitrarily limited the scope to reports published in English during 1990–2000 (11 yr); this effectively encompasses the contemporary DOT era and includes all reports to our knowledge (in English) on DOT for HIV-infected cohorts. The major omission is the many treatment trials conducted before 1990 (and pre-HIV) under the auspices of the British Medical Research Council that employed DOT throughout; this monumental edifice of clinical research is summarized elsewhere (40,64–5). Studies met our inclusion criteria if 1) they reported treatment outcome in a case cohort or clinical trial involving adult TB patients, including data on treatment failure and/or relapse; 2) treatment was directly observed for the entire course; and 3) standard chemotherapy was used, that is, isoniazid and rifampin for 6 months, pyrazinamide for the first 2 months, with or without other drugs in the intensive phase. We allowed several partial exceptions, as noted in the tables. We considered studies that employed culture for diagnosis (Group 1) separately from those that relied on sputum acid-fast bacillus smear alone (Group 2); for the latter we included data on smear-positive pulmonary TB only. For reports that segregated new cases and retreatment cases, we excluded the latter. As most series included patients with drug resistance, we determined its overall prevalence (to any drug) and noted the impact of multidrug-resistance, defined as resistance to isoniazid and rifampin with or without other drug resistance. In accordance with WHO’s categorization (105), we counted successful treatment (completion, cure), treatment failure, death during therapy, major nonadherence (default, prolonged interruption, or loss to follow-up), and transfer out as 5 mutually exclusive outcomes. Relapse rates were mainly calculated as simple proportions of patients, as time-based rates (for example, events per 100 person-years of observation) were infrequently reported. We contacted some authors directly for additional data or clarification. Results We found 34 eligible studies: 24 culture-based (Group 1;Table 1) and 10 smear-based (Group 2;Table 2), comprising 6,822 and 71,431 analyzable cases, respectively. Most were conducted in resource-poor settings. The main geographic sources were sub-Saharan Africa (12 studies; South Africa in 8), the United States (9 studies), and Asia (9 studies). Caution is required in comparing the studies, as they represent a broad diversity of cultural setting, level of TB program development, clinical and mycobacteriologic methods, and prevalence of drug resistance and HIV coinfection. The institutional settings range from well-established TB programs associated with urban academic medical centers to newly organized programs in underserved and impoverished rural sites. Program staffing, the nature and frequency of clinical monitoring, the methods for providing and supervising DOT, and the use of incentives and enablers vary widely. Data quality is difficult to assess in most reports but probably varies substantially as well; the data range from those acquired prospectively in controlled trials to those recorded by lay workers under field conditions and analyzed retrospectively. There are important differences in outcome analysis, particularly in the availability and adequacy of posttreatment follow-up. The studies are therefore not suitable for formal meta-analysis.TABLE 1: Group 1: TB diagnosed by culture of M. tuberculosis *TABLE 1: Group 1: TB diagnosed by culture of M. tuberculosis— *—ContinuedTABLE 2: Group 2: TB diagnosed by AFB smear onlyTABLE 2: ContinuedDespite the major disparities in their methods, most groups reported good efficacy in patients who remained on therapy. Treatment failure, which most studies assessed after 5–6 months of chemotherapy, occurred in <5% of patients in 26 of 30 evaluable reports. Six studies in Group 1 (comprising 641 evaluable patients) and 1 in Group 2 (929 patients) had no failures, while the highest rate (6.8%) was in a study that used a broad definition of failure (13). The average failure rate (unweighted mean ± SD) was 2.4% ± 2.2% for 21 culture-based studies and 2.5% ± 1.7% for 9 smear-based studies (NS). However, if one includes patients who were nonadherent or lost to follow-up in an intention-to-treat analysis, net program effectiveness was substantially lower in most studies. Thus the combined rate of failure plus default was 11.1% ± 6.7% (n = 20) and 10.0% ± 7.5% (n = 9) in culture-and smear-based studies, respectively (NS). The default rate exceeded the failure rate in 16 of 23 evaluable reports, indicating the greater importance of nonadherence. Additionally, poor adherence may account for some failures in patients who did not default from treatment. The inclusion of TB-related deaths would further increase the aggregate “poor outcome” rate at the end of therapy, but information on cause of death was largely unavailable (most deaths during DOT in the HIV-infected are due to other causes). The crude relapse rate was 3.6% ± 2.4% in the 21 culture-based studies that provided posttreatment follow-up, and 3.2% and 3.3% in 2 smear-based studies, respectively. The quality, planned duration, and actual success of follow-up varied widely and are not documented in several studies. Only 