Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Lesser Evidence for Lesser Mortals in Tuberculosis Treatment
- V Murlidhar (6 February 2008)
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Potential Alternative to Univeral DOT
- Thomas S. Moulding (10 February 2008)
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We must practice DOTS, but we must find better ways to individualise the treatment
- Prasanta Raghab Mohapatra, Deepak Aggarwal (12 February 2008)
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DOTS and Democracy
- Niyi Awofeso (13 February 2008)
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DOTS in health care and in public health
- T. Jacob John (13 February 2008)
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All tuberculosis patients need treatment and DOTS today appears feasible though needs further research
- R. K. Bansal, A.B. Pawar, Parul Vadgama (14 February 2008)
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Early diagnosis in tuberculosis and use of DOT in third world countries
- Prof (Dr)Jogenananda Pramanik.MBBS.MD., Tanu Pramanik BSc,MA(Sociology) Medical Sociologist (15 February 2008)
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DOTS for some - not all
- Raj B SINGH (17 February 2008)
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DOTS is not the answer for rising incidence of world Tuberculosis.
- Chettykulam N. Deivanayagam (17 February 2008)
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DOTS - a good start
- Sourabh Chand (19 February 2008)
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DOTS-from patient's perspective
- R.Karthik Deivanayagam (20 February 2008)
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Exogenous reinfection as a confounding factor in TB drug trials outcomes.
- Paul D van Helden, Pieter Uys, Robin M Warren (21 February 2008)
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DOTS may be revisited
- JAYANTI P GUPTA (24 February 2008)
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Identify more the work on Tuberculosis from the Indian subcontinent
- Jecko Varghese (1 March 2008)
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It is not the DOTS strategy but direct observation that is failing.
- Ibrahim Abubakar, Peter Davies, Consultant Chest Physician, Cardiothoracic Centre. Liverpool NHS Trust, Liverpool (4 March 2008)
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I miss a citation
- Arild Bjorndal (5 March 2008)
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DOTS, the baby and the bath water
- Alistair Story, Andrew C Hayward UCL Centre for Infectious Disease Epidemiology, Department of Primary Care and Population Sciences, London (7 March 2008)
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DOTS is god but certain issues need to be addressed.
- Naghman Bashir (7 March 2008)
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Issues in assessing long-term efficacy of DOTS regimen
- Sachin R. Atre, Nerges F. Mistry (8 March 2008)
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Just says there is no good evedence
- Kidangazhiyathmana Ajithkumar (24 March 2008)
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Quality matters in applying standard six-month DOTS regimens under programme conditions
- Kwok C Chang, Chi C Leung, Cheuk M Tam (27 May 2008)
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V Murlidhar, Medical officer, United Nations Assistance Mission in Iraq (UNAMI) Irbil, Iraq
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The recommendations for the treatment of Tuberculosis in low income countries is based on lesser evidence than that recommended by scientific evidence1,2. Helen Cox and her co-authors rightly point this out in their systematic review of DOTS regimens for the treatment of Tuberculosis3. The scientific evidence strongly supports daily dosages during the initial intensive phase of treatment. This is contrary to guidelines suggested for DOTS, a regimen which is used in low-income countries, where a non-daily dosage is recommended. The other recommendation in DOTS about not having to perform basal testing for Liver function and a follow up x-ray is purely based on fiscal considerations and is clearly stated as such. What is surprising is that such practices like basal testing for Liver functions, eye testing, and radiology (both pre and post-treatment) have been part of the standard treatment during the streptomycin era of the seventies in a developing country like India and have been proved to be imperative. Reducing the number of tests implies basing treatment on lesser evidence, which results in false negatives and even deaths due to hepato-toxicity as I have noticed in my experience in India. It appears that when it comes to evidence based medicine some people are more equal than others. 1. World Health Organization. Treatment of Tuberculosis: guidelines for national programmes. 2nd edition. WHO/TB/97.220 2. International Union against Tuberculosis and Lung Disease. Management of tuberculosis: aguide for low income countries, 5th edition. 2000. Available at http://www.iuatld.org/pdf/en/guides_publications/management_of_tb.pdf 3. Helen S. Cox, Martha Morrow, Peter W Deutschmann. Long Term Efficacy of DOTS regimens for tuberculosis: systematic review: BMJ published online 4 Feb 2008; doi:10.1136/bmj.39463.640787 Competing interests: None declared |
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Thomas S. Moulding, Clinical Professor of Medicne Office Address, 214 Via La Soledad, Redondo Beach, CA 90277
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The article by Cox et. al. adds an important neglected component to the never-ending controversy over the value of directly observed therapy (DOT) for all TB patients. They found a lack of adequate data regarding the long-term effectiveness of DOT, and noted suggestive evidence that intermittent regimens lead to higher relapse rates. However, this article, like almost all articles regarding adherence to TB treatment regimens fails to mention a potential alternative solution to the problem. A large percentage but clearly not all patients are sufficiently reliable to take self-administered treatment (SAT) even in a poor developing country.(1) However, it has been documented that health professionals cannot fully judge the adherence of patients.(2) Consequently, universal DOT has been recommended even though it imposes a significant and sometimes overwhelming burden for many patients and programs. Advances in electronic technology have made it possible to design inexpensive portable medication monitors, devices that determine when medication is removed from a container. (3) It is estimated that these monitors could be mass-produced for $5.00 or less.(3) The caregivers could read the adherence record with built in displays without computers or PDA’s in either a clinic or the patient’s home. (3) If SAT was dispensed from medication monitors, reliable patients could be identified and seen only once a month. The less reliable patients could be seen more frequently with intensive counseling or DOT when necessary plus extensions in the duration of therapy based on the monitor record.