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PAPERS: Timothy R Sterling, Harold P Lehmann, and Thomas R Frieden Impact of DOTS compared with DOTS-plus on multidrug resistant tuberculosis and tuberculosis deaths: decision analysis BMJ 2003; 326: 574 [Abstract] [Full text]

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Awareness of DOTS Plus is needed amongst doctors and public

Sangeeta Sharma   (14 March 2003)

MDR-TB: DOTS-plus strengthens, not weakens DOTS

Edward A. Nardell, Donna Barry, Mercedes C. Becerra, Paul E. Farmer, Mary C. Smith Fawzi, Rajesh Gupta, Jim Y. Kim, Carole Mitnick, Joia S. Mukherjee, Michael L. Rich   (13 April 2003)

Re: MDR-TB: DOTS-plus strengthens, not weakens DOTS

Timothy R. Sterling, Harold P. Lehmann, and Thomas R. Frieden   (7 May 2003)

Awareness of DOTS Plus is needed amongst doctors and public 14 March 2003
Sangeeta Sharma, Specialist in LRS Institute of TB & Allied Diseases New Delhi 110030 Send response to journal: Re: Awareness of DOTS Plus is needed amongst doctors and public	The article on DOTS and DOTS plus by WHO is really welcome. There is no doubt that proper implementation of these two programs will lead on to fewer tuberculosis deaths especially in developing countries like India where tuberculosis is already a major epidemic and one of the leading causes of mortality. But proper counselling and training of all the doctors including medical students for DOTS is required so that adequate treatment can be given to the patients to avoid the scourge of MDR TB getting out of hand. With the advent of dual HIV and TB infection even the developed countries are at risk. We should all rise to the occasion and fulfill our moral duty to do our best to curtail the scourge of MDR TB by properly implementing the DOTS and DOTS Plus programs of WHO to prevent a world epidemic of this disease. WHO has come out with guidelines for the management of drug resistant tuberculosis which should be carefully read and implemented by the health providers(1).Financial constraints have to be taken care of especially in developing countries and help of all countries and funding agencies is equired if we have to be serious to control MDR TB and stop it from becoming incurable, which is a distant but achievable goal. References: 1. Crofton J, Chaulet P,Maher D. Guidelines for the Management of Drug- Resistant Tuberculosis. World Health Organisation ,Geneva 1997. Competing interests:   None declared
MDR-TB: DOTS-plus strengthens, not weakens DOTS 13 April 2003
Edward A. Nardell, Associate Professor Department of Social Medicine, Harvard Medical School, 641 Huntington Ave, Boston 02115, Donna Barry, Mercedes C. Becerra, Paul E. Farmer, Mary C. Smith Fawzi, Rajesh Gupta, Jim Y. Kim, Carole Mitnick, Joia S. Mukherjee, Michael L. Rich Send response to journal: Re: MDR-TB: DOTS-plus strengthens, not weakens DOTS	12 April 2003 To the editor: We completely agree with Sterling, et al. that treating the minority of patients with multidrug-resistant (MDR) tuberculosis (TB) must never compromise the effectiveness of treating the majority of patients with drug-susceptible TB. It is also true that treating malaria or pneumonia should not compromise the treatment of TB, or vice versa, but no one is suggesting that these treatable conditions should not be effectively treated. MDR-TB is now known to be treatable even in resource-limited settings and like other life-threatening diseases it must be properly treated without compromising other important programs. The demand for DOTS-plus is growing. In good DOTS programs, patients who fail their first course of therapy are likely to have MDR TB. Such patients will almost certainly not be cured by conventional retreatment regimens, as noted by the authors, and some will develop more resistant TB. Having watched patients die on standard re-treatment DOTS therapy over and over again, providers want to cure their patients with second- line drugs, and many patients, having seen others die after repeated courses of the same drugs, desperately want treatment that is likely to work. Understandably, these reciprocal needs are fueling a demand for effective MDR treatment around the world. While the authors conclude that their modeling exercise “does not indicate that DOTS-plus should not be implemented,” their results and their interpretation suggest that DOTS- plus is an intervention of such marginal benefits that its costs — both financial and the risk to DOTS outcomes — should preclude its consideration in many settings. However, neither patients nor their doctors, nor National TB Program