9 of the 23 provide sufficient information to judge that at least half of “completers” received active or passive surveillance for 2 years or more (15–7,22,29,59,89,92,93,99); in 9 others the mean follow-up exceeded 1 year (8,28,31,36,44,52,63,76,82,95). Given the substantial number of cases with short follow-up, missing data, or undiagnosed death, plus the likelihood that relapse is more frequent among noncompleters (usually excluded from relapse analysis), the overall relapse rate was probably underestimated in many studies. Conversely, reinfection may have falsely increased the apparent relapse rate in some high-prevalence communities (for example, 8,28–9,59,63,76, all with relapse in >4%), although this was excluded in 1 South African cohort (103). Strain typing of initial and recurrent isolates was available for only 17 patients from 6 studies (reporting 25 cultureconfirmed recurrences in all), based on DNA fingerprinting (36,89,93,95,103) or drug resistance pattern (84). Reinfection with a new strain was found in 2 patients (36,84), while 13 showed constant RFLP patterns. In the remaining 2 the RFLP pattern changed slightly, but the investigators favored relapse over reinfection (93,103; DA Mitchison, personal communication). There were no significant differences in failure or relapse when we grouped studies according to 3 factors: prospective research study versus program conditions, urban versus rural/suburban setting, and developing versus developed country; although there tended to be fewer failures in developed countries (data not shown). However, the numbers of studies are small for reliable statistical comparison. Several studies provide data on overall adherence (15,18,24,68,84,90,92) or specify the minimum acceptable adherence, typically 75%–85% of planned doses (31,82), but the majority fail to describe how well DOT was actually effected. The most nonadherent cases are usually categorized under “default,” thus quantifying their negative impact. We hoped to determine whether poor adherence also contributed to failure and relapse, but only 10 of the 34 reports provide any relevant information. In 8 studies, missed doses, incomplete treatment, or both were associated with failure or relapse (8,13,15,29,52,68,99; W El-Sadr, personal communication). Burman et al (13) emphasized the importance of lapses in treatment, finding a nearly 10-fold increase in poor outcomes in patients who met their definition of noncompliance. Caminero et al (15) showed a graded relationship between compliance at 2 months and final cure versus “abandonment.” Irregular clinic attendance and taking leave were the only predictors of failure among gold miners (68), while in another South African study a >50% prolongation of therapy (to compensate for missed doses) was associated with decreased cure (8). In contrast, nonadherence did not explain failure/relapse in the 3 remaining studies: the 2 relapsing patients in Denver missed ≤7% of visits (24), initial multidrug-resistance underlay the 3 poor outcomes at Bellevue Hospital (82), and all 28 Chinese patients who relapsed had taken 100% of prescribed doses (16; reinfection was not excluded, however). Rates of initial drug resistance ranged from 0 to 32% in Group 1 and had variable impact. In 8 studies resistance (range, 5%–25%, >15% in 1) did not contribute appreciably to poor outcomes. Isolates remained susceptible at failure or relapse in 44 of 45 evaluable patients from 6 studies (8,24,31,76,99,103). Of 93 patients from 4 studies (8,31,68,92; C Connolly, personal communication) who had initial resistance to isoniazid and/or streptomycin, only 2 failed treatment. Among relapses in these 8 studies, only 1 of 35 cases with reported susceptibility data had initial resistance (8,24,92,99,103). In 6 other studies, however, drug resistance (range, 7%–32%, >15% in 5) did impair outcomes. Multidrug-resistance underlay 9 of 16 instances of failure/relapse (with adherence either good or unstated) from 3 studies (13,18,82) and was the leading risk factor for failure in southern Mexico (44). Resistance (to any drug) was present in 5 of 6 failures (but in 0 of 6 relapses) in Nepal (70) and was a marginally significant risk factor for TB recurrence in gold miners (59). In the remaining 10 studies initial drug resistance was either excluded (15,36,54,63,95), apparently not related to any poor outcome (52,84,89), or not commented upon (29,108). Discussion Despite the existence of well-proven drug regimens, poor outcomes of TB management remain a major concern. Most cases worldwide arise in regions where the infrastructure for TB control is suboptimal. Unsupervised outpatient treatment has often been associated with notoriously poor cure rates in both wealthy (6,11,74) and disadvantaged regions (22–3,30,43,53,57,70,106). During the last decade the introduction of large-scale DOT has coincided with major improvements in TB control in several American cities (21,41–2,99) and in Beijing (107). Many authorities believe that DOT has been key in effecting such improvements (20–1,41–2,71), calling it the most significant advance in TB treatment in a quarter century (71). However, others have expressed skepticism and caution regarding DOT, particularly its universal application (6,25,32,45,47,71,87,96–7). Effectiveness