(4) If Fixed Dose Combinations of drugs were dispensed it would eliminate monotherapy and reduce the chance of drug resistance.(5) Giving medication daily would reduce the chance of relapse(6). Medication Monitors would be particularly useful for supervising DOT given by a family member, because both the patient and family could be counseled when poor adherence was found. Since poor medication adherence by many patients remains a major obstacle in controlling TB, this alternative approach to the problem needs serious consideration and investigation. Thomas Moulding M.D. tmoulding@earthlink.net 1) Moulding TS, Caymittes M. Managing medication compliance of tuberculosis patients in Haiti with medication monitors. Int J Tuberc Lung Dis 2002: 6:313-9. 2) Moulding TS. The unrealized potential of the medication monitor. Clin Pharmacol Ther 1979; 25: 131-136. 3) Moulding TS, Ellis D. (2007) Compliance monitors: status of development and potential for expanding effective TB treatment programs. Available at: http://www.medicationmonitors.net.accessed February 6, 2008. 4) Moulding T. Adapting to New International Tuberculosis Treatment Standards with Medication Monitors and DOT Given Selectively. Tropical Medicine and International Health 2007; 12: 1302-1308. 5) Moulding TS, Le HQ, Rikleen D, Davidson P. Preventing drug- resistant tuberculosis with a fixed dose combination of isoniazid and rifampin. Int J Tuberc Lung Dis 2004; 8: 743-748. 6) Saltini C. Schedule or Dosage?: The Need to Perfect Intermittent Regimens for Tuberculosis Am. Respir. Crit. Care Med 2006; 174: 1067-1068) Competing interests: I will receive a few stock options from InformationMediary Inc. for serving on their Advisory Committee. The designs on the website, www.medicationmonitors.net are in the public domain and any one is free to them without royalty payments. |
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Prasanta Raghab Mohapatra, Senior Lecturer Govt. Medical College and Hospital, Chandigarh-160030, India, Deepak Aggarwal
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Cox and colleague (1) have shown that there is inadequate evidence in long-term effectiveness of intermittent regimens and evidence of higher relapse rates. Current international TB control strategy has been well constructed based on the evidence from various scientific studies. But the first-line drug regimens are associated with higher rates of treatment failure among the populations where resistance has already spread because of inadequate therapy in the earlier period(2). Study from Hong Kong (3) has shown the relapse was significantly associated with thrice-weekly (versus daily) therapy, and with the presence of cavitation at diagnosis. Prolongation of therapy significantly lowered the estimated odds of relapse. We feel the programme need to consider some changes in approach of individualization of regimens depends on associated factors like diabetes, extensive disease or cavitation who are slow to respond to antitubercular treatment. The extensive disease may necessitate additional drugs/duration of treatment. While we must practice DOTS in our patients, we must find better ways to treat in individualized manner. Again these individualizations must not discourage us from use of DOTS, but should remind us that sophisticated management based on case-specific situation is still needed. Reference 1. Cox HS, Morrow M, Deutschmann PW. Long term efficacy of DOTS regimens for tuberculosis: systematic review. BMJ. 2008 2. MA Espinal, SJ Kim and PG Suarez et al., Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries, JAMA 283 (2000), pp. 2537–2545 3. Chang KC, Leung CC, Yew WW, Ho SC, Tam CM. A nested case-control study on treatment-related risk factors for early relapse of tuberculosis. Am J Respir Crit Care Med 2004;170:1124–1130. Competing interests: None declared |
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Niyi Awofeso, Associate Professor, School of Public Health University of New South Wales, Sydney 2052, Australia.
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It is rather ironic that I’m attempting to draw parallels between Directly Observed Treatment, Short-course (DOTS) and Democracy, giving that DOTS intrinsically implies a paternalistic and directive approach to treatment, in which the patients’ personal circumstances are essentially subordinate to the requirement for their treatment to be under direct observation of the health care provider. Nevertheless, Winston Churchill’s statement about democracy – “It has been said that democracy is the worst form of government except for all others that that has been tried” – is my basis for this association. Yes, DOTS is labour intensive, and may be perceived as demeaning and patronising by patients who would like to have a strong voice in relation to how their health care is organized. Yes, it implies a one-size-fits- all approach for four major groups of TB patients. Yes some DOTS treatment cohorts of apparently ‘never-previously-treated’ patients achieve less than 70% cure rate. And yes, in field settings the opportunity cost for most poor patients undergoing observed treatment may exceed perceived treatment benefits.1 But what are the alternatives – Self Administered Treatment (SAT)?; Individualized Treatment? While SAT has obvious advantages in relation to improved patients’ convenience autonomy, it is also true that the poor, who form the bulk of TB patients are hindered by health belief systems, literacy and economics from consistently following drug-taking instructions. In fact, patient autonomy with regards to DOTS might give rise to poorer outcomes if patients suffer adverse side effects, discontinue regular drug taking but fail to reveal such issues to healthcare providers.2 Individualised treatment was utilized for many decades in the former Soviet Union prior to DOTS. The short and long term outcomes of such an approach to tuberculosis treatment have been less than satisfactory.3 Given that major alternatives to DOTS have even more adverse disadvantages, a rational approach is to focus on how to make DOTS work better as a treatment framework. For example, directly observed therapy may be complemented with food stamps and transport re-imbursement for indigent patients, with centres conveniently located along major transport routes as in currently the case in Latvia and Estonia. Second intermittent (3 days per week) DOTS regimen may be used in poor countries instead of the daily treatment regimen, to reduce logistic obstacles for patients and TB staff. Third, DOTS should be DIRECTLY OBSERVED. My experience in relation to DOTS treatment in prison settings indicate that many patients devise a variety of tricks to not take their medications in the clinics, as the financial incentives to sell such medications to fellow prisoners is considerable. Finally, greater use should be made of accurately prepared cohort analysis to guide DOTS treatment outcomes. Such analyses will provide evidence base to guide DOTS reform, as exemplified by the introduction of the DOTS-plus regimen. Let’s not throw away the baby with the bathwater. References 1) Cox HS, Morrow M, Deutschmann PW. Long-term efficacy of DOTS regimens for tuberculosis: systematic review. BMJ, 2008, 4 February 2) Awofeso N. Anti-tuberculosis medication side effects constitute major factor for tuberculosis trweatment adherence. Bull WHO, 2007, URL: http://www.who.int/bulletin/volumes/85/07.043802.pdf 3) World Bank. Stopping TB in Centrral Asia: priorities for control. Washington, World Bank, 2005. Competing interests: None declared |
