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Impact of DOTS compared with DOTS-plus on multidrug resistant tuberculosis and tuberculosis deaths: decision analysis

Timothy R Sterling, associate professor of medicine and epidemiology ^a, Harold P Lehmann, associate professor ^b, Thomas R Frieden, commissioner of health ^c. 

^a Johns Hopkins University Center for Tuberculosis Research, 424 N Bond Street, Baltimore, MD 21231, USA, ^b Department of Health Sciences Information, Johns Hopkins University School of Medicine, 2024 E Monument Street, Baltimore, MD 21287-0007, ^c New York City Department of Health, 125 Worth Street, New York, NY 10013, USA

Correspondence to: T R Sterling
tsterls{at}jhmi.edu

	Abstract

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Objective: This study sought to determine the impact of the World Health Organization's tuberculosis treatment strategy (DOTS) compared with that of DOTS-plus on tuberculosis deaths, mainly in the developing world.
Design: Decision analysis with Monte Carlo simulation of a Markov decision tree.
Data sources: People with smear positive pulmonary tuberculosis.
Data analysis: Analyses modelled different levels of programme effectiveness of DOTS and DOTS-plus, and high (10%) and intermediate (3%) proportions of primary multidrug resistant tuberculosis, while accounting for exogenous reinfection.
Main outcome measure: The cumulative number of tuberculosis deaths per 100 000 population over 10 years.
Results: The model predicted that under DOTS, 276 people would die from tuberculosis (24 multidrug resistant and 252 not multidrug resistant) over 10 years under optimal implementation in an area with 3% primary multidrug resistant tuberculosis. Optimal implementation of DOTS-plus would result in four (1.5%) fewer deaths. If implementation of DOTS-plus were to result in a decrease of just 5% in the effectiveness of DOTS, 16% more people would die with tuberculosis than under DOTS alone. In an area with 10% primary multidrug resistant tuberculosis, 10% fewer deaths would occur under optimal DOTS-plus than under optimal DOTS, but 16% more deaths would occur if implementation of DOTS-plus were to result in a 5% decrease in the effectiveness of DOTS
Conclusions: Under optimal implementation, fewer tuberculosis deaths would occur under DOTS-plus than under DOTS. If, however, implementation of DOTS-plus were associated with even minimal decreases in the effectiveness of treatment, substantially more patients would die than under DOTS.

What is already known on this topic DOTS is an effective, albeit underused, strategy for treating tuberculosis DOTS may be insufficiently effective in treating multidrug resistant tuberculosis The use of toxic reserve drugs (DOTS-plus) is an effective but costly strategy for treating multidrug resistant tuberculosis The impact of the implementation of DOTS-plus on overall tuberculosis control is unknown What this study adds If implementation of DOTS-plus is associated with even minimal decreases in the effectiveness of DOTS, more patients would die from tuberculosis under DOTS-plus than under DOTS alone If DOTS-plus is implemented, it must not divert resources from and decrease the effectiveness of DOTS

	Introduction

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The current recommendation for initial treatment of tuberculosis includes the standard first line regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol. Since 1993 it has been recommended that treatment be given as part of a policy known as DOTS (directly observed treatment, short course; box).¹ However, outcomes are poor when patients who are infected with Mycobacterium tuberculosis resistant to isoniazid and rifampicin (multidrug resistant tuberculosis) are treated with the standard regimen. ^{2 3} Reserve or second line antituberculosis drugs have therefore become components of an approach known as DOTS-plus (box).⁴ Although reported to attain high rates of success in patients with multidrug resistant tuberculosis, ^{5 6} the proposed widespread implementation of DOTS-plus has been controversial.⁷

DOTS and DOTS-plus: treatment strategies for pulmonary tuberculosis in the developing world DOTS is a package of five points: Commitment of governments to a national tuberculosis programme Detection of cases through case finding by sputum smear microscopy examination of patients with suspected tuberculosis in general health services Standardised short course chemotherapy with the first line drugs isoniazid, rifampicin, pyrazinamide, and ethambutol (or streptomycin) for, at least, all smear positive cases of tuberculosis under proper conditions of case management Regular, uninterrupted supply of all essential antituberculosis drugs A monitoring system for programme supervision and evaluation. In addition: Mycobacterial cultures and drug susceptibility testing are not required Treatment is started on the basis of symptoms or a positive smear Second line drugs are not used Three categories of treatment regimens exist; all are directly observed In the developing world, mycobacterial cultures and susceptibility testing are generally not performed, so drug resistance is not detected even if it is present In DOTS-plus: Second line antituberculosis drugs (more toxic and expensive, and less effective, than first line drugs) are used. The regimen includes two or more drugs to which the isolate is susceptible, including one drug given parenterally for six months or more. Total duration of treatment 18-24 months; treatment is directly observed Treatment regimen is either: Individualised according to drug susceptibility test results of the M tuberculosis isolate identified on culture; or Given as a standardised regimen to patients who fail supervised retreatment (for example, when culture and drug susceptibility testing are not performed). Mycobacterial cultures and drug susceptibility testing may be performed.