of DOT Two recent surveys focused on treatment completion as an index of DOT’s effectiveness (6,20). While a high completion rate is essential to good TB control, completion does not guarantee long-term cure. We focus on failure and default (together with death and transfer, the reverse of completion) and on relapse, a standard measure of regimen efficacy (29,40,48), in an effort to understand how often and why DOT may be unsuccessful. Ideally, one would assess the effectiveness of DOT with a randomized, controlled trial comparing it with concurrent unsupervised therapy in an otherwise identical setting (blinding is not possible). In practice, the recent claim of DOT’s superiority over unsupervised treatment is based almost entirely on comparisons with historical and/or uncontrolled data, fortified by clinical impression and common sense (5,6,35,42,61,72,99,100). None of the 34 studies reviewed affords a state-of-the-art assessment of failure and relapse rates with DOT versus self-treatment, and 25 make no reference to pre-DOT outcomes in their districts. The remaining 9 all noted substantial improvements in completion and/or cure rates with the advent of DOT. In 6 (22,23,53,57,70,106), DOT was introduced as part of a broader initiative (“DOTS strategy”) to upgrade the program infrastructure in an underserved region with inadequate TB control. In the other 3 (15,82,99), adherence to unsupervised therapy had been poor despite a well-developed health care system. Of these 9 studies, only 2 provide evaluable historical data. In urban Texas the near-systematic use of DOT (90.5% of patients) reduced the rates of total relapse, multidrug-resistant relapse, and acquired resistance to 26%, 15%, and 14% of their prior values, respectively (99). In Thailand DOT improved completion and cure rates at provincial and district hospitals, but not at 4 referral centers (53). We found 3 randomized, controlled trials, all conducted in low-resource settings, that compare conventional DOT with concurrent “self-supervision” (53,97,108). Unfortunately, each has weaknesses and/or limited general applicability. The first did not favor DOT, but its overall results were atypically poor, due largely to nonadherence (32,108). The reliability of the authors’ conclusions are questionable for several other reasons: many patients were excluded from randomization, posttreatment outcome was not assessed, and transfer to another facility was counted as “not successful.” Moreover, the selfsupervised patients had to present their adherence record card to a nurse weekly; thus they were monitored more closely than is usual for unsupervised therapy, which may have enhanced their adherence. In a related study comparing clinic-based DOT, off-site DOT supervised by a lay volunteer, and selfsupervision, the same authors found no significant outcome differences among the 3 arms, with a trend favoring DOT by lay health workers (109). This study also has limitations regarding outcome assessment, case-holding, and statistical power, making interpretation difficult. The authors do not address the behavioral factors leading to relatively low patient adherence at their DOT clinic. In the second randomized, controlled trial (53), DOT yielded modest but significant improvements in case-holding and cure at 6 months. Both DOT and self-supervised patients fared better than a pre-study comparison cohort. This study too has methodologic weaknesses (lack of cultures and relapse data, supervision by family) that limit its conclusiveness. The third randomized, controlled trial (97) was not eligible for our analysis (published after 2000, no rifampin in continuation phase). It compared 3 strategies: unsupervised therapy, observation by a health-worker (either at a health facility or in the community), and observation by a family member. The respective cure/completion rates (smear-based) did not differ (65%, 67%, 62%, respectively) and were again substandard, reflecting difficult program conditions. Outcomes across all 3 strategies were improved over historical results, owing to other (unspecified) aspects of “service strengthening” under DOTS. The relative inconvenience and poor acceptance of DOT apparently explain its failure to surpass unsupervised treatment. The Group 1 outcomes (see Table 1) approach those obtained in benchmark studies conducted by the British Medical Research Council and others in the pre-HIV era. The appropriate comparison studies employed the core regimen of isoniazid-rifampinpyrazinamide, with or without streptomycin or ethambutol, given by DOT for 6 months (40,86). These rigorous randomized, controlled trials achieved treatment failure rates at 6 months that were uniformly ≤2% (0 in some trials) and relapse rates at 18–24 months posttreatment that were uniformly <5% (often <2%), using both daily and intermittent regimens. Most Group 1 outcomes also compare favorably with those achieved under program conditions by the Hong Kong Chest Service in 1983 (19) and by selected countries in the WHO drugresistance surveillance project in the mid-1990s (37). On the other hand, typical DOT program results (see Table 1) are not superior to—and in some instances are worse than—those achieved in prominent randomized, controlled trials that relied