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T. Jacob John, None (Retired: formerly Prof and Head Depts of clinical microbiolgy and clinical virology, Christian Medical College, Vellore, India 632 002
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There are two purposes of treating bacillary pulmonary tuberculosis - - one for clinical and microbiological cure in the best interests of the individual and second, for microbiological cure for "public health". It is for the second reason that DOTS is provided free of charge. In many situations the best interests of the individual and that of the community may not coincide. Regimented DOTS is one such example. In situations in which health care is reasonably satisfactory, DOTS in public health is an important additional intervention. Where health care is substandard, DOTS may not be the best treatment for the individual, but it is better than nothing. In short, where there is no primary health care, public health will not be efficient. WHO and TB experts have an impoprtant role of helping countries to improve health care along with promoting DOTS. Competing interests: None |
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R. K. Bansal, Professor Surat Municipal Inst. of Medical Education and Research, Surat- 395010, Gujarat, India, A.B. Pawar, Parul Vadgama
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The recent article by Helen cox and the rapid responses have aired some important issues on whether DOTS is appropriate or needs a change. Niyi Awofeso gave interesting observations in the context of DOTS and democracy and discussed on how to make DOTS work better as a treatment framework given the lack of viable alternatives. Similarly T Jacob John had pointed out the benefits of DOTS both for the patient and for public health. An important factor that also needs attention is how to ensure that the private practitioners fully participate in this strategy and whatever the strategy, the economically disadvantaged patients actually receive treatment. Our experiences show that often poor patients go to private providers and come to a DOTS centre when they are unable to afford the prescribed medications and when they had ceased treatment for some period and had defaulted. The problem of default merits urgent attention, for instance in Surat the default cases in CAT II range from 15 to 20 percent. The private providers are reluctant to refer their TB patients to a DOTS centre as they lose that patient and other patients who may accompany this patient during the long treatment period. It needs to be mentioned that even non-qualified or providers of alternative systems of medicine manage to practice allopathic medicine in India and often there is a fierce competition and low income levels among the younger medical practitioners. This translates into a tendency by the private providers not to refer TB patients to DOTS centres, not even for sputum microscopy as revealed from our OPD registers and rather retain them for financial gains. These private providers do not readily opt for various schemes under Revised National Tuberculosis Control Programme for private practitioners as these do not appear to be financially realistic to them. Given the problem of skills competencies among non-qualified and alternatively qualified practitioners, DOTS appears to be the only viable alternative left for pulmonary TB cases despite the infringement on the autonomy of medical professionals given conflicting arguments for DOTS. Therefore there is a strong need to ensure that all of the poor patients who actually need free medicines are universally referred to a DOTS centre in a low income democratic country. The need to focus on how to make DOTS work better as a treatment framework or on how to complement it with food stamps, transport re-imbursements, etc. as pointed out by Niyi Awofeso is worth exploring. In case such a mandatory referral is unrealistic then all providers need to be trained for standardised treatment and for timely referring of complicated cases. There is a need for studies on issues as whether the CAT III treatment of 6 months is sufficient for patients of cervical lymphadenopathy, as our experiences reveal the problem of relapse amongst them. We also feel the need to gather additional evidence for individualisation of treatment in extra-pulmonary TB cases. Competing interests: None declared |
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Prof (Dr)Jogenananda Pramanik.MBBS.MD., Professor,Faculty of Medicine St.Martinus University,Otrobanda,Curacao,Netherlands Antilles.www.martinus.edu, Tanu Pramanik BSc,MA(Sociology) Medical Sociologist
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Tuberculosis is re-emerging as a dreaded killer disease in western and eastern countries alike.Early diagnosis of this disease, intensive treatment and follow up -are imparative in all the cases diagnosed.Long term follow up and maintainance of required nutritional level -are often found to be neglected in developing countries.These neglected cases are the reservoir of the infectious organism-Mycobacterium tuberculosis.Incomplete treatment or inadequale doses lead to emergence of multi-drug resistant tuberculosis cases.On the otherhand, Acquired immunodeficiency syndrome is playing another havoc joining hands with tuberculosis in under privilaged population of third world countries. The recommendations for the treatment of Tuberculosis in low income countries is based on lesser evidence than that recommended by scientific evidence. Helen Cox and her co-authors rightly point this out in their systematic review of DOTS regimens for the treatment of Tuberculosis(1).The article by Cox et. al. adds an important neglected component to the never-ending controversy over the value of directly observed therapy (DOT) for all TB patients. They found a lack of adequate data regarding the long-term effectiveness of DOT, and noted suggestive evidence that intermittent regimens lead to higher relapse rates. However, this article, like almost all articles regarding adherence to TB treatment regimens fails to mention a potential alternative solution to the problem.Most important disadvantage in tuberculosis treatment follow up