managers are likely to be dissuaded from seeking good treatment by theoretical arguments, especially those based on questionable assumptions. In their decision analysis, the authors have greatly underestimated the potential for cure with DOTS-plus while overestimating the potential disruption to DOTS programs. The authors present as their hypothesis that, “the implementation of DOTS plus might divert resources from DOTS, decreasing the effectiveness of DOTS.” However, that hypothesis is never tested in the study, nor is it a hypothesis subject to testing by decision analysis. Rather, the authors simply assume that DOTS plus could decrease the effectiveness of DOTS by 5 to 10% and use decision analysis to quantify the resulting hypothetical trade-off in cures between drug-susceptible and drug-resistant cases. The authors offer no evidence that DOTS-plus has ever diminished the efficacy of DOTS. On the contrary, under the current rigorous procedure for obtaining second-line drugs at drastically reduced prices, the Green Light Committee (GLC) of the WHO assures that only programs with demonstrably strong DOTS programs and a strong plan of action to implement DOTS-plus are able to obtain second-line drugs, and then only under the continuous, close supervision of the GLC.(1) The effect of this screening and monitoring procedure for obtaining second-line drugs is to strengthen DOTS programs, not weaken them. The positive impact of the GLC and DOTS-Plus on improving DOTS has been documented.(2,3) Sterling and colleagues should have considered the very real possibility that implementing DOTS-plus increases, not decreases, the effectiveness of DOTS. As with all decision analyses, the outcome or utility is strongly influenced by the selection of the input data from the wide range of choices available in the literature. The authors used a 47% cure rate (defined as a negative smear at the end of therapy) for MDR TB under DOTS (range 6 to 59% in 6 countries).(4) But using the same definition of cure, CDC reported that DOTS cured only 5% of MDR-TB cases in Ivanavo oblast, Russia, compared to a 77% cure rate for drug-susceptible cases.(5) Among prisoners in Baku, Azerbaijan, Coninx et al. reported a treatment success rate of 30% or less for cases whose isolates were resistant to 3 or more drugs, compared to a success rate of 88% where no drug resistance was found.(6) Moreover, Migliori, et al. acknowledged a 25% rate of “late failures” among chronic MDR-TB patients in Russia who were smear negative (i.e., considered cured) at the end of treatment, indicating that the true cure rate by a stricter definition for MDR-TB treated with DOTS would be much lower than 47%.(7) The authors selected the same 47% cure rate for treatment of MDR-TB with DOTS-plus, a figure derived from chronic cases, suggesting no improvement over treatment with DOTS alone.(8) Although the authors assume that incident cases should fare better than chronic ones, they apply the lower cure rate derived from chronic cases to represent the outcome of all MDR TB cases under DOTS-plus. However, Mitnick and colleagues have recently reported cure rates of over 80% for mostly chronic MDR-TB cases treated in Peru with individualized DOT-plus regimens in a community-based program.(9) Even with the exclusion of surgery (a questionable exclusion criteria used by the authors who purport to be modeling results that could be achieved in an ‘optimal’ program), excellent treatment results have been reported from Turkey and Korea.(10,11) Had the authors’ sensitivity analyses considered cure rates of MDR-TB patients under DOTS-plus as high as 80% along with a lower cure rate of MDR-TB patients under DOTS, the benefits of DOTS-plus would be far more robust and less vulnerable to undermining by the hypothetical possibility of less effective DOTS, which we maintain need not occur. The authors acknowledge that their model did not include the benefits of preventing further MDR transmission through effective treatment. This is a serious omission that cannot be dismissed by merely acknowledging it. In households, but especially in institutional settings such as hospitals, prisons, shelters, and worker hostels, where HIV co-infection may be commonplace, transmission of MDR-TB is a major source of disease propagation.(12,13) In New York City, as one of the authors reported, MDR transmission was halted only when effective therapy, combined with improved infection control, reduced both acquired and transmitted disease.