on unsupervised pill-taking under program conditions. The latest such trials in Britain (10) and the United States (26) achieved 2-year relapse rates of 1.6% and 4.8%, respectively, and the failure rate was 0 in the British trial (pyrazinamide arms, n = 287). In HIVinfected patients, relapse (or recurrence) rates after DOT varied considerably, from ≤3% (36,54,82) to 9%–12% (59,76,95), compared with the 8% observed after unsupervised treatment in both Madrid (78) and Kampala (51). Such comparisons are hazardous and possibly misleading, given the less rigorous diagnostic methods and clinical follow-up in most program-based DOT studies. One cannot determine from most reports whether the poor outcomes under DOT reflect intrinsic limitations to drug efficacy (even when perfectly administered) or suboptimal patient adherence and/or program performance. Additionally, publication bias may come into play, in that DOT programs with poorer organization and outcomes are less likely to report their experience. From the scientific standpoint, therefore, the superiority of DOT over unsupervised therapy for routine TB care has not yet been shown in an evidence-based fashion. Nonetheless, most authorities are convinced that DOT improves treatment effectiveness, drug resistance rates, and overall TB control (3,21,41–2,50,100). Economics of DOT By reducing poor outcomes (failure, relapse, acquired drug resistance), which are usually more frequent with unsupervised treatment and costly to manage, DOT can shrink overall expenditures for TB control despite its higher initial funding requirement. Four economic analyses used decision models to address the cost-effectiveness of DOT, based on predominantly urban experience in the United States. Three estimated that universal DOT is both more effective and less costly (per case cured) than unsupervised treatment (14,66,75). The fourth questioned the cost-effectiveness of universal DOT, based on outcomes in selected patients at low risk of default (unsupervised treatment, state of California), and suggested that enhancing the quality of suboptimal TB programs may be more useful than expanding DOT coverage nonselectively (87). A retrospective analysis of actual program costs found that DOT saved money in Tarrant County, Texas (101). Several less rigorous American estimates of net cost have also favored DOT (21,42,50,100). Few studies have addressed the economics of DOT in low-resource settings (39,98). One found that DOT was cost-effective in rural South Africa (39), but expenditures for the “conventional approach” were dominated by an initial 2-month hospitalization, which would not be realistic for many programs. TB mortality Interpreting and comparing mortality rates during TB treatment is problematic, as deaths are often attributable to factors other than the severity and site or sites of involvement of the TB itself. Major codeterminants include age, concomitant diseases, general health conditions in the population under study (for example, nutrition), and the adequacy of medical services (including accessibility of care, timely diagnosis of TB, and appropriate use of first-line drugs). Where HIV infection is prevalent, other complications of AIDS dominate overall mortality during TB care. Moreover, the cause for most fatalities in the 34 cohorts was not identified, and some deaths might have gone undetected among patients lost to follow-up. Nonetheless, TB-attributable mortality was reportedly <3% in 18 of 19 evaluable studies, irrespective of HIV status, and was ≤1% in 13 of these. The sole exception (5%) was in a predominantly HIV-positive cohort in Zaire (Congo), but the role of TB in some of these 26 deaths seems uncertain (76). Given the confounding variables and the lack of site-specific historical data, we could not discern whether DOT reduced fatality:case ratios in the locales studied, although such a benefit is plausible. It might be especially likely in communities with a high prevalence of multiple drug resistance, as these cases often fare poorly with unsupervised treatment. With mainly unsupervised therapy in the rifampin era, national case-fatality rates (death from all causes during TB treatment) have typically been ∼5%–10% in developed countries, and similar rates have been reported from Africa (67). However, rates of ∼15%–35% have been observed where HIV-coinfection is common (67,73) and in high-risk hospitalized patients (79). WHO estimated the 1997 global case-fatality rate at 23% (33). The comparatively low mortality in most DOT programs (see Table 1 and 2) may indicate a survival advantage, but it should be noted that treatment trials and outpatient TB programs often have lower-than-average case-fatality rates (10,19,26). This reflects case selection (54,63,92,108) and the fact that deaths from TB often occur before or soon after the commencement of treatment (2,46,67–8,73,80), usually in hospital, which would preclude entry into many DOT cohorts. Adherence to DOT In everyday practice a substantial fraction of DOT patients miss doses occasionally (13,81). If frequent enough this might compromise outcome, either by impairing the eradication of persisting bacilli or by fostering acquired drug resistance, as Mitchison et al (65) recently proposed. The effect of partial