is in monitoring therapeutic effectiveness of DOT. Immunological parameters are often reveals dubious results due to a number of reasons.However,early diagnosis of tuberculosis using thyroxine in in-vitro culture media showed encourging responses(2).A well designed case control study on early diagnosis,intensive treatment follow up method may be an alternative measure to face present gloomy situation. Prof (Dr) Jogenananda Pramanik.MBBS.MD,Professor,Faculty of Medicine,St.Martinus University,Otrobanda,Curacao,Netherlands. Antilles,and Tanu Pramanik.BSc,MA(Sociology)Medical Sociologist. Correspondence: e-mail:pramanik_dr2000@yahoo.co.uk Reference: 1.Helen S Cox, Martha Morrow, and Peter W Deutschmann Long term efficacy of DOTS regimens for tuberculosis: systematic review BMJ 2008; 0: bmj.39463.640787 2.INCREASED YIELD OF EXCRETORY-SECRETORY ANTIGEN WITH THYROXINE: Dr.J.Pramanik et.al lrsitbrd.nic.in/IJTB/Year%201997/Octuber%201997/OCT1997%20D.pdf Competing interests: The author worked on development and field trial of tuberculosis diagnostics kits in India,Nepal and China during the period 1994 to 2002. |
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Raj B SINGH, Head, Department of Respiratory Medicine Apollo Hospital, Chennai 600 006
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For many of us practising medicine in India, the findings of Cox et al come as no surprise. The best way to treat tuberculosis is to give the appropriate regimen in adequate doses DAILY. In situations where this is not possible, the compromise approach of DOTS has been recommended and found to be useful. The main reason for using DOTS would be poor compliance of patients. It is assumed that most patients in low income countries would fall into this category. But our experience has been otherwise. Most patients, if given access to medication, care (and perhaps most importantly, counselling) at affordable costs would take their medication correctly. In the last 20 years of my practice in Chennai (Madras) I have used DOTS only on 5 patients. Undoubtedly there is a need for DOTS among some patients. But one should be aware that this is merely a second best option which one is compelled to use under certain circumstances. DOTS may perhaps be more likely to be required among low income PEOPLE - regardless of which country they live in. Competing interests: None declared |
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Chettykulam N. Deivanayagam, President,Health India Foundation Chennai 600017 Tamilnadu India
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Helen Cox and colleagues are to be congratulated for publishing what we anticipated many years ago.DOTS was based on wrong premises- 1.Tuberculosis is cured by chemicals.2.Main problem in failure to control the bacteria is lack of adherence to chemical intake 3.The patient,his family and social and economic milieu are not important for outcome. We need to remember the steady fall in mortality and incidence of pulmonary tuberculosis from the late 19th.century right through to the close of World War II,in England and Wales(Remember the falling line in the mortality graph found in Crofton and Douglas's Textbook?)all before the introduction of the first chemical Streptomycin in mid 1940s. Yes tuberculosis is quintessentially a disease of poverty and exclusion.Improve the environment,sanitation,water quality,nutrition,housing and abundant sunlight-well known parameters of quality of life and we shall witness the decline and fall of the "White Plague".Undoubtedly we need effective anti tuberculosis drugs and we can let each region devise its own treatment regimes and monitoring.Do not forget to factor in the Social stigma of TB in many communities of the world.Let DOTS be one of the options offered to the patient-not the only option. Competing interests: None declared |
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Sourabh Chand, ST2 Core Medical Training Russells Hall Hospital, Pensnett Road, Dudley, West Midlands, DY1 2HQ
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The inital idea for DOTS was the introduction of a standardised way to tackle tuberculosis (TB) by setting a political willingness and sharing best practice environment especially in countries that were lacking such an approach in the late 90s. This was vitally important to increase the awareness of the burden of TB. However the variabilty of differing clinicans in the use of DOTS has removed the potential effectiveness of the programme. During my elective in Rajasthan in 2002, it was clear that clincians in the community were diagnosing TB from a patient's history and starting anti-TB therapy without chest X-rays or sputum culture. The duration of the intial phase and maintenance phase of treament varied greatly as well as the drugs used but improved with the volume of TB patients seen. There also appeared to be some confusion who was responsible for contact tracing with 35% of clinicians interviewed unaware who was responsible. These factors will undermine the effects of the DOTS programme and make it diffcult to assess its success. Competing interests: None declared |
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R.Karthik Deivanayagam, Fellow, Hiv Medicine ghtm,gst road,tambaram,chennai,tamil nadu ,india-600047
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1. An ambulant TB patient with a reasonable quality of life has to come to dots center thrice weekly initially, then weekly,to get drugs which results in work absenteesm for 12 days a month.this costs around Rs1000 to 1200 per month in india. 2.then consider the plight of seriously ill people who has to travel to dots center ,stand in queue for hours together OFTEN. 3.it is a well known fact that HIGH DOSE,INTERMITTENT ATT has higher degree of side effects[goodman&gilman textbook of pharmacology]. 4. now reports are coming out with evidence of high relapses and recurrences.this shows that we have find viable and effective alternative to dots.public health cannot be achieved at the cost of indidvdual patient. 5.still we cannot ignore the value of DOTS in specific group of patients whose compliance is in question. Competing interests: None declared |
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Paul D van Helden, research director Biomedical Science, Stellenbosch University, Tygerberg, South Africa, 7505, Pieter Uys, Robin M Warren