(14) The authors’ results would have been quite different if each year untreated MDR-TB cases generated additional infectious, and ultimately fatal, MDR-TB cases in the community. The cost data used in the authors’ analysis do not reflect the greatly discounted GLC prices for second-line drugs whereas the cost used for basic DOTS drugs in India are among the lowest in the world. This heavily biases the outcome in favor of the cost effectiveness of DOTS compared to DOTS-plus. Had the appropriate comparison prices for second- line drugs been used, along with higher cure rates observed with DOTS-plus in developing countries, the cost of curing an MDR case would have been much lower. While we agree with the authors that DOTS-plus should never compromise the effectiveness of DOTS, we also believe that distinguishing DOTS from DOTS-plus has outlived its usefulness. We should be discussing effective programs for the treatment of all TB patients, many with MDR-TB in most countries in the world. MDR treatment is part of treating all TB cases, not competitive with it. From both the public health and individual health perspectives, the right thing to do is to simply treat all tuberculosis effectively, thereby saving lives, reducing suffering, and preventing MDR propagation in the community. Reference List 1. Gupta R, Cegielski JP, Espinal MA et al. Increasing transparency in partnerships for health--introducing the Green Light Committee. Trop Med Int Health 2002; 7(11):970-6. 2. Kim JY, Mate K, Rich ML, Mukherjee JS, Bayona J, Becerra M . From multidrug-resistant tuberculosis to DOTS expansion and beyond: making the most of a paradigm shift. Tuberculosis (in press, 2003). 3. Gupta R, Espinal MA, Raviglione MC. Rebuttal: Evidence and uncertainties. Int J Tuberc Lung Dis 2002; 6(8):651-3. 4. Espinal MA, Kim SJ, Suarez PG et al. Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. JAMA 2000; 283(19):2537-45. 5. Primary multidrug-resistant tuberculosis--Ivanovo Oblast, Russia, 1999. MMWR Morb Mortal Wkly Rep 1999; 48(30):661-4. 6. Coninx R, Pfyffer GE, Mathieu C et al. Drug resistant tuberculosis in prisons in Azerbaijan: case study. BMJ 1998; 316(7142):1423-5. 7. Migliori GB, Espinal M, Danilova ID, Punga VV, Grzemska M, Raviglione MC. Frequency of recurrence among MDR-tB cases 'successfully' treated with standardised short-course chemotherapy. Int J Tuberc Lung Dis 2002; 6(10):858-64. 8. Suarez PG, Floyd K, Portocarrero J et al. Feasibility and cost- effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002; 359(9322):1980-9. 9. Mitnick C, Bayona J, Palacios E et al. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 2003; 348:119-28. 10. Tahaoglu K, Torun T, Sevin T, et.al. The treatment of multidrug- resistant tuberculosis in Turkey. N Engl J Med 2001; 345:170-4. 11. Park SK, Kim CT, Song SD, et.al. Outcomes of chemotherapy in 107 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. Int J Tuberc Lung Dis 1998; 2:877-84. 12. Kruuner A, Hoffner SE, Sillastu H et al. Spread of drug- resistant pulmonary tuberculosis in Estonia. J Clin Microbiol 2001; 39(9):3339-45. 13. Nivin B, Nicholas P, Gayer M, Frieden TR, Fujiwara PI. A continuing outbreak of multidrug-resistant tuberculosis, with transmission in a hospital nursery. Clin Infect Dis 1998; 26(2):303-7. 14. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in New York City--turning the tide. N Engl J Med 1995; 333(4):229-33. Competing interests:   None declared
Re: MDR-TB: DOTS-plus strengthens, not weakens DOTS 7 May 2003
Timothy R. Sterling, Associate Professor of Medicine and Epidemiology Johns Hopkins University School of Medicine, 424 N. Bond Street, Baltimore, MD 21231, Harold P. Lehmann, and Thomas R. Frieden Send response to journal: Re: Re: MDR-TB: DOTS-plus strengthens, not weakens DOTS	We appreciate the comments of Sharma and Nardell et al. We agree with Sharma that proper training of doctors is critical to global tuberculosis control. We are also pleased that Nardell et al concur with our conclusion that DOTS-Plus should never be implemented in a way that might compromise the effectiveness of standard DOTS programs. However, Nardell et al’s suggestion that DOTS-Plus is associated only with benefits (i.e., improved treatment outcomes of multidrug-resistant tuberculosis [MDR-TB] and improved effectiveness of DOTS) ignores the potential negative effects of executing this costly and labor-intensive program, as well as the realities of providing health care to a large population. In the role of physicians caring for individual patients, we advocate for the maximum resources to cure every patient. That MDR-TB is curable brings with it an ethical mandate for us to advocate for its treatment in