adherence may depend on the temporal pattern of missed doses, whether the regimen is daily or intermittent, and such biologic factors as pharmacokinetics, the host’s immune response, and the site of disease. How many doses can be missed without a measurable decline in long-term cure remains unknown (13,62,81) and would be difficult to estimate from observational data, given that the relevant outcomes (stratified by adherence) are few in number and influenced by confounding variables. The 34 studies do little to clarify the impact of missed doses on failure/relapse. There are virtually no data relating adherence quantitatively to poor outcomes, and the available post hoc analyses comprise relatively few adverse events (8,13,15,68). Nonetheless, it is clear from the default data alone that major nonadherence remains more frequent than failure/ relapse, even under DOT. Several reviews summarize methods by which DOT programs may enhance adherence (9,20,42,91,96). Accumulated experience suggests that current first-line regimens have a substantial safety margin, at least against drug-sensitive TB in immunocompetent patients. Intermittent treatment works as well as daily (albeit with higher doses), patients whose lapses are sporadic and amount to <25% of planned doses usually achieve cure, and even the loss of isoniazid susceptibility has little effect on outcome in newly treated cases (28,31,37,64,68,92–3). In a trial of rifapentene and isoniazid given once weekly in the continuation phase, deliberate omission of every third dose (to mimic poor adherence) caused little increment in adverse outcomes (92–3). However, both rifapentene arms showed relatively high relapse rates, and the relevance of these data to standard rifampin-based regimens is uncertain. An empiric criterion for acceptable adherence, ≥80% of planned doses, has been widely applied in clinical trials and studies (26,30,35,80–1,94) and is the performance standard of a number of local (12,42) and national health authorities. Based on much clinical experience, the 80% rule seems a reasonable benchmark, although it has not been scientifically validated as the optimal cutpoint and it was originally chosen for daily, not intermittent, regimens. To compensate for missed doses, a commensurate extension of the treatment period is recommended (8,12–3,100); clinical judgment is often required, depending on the pattern of nonadherence and other prognostic factors. Program staff as well as patients may be nonadherent. The nominal provision of DOT cannot guarantee success if case-holding is weak, staff are lax or dishonest with regard to actual observation, and pill ingestion is not strictly verified (5,30,32,43,58,61,77,88). Moreover, some instances of concealed pill dumping may escape even assiduous observation (85). The frequency of poor staff performance is largely unknown or undisclosed, but can be substantial both in (88) and out (5) of hospital; in 1 program an estimated 27% of outpatients were not actually observed (5). Drug resistance Apart from the predictable adverse effect of multidrug-resistance, when present, the majority of failure/ relapse in Group 1 was not attributable to initial drug resistance. Three studies (8,68,92) confirmed prior evidence (64) that resistance to 1–2 drugs (including isoniazid, but excluding multidrug-resistance) does not vitiate standard treatment. There were only a few instances of acquired resistance (13,36,89,92), which rarely develops during DOT (8,31,76,95,99). While resistance was of secondary importance in new cases overall (Group 1), it probably contributed more often to poor outcomes during retreatment (22,44,68,70,106). Its prevalence is typically increased 2-fold or more in retreatment cases, in whom multidrug-resistance is amplified even more (44,70). The impact of resistance in smear-based studies is unknown, but its prevalence may be substantial in at least several of the populations studied (1,16,22,23,106). Finally, even standard first-line and retreatment regimens can yield disastrous results when administered blindly to populations with frequent drug resistance, as illustrated recently in Peru (7), Mexico (44), and among prisoners in former Soviet states (27). Under these circumstances treatment failure (despite well-administered DOT) becomes a barometer of local drug or multi-drug resistance (7,27). HIV effect The now-extensive experience in treating TB patients with AIDS and other immunodeficiencies suggests that the drugs themselves, not the host’s defenses, carry most of the burden of cure. For example, those with far-advanced HIV disease (<50 circulating CD4+ cells/μL) often have multifocal or disseminated TB, yet in most instances they respond promptly to chemotherapy and have a favorable course (2,46,52; AR Hill, unpublished observations). Studies in varied settings have found failure rates to be unaffected by HIV coinfection (18,31,36,68,76), although the degree of immunodeficiency (as assessed by CD4 count) was moderate in many patients (18,68,76). Long-term cure rates are less clear, as" @default.
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W2328779957 title "Effectiveness of Directly Observed Therapy (DOT) for Tuberculosis" @default.
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