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The literature concerning the phenomenon of treatment failure as a function of recurrence has been admirably reviewed by Helen Cox et al. However, simply quantifying recurrence and comparing across different times (even decades) and different regions may be problematical without understanding what relative proportions result from endogenous reactivation or exogenous reinfection.1 Exogenous reinfection involving different strains is measurable and has been noted in several studies.2-4 However, we acknowledge that the true quantification of exogenous reinfection may be complicated by the fact that the strain causing the initial disease episode may have been the epidemiologically dominant strain in that region and hence the strain most likely to cause a recurrence. Thus there may be cases conventionally attributed to endogenous reactivation that in fact are due to exogenous reinfection with the same strain. Unfortunately, most of the studies used for this review do not provide molecular epidemiological information. Thus, associations drawn between treatment efficacy and recurrence may be biased since patients with recurrence due to exogenous reinfection progress more readily to disease and therefore are more likely to be observed.5 Furthermore, the contribution of exogenous reinfection to recurrence is a function of the overall immune status of the population,4 the TB incidence6 and ultimately the efficacy of the TB control programme in the study setting.7 Perhaps these confounding factors should be taken into account before making final conclusions about the correlation between recurrence and efficacy of treatment in TB. We think that in future that molecular epidemiological data should be collected as it is essential to our proper understanding of treatment efficacy. However, we acknowledge that where a clinical trial contains multiple arms and is done in the same community, exogenous reinfection will be a constant and thereby any change in outcome with be a more true reflection of treatment efficacy. Uys, P. Warren, R.M. van Helden P.D. DST/NRF Centre of Excellence for Biomedical TB Research/MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Health Science, Stellenbosch University Reference List (1) Lambert ML, Hasker E, Van DA, Roberfroid D, Boelaert M, Van der SP. Recurrence in tuberculosis: relapse or reinfection? Lancet Infect Dis 2003; 3(5):282-287. (2) van Rie A, Warren R, Richardson M, Victor TC, Gie RP, Enarson DA et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 1999; 341(16):1174-1179. (3) Caminero JA, Pena MJ, Campos-Herrero MI, Rodriguez JC, Afonso O, Martin C et al. Exogenous reinfection with tuberculosis on a European island with a moderate incidence of disease. Am J Respir Crit Care Med 2001; 163(3 Pt 1):717-720. (4) Sonnenberg P, Murray J, Glynn JR, Shearer S, Kambashi B, Godfrey -Faussett P. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001; 358(9294):1687-1693. (5) Verver S, Warren RM, Beyers N, Richardson M, van der Spuy GD, Borgdorff MW et al. Rate of reinfection tuberculosis after successful treatment is higher than rate of new tuberculosis. Am J Respir Crit Care Med 2005; 171(12):1430-1435. (6) van Helden PD, Warren RM, Uys P. Predicting reinfection in tuberculosis. J Infect Dis 2008; 197(1):172-173. (7) Fine PE, Small PM. Exogenous reinfection in tuberculosis. N Engl J Med 1999; 341(16):1226-1227. Competing interests: None declared |
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JAYANTI P GUPTA, CONSULTANT PHUSICIAN MANAV MEDICARE CENTRE, SOUTH EXT. -I, NEW DELHI 110049, INDIA
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DOTS should be daily medicines in appropriate dose. Pre and post regimen LFT (Liver Function Tests) especially SGPT(SALT) can not be ignored. Other tests may be warrented as per symptoms that need to be explained. Some responsibility can be directly shared by the pharmaceutical companies for supply of medicines to the deserving. Role of DOTS vis-a-vis non-compliance in the emergence of MDR Tuberculosis needs to be explored. Competing interests: None declared |
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Jecko Varghese, Physician Calicut Medical College, Kerala, India
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Cox et al described the lack of enough studies which assessed the ability of standard directly observed treatment regimens despite being over 10 years old and millions of patients being treated [1]. The Indian subcontinent, a country which has the maximum number of cases of tuberculosis in the world, has certainly a major part to play in the implementation of these studies and analyzing the data and improving the outcomes of its several subjects affected by tuberculosis. It was surprising to note that of the 3432 citations in the thorough search by the authors; only 16 studies were identified to be eligible for inclusion, of which only four are from the Indian subcontinent. One of these studies was excluded on the basis that recurrence was not reported after treatment success [2]. This implies the need for more work which should translate into more successful outcomes. It is also surprising to observe in a recent seminar on tuberculosis with 223 references compiled from databases and highly regarded older publications quoted, only seven from institutions of the Indian subcontinent and most of these were on HLA linkage with tuberculosis [3]. Why is there is this inertia from our side? Or is it just that we are being under represented? The former is probably unlikely as evidenced by the citations in this article (three out of the 16 studies) and the many rapid responses already to this topic. It is also important to remember in this context, that pioneering work was conducted in Madras Tuberculosis Research Center where a non superiority was demonstrated for treatment in sanatoria care paving the way for domiciliary treatment for tuberculosis. Also, one of the few disease-dedicated journals, the “Indian Journal of Tuberculosis”, has been in publication for over fifty years. There are now several government and privately funded institutions in the subcontinent with sophisticated laboratories and experimental methodologies. However, malpractices and fraudulent works have very occasionally tarnished their images reducing the credibility of literature produced from the country in general. At the same time, research fraud is not rare in most western countries, but the general acceptance rate of genuine research work from authors from the subcontinent is comparatively much less. There is an increasing need on both parties, the journals and the authors, to merit quality work based on improving current health standards in developing and developed world rather than achieving a higher impact factor or fame. Also, it is important to note that the focus for the Indian physicians has been on the control of the disease in an expanding population rather than on data collection and research work. Unfortunately, the onus of available research seems to have shifted from tuberculosis in recent days. The disease is not considered so significant and important among the people (including major financial contributors like Bill Gates and Melinda Gates foundation and the mega rich movie stars) who promote increasing awareness of a “famous disease”, human immunodeficiency virus (HIV) infection rather than the less popular tuberculosis. This shift of spotlight does not mean that time and energy is not being spent on tuberculosis research. In summary, more important work on tuberculosis should be expected, identified and acknowledged from the Indian subcontinent, a country which is making big advances in improving the economic and health status of its people. References 1. Cox HS, Morrow M, Deutschmann PW. Long term efficacy of DOTS regimens for tuberculosis: systematic review. BMJ. 2008; 336(7642):484 2. Balasubramanian VN, Oommen K, Samuel R. DOT or not? Direct observation of anti-tuberculosis treatment and patient outcomes, Kerala State, India. Int J Tuberc Lung Dis 2000;4:409-13. 3. Maartens G, WilkinsonRJ Tuberculosis. Lancet. 2007; 370:2030–43 Competing interests: None declared |