Second line agents that would be used under DOTS-plus are more expensive, more difficult to administer, and often poorly tolerated. Our hypothesis is that the implementation of DOTS-plus might divert resources from DOTS, decreasing the effectiveness of DOTS. In addition, if DOTS-plus were to be implemented incompletely the bacterium could develop resistance to second line agents.

A randomised controlled clinical trial assessing the effectiveness of DOTS compared with that of DOTS-plus is unlikely ever to be conducted because of logistical and ethical concerns. We used decision analysis to compare the possible outcomes of the two treatment strategies and to assess the impact of varying levels of effectiveness.

	Methods

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We analysed data for adults in the developing world who had smear positive pulmonary tuberculosis. Not enough data on the effectiveness of DOTS and DOTS-plus in HIV positive patients were available to be included in the analysis. We analysed DOTS and DOTS-plus for differing levels of effectiveness of the programmes, under conditions with moderate (3%) and high (10%) proportions of cases of incident multidrug resistant tuberculosis. We assessed the impact of the different treatment strategies by tabulating the cumulative number of tuberculosis deaths that occurred for each scenario over a period of 10 years.

Model
We used a Monte Carlo simulation of a Markov model (figure) to perform the decision analysis.⁸ For each scenario we followed a hypothetical cohort for 10 years, with a cycle length of one year. We defined the probability of each event for each cycle. For each analysis we performed 25 000 Monte Carlo simulations and expressed the cumulative number of tuberculosis deaths as the rate per 100 000 people during the 10 year period. To allow for a valid comparison between the different scenarios of treatment, and because the number of multidrug resistant and highly drug resistant outcomes was small, we used the same random sequence for all analyses.

View larger version (48K): [in this window] [in a new window]   Transition states of the Markov analysis

Probability estimates
We obtained probability estimates from articles published in peer reviewed journals identified through a Medline search and from global reports published by WHO. See bmj.com for tables showing estimates used for the analyses of optimal DOTS and DOTS-plus and their references.

The probabilities under optimal DOTS-plus differed from those under DOTS in that rates of survival and cure of patients with multidrug resistant tuberculosis were higher under DOTS-plus. In addition, patients treated under DOTS-plus receive second line agents and could therefore develop resistance to these drugs (and consequently develop highly drug resistant tuberculosis), but we assumed that patients treated under DOTS could not. For analyses of the optimal implementation of DOTS and DOTS-plus we used the baseline probabilities for survival and cure rates. When we assessed DOTS-plus for decreased levels of effectiveness of the programme, survival and cure rates of multidrug resistant, highly drug resistant, and non-multidrug resistant tuberculosis fell by a percentage of the baseline rate (for example, 5%), and the rate of patients developing highly drug resistant tuberculosis rose.

Cost effectiveness
In the example used for this analysis, we used marginal cost estimates from India. For DOTS, the marginal cost per patient was $10 (£6; 10) (T R Frieden, unpublished data, 2000).⁹ For DOTS-plus, we assumed that no more than 10% of patients would receive second line drugs and culture and susceptibility testing. The average cost per patient under DOTS-plus would be approximately $230 and the marginal added cost of DOTS-plus (compared with DOTS) would be $230$10=$220 (see bmj.com for details.)

	Results

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Optimal implementation of DOTS
Based on the probabilities for a hypothetical cohort treated with DOTS and for a setting in which the proportion of primary multidrug resistant tuberculosis is 3%, 276 deaths per 100 000 population would occur during a 10 year period among smear positive cases of pulmonary tuberculosis. Of these, 252 would have non-multidrug resistant and 24 multidrug resistant disease (table).

Optimal implementation of DOTS-plus
Four (1.5%) fewer patients would die with tuberculosis under optimal implementation of DOTS-plus than under DOTS. Eight fewer patients would die with multidrug resistant tuberculosis, but four more would die with non-multidrug resistant tuberculosis (table).

Suboptimal implementation of DOTS-plus
Since DOTS-plus may not be implemented optimally and its effectiveness would therefore be diminished, we performed the analysis for scenarios in which the survival and cure rates of patients with non-multidrug resistant and multidrug resistant tuberculosis were each 5% or 10% less effective than in the DOTS analysis. In addition, the risk of developing highly drug resistant tuberculosis increased with decreasing effectiveness of the programme. If attention to DOTS-plus were to divert resources from DOTS and result in tuberculosis survival and cure rates just 5% less than those under DOTS, 44 more patients would die with tuberculosis than under DOTS, which represents a 16% increase in the number of deaths. If DOTS-plus were 10% less effective than optimal DOTS, 144 additional patients would die compared with DOTS, which represents a 52% increase (table).