all contexts. But as public health practitioners responsible for the health of communities, an additional ethic applies—ensuring maximum overall societal benefit—because we must also consider the needs of patients who lose the opportunity for effective treatment if resources are spent elsewhere. It would be irresponsible for any decision-maker not to account for potential negative impacts of DOTS-Plus or any other health program. In our decision analysis, we took this societal perspective. Our inference that support of DOTS-Plus could diminish the efficacy of DOTS relates to finances, human resources, and implementation capacity. Fixed budgets and limited medical, administrative, and supervisory capacity are a reality for most health systems; resources directed to DOTS -Plus may thus be unavailable for DOTS, and this lack of resources can certainly reduce program effectiveness. Clearly, both financial and human resources are required to properly run even the less-intensive standard DOTS programs; the lack of such resources is an important cause of the current low global implementation rate of DOTS. We do not argue that the difficulty of implementing DOTS-Plus “should preclude its consideration in many settings.” Quite the opposite. We demonstrate that careful consideration and implementation is essential in order to reduce the number of patients who die from tuberculosis. Nardell et al also take issue with some of our probability estimates. For our base-case scenario, we used available data for the developing world, which was the setting chosen for this analysis. Cure of both drug- resistant and drug-susceptible tuberculosis is generally assessed at the end of therapy, and does not take into account subsequent relapse. While relapse can certainly occur with MDR-TB (as well as with drug-susceptible disease), there are an insufficient number of studies that have reported on both outcomes under both DOTS and DOTS-Plus, to be included in the analysis. The recent study by Mitnick et al, published after our analysis was performed, provides encouraging results, although they reported on only 75 of 731 (10%) of the MDR-TB cases referred for evaluation.1 Knowing the effectiveness of DOTS-Plus among larger, more representative populations would be of great value. Surgery may indeed improve treatment outcomes, but is not available in many developing countries, and its specific contribution to improved outcomes is not documented; therefore, it was not included in our analysis. We have performed additional sensitivity analyses using Nardell et al’s estimates. For cure rates of MDR-TB as low as 30% under DOTS, and as high as 80% under DOTS-Plus, there was no change in the results of the analysis. As noted in the paper, the decision analysis was not greatly influenced by this probability estimate. The cost estimates for second- line DOTS-Plus drugs used in the analysis were based on actual data from India, and are not substantially different from those reported by the Green Light Committee in 2001 and 2002.2 As we noted, Markov models cannot represent epidemics and disease transmission. There are clearly some circumstances (e.g., crowded prisons or other congregate facilities with immunocompromised populations) in which failure to treat MDR-TB would likely result in widespread transmission. There may also be epidemiologic contexts (e.g., non- immunocompromised populations with no access to DOTS and widespread poor- quality non-DOTS treatment) in which success would best be achieved via phased implementation of DOTS, followed by DOTS-Plus if resources allow. We agree that the treatment of MDR-TB should be one of the components of comprehensive tuberculosis treatment, not competitive with it. For any given patient with tuberculosis, an initial treatment plan should be developed, as well as a back-up treatment plan and a plan for treatment if drug resistance is present. On both a theoretical and ethical basis, universal treatment of both drug-susceptible and drug-resistant tuberculosis is desirable. But the reality is that in some countries, implementation of DOTS may so tax existing resources that it may be the best course of action to defer implementation of DOTS-Plus until human and financial resources allow this to be accomplished without undermining DOTS. References 1.Mitnick C, Bayona J, Palacios E et al. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 2003; 348(2):119-128. 2.MDR-TB Treatment Regimen Costs. Confirmed May 4, 2003. http://www.who.int/gtb/policyrd/images/drug-prices-&-pilot-proje.gif 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.