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Ibrahim Abubakar, Consultant Epidemiologist Tuberculosis Section, Health Protection Agency Centre for Infections, London NW9 5EQ, Peter Davies, Consultant Chest Physician, Cardiothoracic Centre. Liverpool NHS Trust, Liverpool
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Cox and colleagues’ systematic review failed to identify evidence to support the effectiveness of directly observed therapy in reducing relapse rates.1 The UK is one of a limited number of countries that does not have a universal policy of direct observation for tuberculosis (TB) patients.2 A review of the evidence during the development of UK guidelines on this aspect of the strategy informed the policy.3 Other components of the Directly Observed Therapy Short Course (DOTS) strategy, such as ensuring availability of drugs, are implemented. The attraction of DOTS rests on its simplicity – five key measures that aim to improve adherence to an effective treatment regimen. The simplicity of the approach is, however, the key issue that makes the implementation and effectiveness of DOTS so variable in different settings. The UK decision not to use universal direct observation is also based on local clinical experience, which predates DOTS, that the majority of patients who are appropriately informed of the consequences of TB diseases and provided with anti-TB drugs usually adhere to and complete the course of treatment. The UK treatment completion rates remain high especially if one accounts for patients who die with, rather than of, TB.4 Despite increasing rates of TB, the majority of cases occur among non UK born persons, who probably acquired the infection abroad,5 and not due to local transmission fuelled by high relapse rates. Perhaps what’s misleading about DOTS is the undue focus given to the direct observation component of the strategy, possibly because of its inclusion in the acronym, rather than the principle of a well functioning programme with drugs readily available. The majority of TB cases in the UK are immigrants from the Indian subcontinent and sub Saharan Africa.5 Experience suggests that these patients complete their treatment without direct observation. The process of direct observation is expensive, even in resource rich settings, leading to variable implementation. It also has an opportunity cost due to diversion of resources from other aspects of the TB control programme. The DOTS strategy also assumes that, even if a proportion of cases have multi drug resistance, TB will be controlled at the population level if 70% of infectious cases are detected and 85% complete treatment. This assumption has been shown to be flawed.6 National TB programmes usually have a register of TB cases. The WHO may set a target for relapse rates and use simple record linkage within local programmes to allow the proportion of TB cases who relapse to be monitored. Relapse rate among re-treatment cases are already monitored in many countries.2 DOTS is only a means to an end: the cure of at least 85% of cases and the prevention of drug resistance emerging, not an end in itself. If a programme exceeds this by whatever method then the end is being achieved with or without DOTS. Reference List (1) Cox HS, Morrow M, Deutschmann PW. Long term efficacy of DOTS regimens for tuberculosis: systematic review. BMJ 2008; 336 (7642)484-487. (2) World Health Organisation. Global tuberculosis control: Surveillance, planning and financing. WHO report. WHO/HTM/TB/2006.362. 2006. Geneva, WHO. (3) National Collaborating Centre for Chronic Conditions. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. 2006. London, Royal College of Physicians. (4) Ditah IC, Reacher M, Palmer C, Watson JM, Innes J, Kruijshaar ME et al. Monitoring tuberculosis treatment outcome: analysis of national surveillance data from a clinical perspective. Thorax 2007. Published Online First. (5) Kruijshaar ME, French CE, Anderson C, Abubakar I. Tuberculosis in the UK: Annual Report on Tuberculosis Surveillance and Control in the UK. ISBN 978-0-901 144-96-6. 2007. London, Health Protection Agency. (6) Cohen T, Murray M. Modeling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness. Nat Med 2004; 10(10):1117-1121. Competing interests: None declared |
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Arild Bjorndal, Professor University of Oslo
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Thanks for a well written article on an important subject. However, why not cite - and build on - the systematic review in the Cochrane Library by Volmink & Gardner from 2007? Competing interests: None declared |
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Alistair Story, Consultant TB Nurse Tuberculosis Section, Health Protection Agency Centre for Infections, London NW9 5EQ,, Andrew C Hayward UCL Centre for Infectious Disease Epidemiology, Department of Primary Care and Population Sciences, London
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The admirable review by Helen Cox and colleagues [1] again illustrates that DOTS is not a panacea. In some patients poor adherence is highly predictable and these findings must not undermine efforts to promote treatment completion through direct observation. Among homeless people, problem drug users and prisoners with tuberculosis in London, 41% took treatment intermittently during the initiation phase. Alarmingly, most of these cases were switched from self observed treatment to direct observation after demonstrating poor adherence. [2] Adherence is most crucial in the initiation phase of treatment as the risk of acquired drug resistance is greatest when bacterial load is high. Around one in five of the total caseload in London are homeless people, problem drug users or prisoners but this group comprise around one third of all smear positive cases and almost half of cases lost to follow up care. Investment in detecting these cases early and ensuring treatment continuity and completion through DOTS is essential to control tuberculosis at a population level. Direct observation provides the best objective measure that treatment in actually taken. Intensive case management including direct observation also provides the opportunity to deliver a package of supportive care tailored to patients’ needs. [3] This latter point is most likely to make DOTS work. [4] The true costs of DOTS in conjunction with supportive care, however, may be substantially underestimated. [5] [1] Cox HS, Morrow M, Deutschmann PW. Long term efficacy of DOTS regimens for tuberculosis: systematic review. BMJ 2008; 336 (7642)484-487. [2] Story A, Murad S, Roberts W, Verheyen M, Hayward AC; London Tuberculosis Nurses Network. Tuberculosis in London: the importance of homelessness, problem drug use and prison. Thorax. 2007 Aug;62(8):667-71. Epub 2007 Feb 8. [3] Sumartojo E. When tuberculosis treatment fails: a social behavioural account of patient adherence. Am Rev Respir Dis 1993;147:1311–20. [4] Volmink J, Matchaba P, Garner P. Directly observed therapy and treatment adherence. Lancet 2000;355:1345–50. [5] Rubado DJ, Choi D, Becker T, Winthrop K, Schafer S. Determining the cost of tuberculosis case management in a low-incidence state. Int J Tuberc Lung Dis. 2008 Mar;12(3):301-7. Competing interests: None declared |