DOTS and DOTS-plus in "hotspots" of multidrug resistant tuberculosis
We then compared the effectiveness of DOTS and DOTS-plus in an area where a high proportion (10%) of cases of incident tuberculosis had multidrug resistance and also adjusted the prevalence of multidrug resistant and non-multidrug resistant tuberculosis. Under optimal conditions, DOTS-plus would result in 40 fewer deaths from multidrug resistant tuberculosis than DOTS but also four deaths from highly drug resistant tuberculosis that would not have occurred under DOTS. Overall, optimal DOTS-plus would result in 10% fewer deaths than DOTS. If DOTS-plus were to divert resources from DOTS such that DOTS was just 5% less effective than under optimal conditions, however, 52 more patients would die from tuberculosis than under baseline DOTS, representing a 16% increase in the number of deaths (see table). If the effectiveness of the control programme decreased by 10%, 128 more patients would die with tuberculosis than under DOTS, representing a 40% increase.

Incremental cost effectiveness of DOTS-plus
In a setting in which the proportion of primary multidrug resistant tuberculosis is 3%, the number needed to treat under DOTS-plus to avert one death compared with treating all patients under DOTS would be 1/(276272)/1250=313 patients, where the denominator of 1250 represents prevalent and incident cases per 100 000 population with initial treatment over 10 years. Assuming a marginal added cost of DOTS-plus of $220, the incremental cost effectiveness ratio would be $220×313=$68 860 spent for each death averted. In a setting where the proportion of primary multidrug resistant tuberculosis is 10%, the number needed to treat under DOTS-plus would be 1/(320288)/1250=39 patients, with an incremental cost effectiveness ratio of $220×39=$8580.

	Discussion

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Limitations of the study
This study has several limitations. Firstly, we did not include morbidity due to adverse reactions to the drugs in the analysis. Given the greater toxicity of the second line antituberculosis agents used for DOTS-plus, this would be yet another caution against widespread use of the strategy. Secondly, although the model incorporated the risk of reinfection with M tuberculosis, it did not measure the impact of secondary transmission from people with active tuberculosis. This would tend to underestimate both the potential benefits of DOTS and the potential negative impact of poor implementation. Thirdly, we assumed that highly drug resistant tuberculosis could not develop in settings where second line drugs were not used in the treatment regimen. This may not be true in areas where agents such as fluoroquinolones are widely available. However, the risk of developing highly drug resistant tuberculosis in such settings has not been measured and was therefore not included in the analysis. HIV was not accounted for in the analysis because of insufficient data on the effectiveness of DOTS and DOTS-plus among HIV positive patients. Although HIV infection is associated with an increased risk of tuberculosis among patients infected with M tuberculosis, it is not associated with an increased rate of drug resistant tuberculosis.¹⁰

Strengths of the study
Although our baseline analysis assumed that DOTS-plus can be implemented effectively, the proportion of patients completing even standard treatment regimens is low in areas where multidrug resistant tuberculosis has become a major problem.¹¹ In areas where direct smear microscopy and giving two to four relatively non-toxic drugs for six months is impossible, routinely performing mycobacterial cultures and first and second line susceptibility testing as well as administering four to seven toxic drugs for 18-24 months is unlikely to be possible.

A tuberculosis control programme should have implemented effective DOTS before implementing DOTS-plus.¹² A poorly run control programme can generate multidrug resistant tuberculosis, but effective DOTS can decrease the rates of multidrug resistant tuberculosis.¹³ More widespread implementation of effective DOTS would therefore decrease the number of cases for which DOTS-plus would be necessary.¹⁴ Currently, 77% of tuberculosis cases worldwide are not treated even with DOTS.¹⁵

The incremental cost effectiveness ratio in our baseline model for DOTS-plus ($68 860 to avert one death under DOTS-plus compared with DOTS) is within range of other treatments. However, when the implementation of DOTS-plus leads to reduced effectiveness of DOTS, the DOTS-plus strategy is both less effective and more costly. Given the variation in costs per patient, fixed programme costs, and drug resistance among different geographical regions, as well as population size, further modelling would be necessary to make a recommendation for a local jurisdiction.

This analysis does not indicate that DOTS-plus should not be implemented. Rather, it shows the very notable risks associated with implementation of DOTS-plus and shows that, where the strategy is implemented, second line drugs must be used effectively and first line treatment strengthened and insulated from the demands of providing second line drugs on a programme basis.

	Acknowledgments

We thank John Wong for advice related to decision tree design and Christopher Dye, Charles Wells, Thomas Navin, Michael Iademarco, and Zachary Taylor for their review of the manuscript. This paper was presented in part at the American Thoracic Society International Conference in San Francisco, May 2001.

Contributors: see bmj.com

	Footnotes

Funding: TRS was funded by the National Institute on Allergy and Infectious Diseases (AI01654).

Competing interests: TRF was on loan from the Centers for Disease Control and Prevention to the World Health Organization (Regional Office for South East Asia, New Delhi, India) from 1996-2002 but is no longer affiliated to WHO. The results of this study could benefit WHO because they support WHO recommendations for treating tuberculosis, which could increase funding for the organisation.

This is an abridged version; the full version is on bmj.com

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(Accepted 16 December 2002)