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Naghman Bashir, Senior Medical Officer Holy Family Hospital, Rawalpindi. 42600 Pakistan
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While DOTS is definitely valuable in treatment of tuberculosis, certain other factors need our consideration to make DOTS end-of-treatment response successful. Two drug regimen (INH and ethambutol) is one of the recommendation during the continuation phase. DOTS program provides two drug FDC in the continuation phase in Pakistan. In high burden countries (like in Pakistan) resistance to INH has been reported as 11% in 1993 increasing to 27% in 1997 in Pakistan (1) and as high as 32.9% in India (2). The reported resistance to ethambutol is 5% in 1993 increasing to 15% in 1997 (1). In the setting of such high resistance to INH and ethambutol, two drug regimen in continuation phase needs to be reviewed specially in high burden countries. In situations like Tuberculous meningitis, or pericarditis, or other severe forms of tuberculosis, there are no clear cut guidelines. Two drugs in continuation phase would not be recommendable. Rifampicin must be added to regimen and guidelines must look into it. Moreover duration of therapy of such patients needs to be redefined in such high risk patients. In low income countries many anti-tuberculous brands are available in the market. Some of these brands do not have proven bioavailability. The storage conditions are also not standardized. Therefore patients get under -dosed or get poor quality drugs leading to the risk of developing MDRTb. NTPs must look into it; strategy should be developed to make ALL anti- tuberculous drugs available ONLY at DOTS centers across the country so that risk of failure, relapse, or MDRTb is minimized. Naghman Bashir naghman@gmail.com 1. J. A. Khan, A. Malik. Tuberculosis in Pakistan: Are We losing the battle? JPMA Vol:53, No:8 August, 2003 2. C.N. Paramasivan & P. Venkataraman. Drug resistance in tuberculosis in India. Indian J Med Res 120, October 2004, pp 377-386 Competing interests: None declared |
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Sachin R. Atre, Research officer Foundation for Research in Community Health, 85 Anand Park Aundh, Pune-411007, Nerges F. Mistry
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The article by Cox et al.underscores the importance of assessing efficacy of DOTS regimens with regard to rising recurrence of tuberculosis (0-14%) after successful treatment in different regions(1). The wide variation in recurrence rates suggests that the treatment regimens recommended under DOTS may not be universally successful. The authors attribute this variation to a considerable heterogeneity across studies included in this review. One limitation of their analysis is the inclusion of studies conducted over a long window of time viz. 1979-2002. With the intense application of antibiotics over more than three decades, sufficient drug pressures would have been created boosting the level of acquired drug resistance in the recently conducted programs. More severe forms such as multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB), which are being increasingly reported in recent years (2, 3), provide support to this hypothesis. Since DOTS regimens are not effective to treat MDR-TB cases (3, 4), a considerable recurrence of TB will be observed in the regions where the diagnostic and treatment facilities for MDR-TB are yet unavailable. In such a scenario, it is likely that MDR-TB cases will be treated with the DOTS regimens leading to treatment failures and disease recurrence. Technical insufficiencies in control programs can also extend to poor quality sputum microscopy that is unable to identify treatment failures at the point of release from treatment. The data on recurrence will be useful for designing strategies to control drug-resistant TB, however, it is possible to obtain such information only from those sites, where treatment outcome records (cure/failure) are authentic and an active follow up of cases is feasible. In this context, obtaining information especially on migrants remains a major challenge. A recent RNTCP based study in India reveals that 13% of patients presenting as new TB cases from urban areas (Mumbai) and 9% from the rural areas of Pune district, admitted after screening that they had received anti-TB treatment previously for more than a month (5). Factors such as a lack of screening for prior anti-TB treatment, a target-oriented approach of the program and patient's reluctance to disclose the history of anti-TB treatment were responsible for their erroneous categorization as new cases. Further, being categorized as new cases, those patients were continued on the four-drug (DOTS) regimen. Such practices may indicate an unexpected rise in the level of primary drug resistance due to erroneous inclusion of previously treated cases and can also lead to amplification of drug resistance among patients having MDR-TB strains (3). These observations suggest that in high-burden countries like India, current data on TB recurrence is in all likelihood, underestimated. In our opinion, subsequent assessments of long-term efficacy of DOTS regimens should have power to discriminate between drug-susceptible and drug-resistant cases, both at point of entry in control programs and at point of release from treatment. References 1.Cox H., Morrow M, Deutschmann P. Long term efficacy of DOTS regimens for tuberculosis: systematic review. British Medical Journal 2008 (February) 2.Pillay M, Sturm A. Evolution of the extensively drug-resistant F15/LAM4/KZN strain of Mycobacterium tuberculosis in Kwa-Zulu-Natal, South Africa. Clinical Infectious Disease 2007; 45(11):1409-14. 3.Farmer P, Kim J. Community based approaches to the control of multi drug resistant tuberculosis: Introducing DOTS-Plus. British Medical Journal 1998; 317: 671-74. 4.Dye C, Williams B, Espinal M, et al. Erasing the World’s slow stain: Strategies to beat multi drug-resistant tuberculosis. Science 2002; 295: 2042-46. 5.Atre S, D'Souza D, Dholakia Y, Mistry N. Observations on categorization of new TB cases: implications for controlling drug resistance. The International Journal of Tuberculosis and Lung Disease 2007; 11(10): 1152-53. Competing interests: None declared |
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Kidangazhiyathmana Ajithkumar, Assistat professor ,Medical college Trichur Trichur, Kerala, India
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This systematic reveiw says that there is no good evedence regarding the relapse rate after DOTs. When we read this we should rememeber many of our public health program are built on no sound evedence or no or bad evedence.It is true that many a time it is not possible to wait till good evedence for a public health program launch . But where we miss is that the opertunity to get good evedence from the program.We have similler situation in Leprosy and we should expect the same in HIV. It is important to include long term follow up and research componant into the program itself and make the program a " living program".The program should be planned in such a way that it is not difficult to modify it even in the field as new evedence is coming into the program. Competing interests: None declared |
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Kwok C Chang, Senior Medical & Health Officer, TB & Chest Services, Department of Health, Hong Kong, China Wanchai Chest Clinic, 1st Floor, Wanchai Polyclinic, 99, Kennedy Road, Wanchai, Hong Kong, China, Chi C Leung, Cheuk M Tam
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To: Editor
Cox HS et al conducted a systematic review of the long-term efficacy of standard six-month DOTS regimens for tuberculosis [1]. They found a wide variation (0% to 14%) in recurrence after successful treatment, concluded that considerable heterogeneity across studies had precluded systematic assessment of factors contributing to tuberculosis recurrence, and suggested that few studies had assessed the ability of standard six-month DOTS regimens for achieving lasting cure under routine programme conditions. Their systematic review may be interpreted from a different perspective. Table 1, which is adapted from the systematic review by Cox HS et al [1], shows the recurrence rates of different study arms included in the review. Although the recurrence rates of all study arms are too heterogeneous for obtaining a summary measure, the chi-square test for heterogeneity suggests that it may be possible to combine study arms stratified by study design and quality rating of treatment, which reflects treatment adherence. While the recurrence rates of standard six-month DOTS regimens shown in programme settings with poor rating were all above 5% and largely above 10%, the corresponding rates in programme settings with average rating were all below 5%. The DOTS strategy consists of five components [2], of which directly observed treatment has been a highly contentious topic. Successful implementation of DOTS calls for proper implementation of directly observed treatment in the presence of a sound health infrastructure with adequate training, facilities, and other human and environmental resources [2]. It has been shown that the cure rates of DOTS regimens could also be low under suboptimal controlled trial settings [3, 4]. Whether high cure rates and low recurrence rates can be achieved for DOTS regimens is critically dependent on the quality of DOTS. Thus one of the six components in the Stop TB strategy is the pursuit of high-quality DOTS expansion and enhancement [5]. As patients with concomitant diseases were often excluded from published controlled clinical trials, it is not certain whether standard six-month DOTS regimens are equally efficacious among them. However, just as the overall relapse rates of standard six-month DOTS regimens are not significantly affected by higher risk of relapse among subgroups of patients with cavitary pulmonary tuberculosis and positive two-month culture [6], the impact of concomitant diseases on the overall relapse rates of standard six-month DOTS regimens given under quality programme conditions may be acceptable, as illustrated by the low risk of recurrence in two studies involving a total of 1789 assessable patients (see Table 1). In conclusion, there is ample evidence from existing clinical trials that standard six-month DOTS regimens are efficacious when they are given under quality programme conditions. While a higher risk of relapse may be observed in certain subgroups, both cure and relapse rates are often acceptable in the absence of an overwhelming prevalence of these patients. Kwok Chiu Chang
Table 1. Recurrence rates stratified by study design and quality rating of treatment* References¡Ï Study design Quality rating of treatment‡ Number of assessed subjects Number of recurrence Recurrence rate (%) Q¡± w1-3 CCT High 127 4 3.1 1.5 w1-3 CCT High 119 2 1.7 w8 CCT Average 212 6 2.8 w12-14 RCT Average 80 2 2.5 w15-16 RCT High 166 4 2.4 w19-20 RCT Average 96 2 2.1 w21-22 RCT Average 47 0 0 w24-26 RCT Average 172 7 4.1 w4 RCT Poor 119 1 0.8 1.0 w18 CCT Poor 17 1 5.9 w9 Obs Average 1483 63 4.2 0.5 w23 Obs Average 306 10 3.3 w5-6 Obs Poor 169 24 14.2 7.4 w7 Obs Poor 67 9 13.4 w10 Obs Poor 132 15 11.4 w11 Obs Poor 503 62 12.3 w17 Obs Poor 232 13 5.6 CCT = controlled clinical trial; Obs = observational study under programmeme conditions; Q = chi-square for the chi- square test of heterogeneity; RCT = randomized controlled trial * Data are abstracted from the original review [1] and supplemented by the chi-square test of heterogeneity. ¡Ï Using the same references as in the online supplement of the original review [1]. ‡ As defined in the original review [1]. ¡±The study arm with the largest number of assessable patients is the reference arm within the subgroup for computing the chi square. Q for all 17 study arms is 70.8, which implies considerable heterogeneity. Q for subgroups stratified by study design (RCT or CCT versus Obs) and quality rating of treatment (high or average versus poor) shows no evidence of heterogeneity. References 1. Cox HS, Morrow M, Deutschmann PW. Long term efficacy of DOTS regimens for tuberculosis: systematic review. BMJ 2008;336:484-7. 2. WHO. Treatment of tuberculosis: guidelines for national programmes. Geneva: WHO, 2003. Report No WHO/CDS/TB/2003.313. 3. Zwarenstein M, Schoeman JH, Vundule C, Lombard CJ, Tatley M. Randomised controlled trial of self-supervised and directly observed treatment of tuberculosis. Lancet 1998;352:1340-3. 4. Walley JD, Khan MA, Newell JN, Khan MH.Effectiveness of the direct observation component of DOTS for tuberculosis: a randomised controlled trial in Pakistan. Lancet 2001;357:664-9. 5. WHO. The Stop TB strategy, Building on and enhancing DOTS to meet the TB-related Millennium Development Goals. Geneva: WHO, 2006. Report No WHO/HTM/TB/2006.368. 6. Chang KC, Leung CC, Yew WW, Chan SL, Tam CM. Dosing schedules of 6-month regimens and relapse for pulmonary tuberculosis. Am J Respir Crit Care Med 2006;174:1153-8. Competing interests: None declared |
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