WARNING: TECHNICAL ALERT!
Just for the sake of review and for those like myself who are interested, and for the sake of defining our terms - for our consideration there is this from the WHO's (2003) Treatment of Tuberculosis: Guidelines for National Programmes:
"GLOBAL EPIDEMIOLOGY AND BURDEN OF DISEASE:
Nearly one third of the global population - i.e. two billion people - is infected with mycobacterium tuberculosis and at risk of developing the disease. More than eight million people develop active tuberculosis (TB) every year, and about two million die.
More than 90% of the global TB cases and deaths occur in the developing world where 75% off cases are in the most economically productive group (15-54 years). An adult with TB loses an average of three to four months (annually) of work time. This results in the loss of 20-30% of annual household income and if the patient dies of TB, and average of 15 years of lost income. In addition to the devastating economic costs, TB imposes indirect negative consequences - children leave school because of their parents' tubecuolsis, and women abandoned by their families as a result of the disease.
Coinfection with human immunodeficiency virus 9HIV) significantly increases the risk of developing TB. Countries with high prevelance of HIV, particularly those in sub-sharan Africa, have witnessed a profound increase in the number of TB cases, with reported incidence rates increasing two to three fold in the 1990's.
At the same time, multi-drug resistance which is caused by poorly managed TB treatment, is a growing problem of serious concern in many countries around the world.".
"REASONS FOR THE GLOBAL TB BURDEN:
The main reasons for the increasing burdne of TB globally are:
- Poverty and the widening gap between rich and poor in various populations, eg. developing countries, disenfranchised urban populations in developed countries.
- Neglect of the disease (inadequate case detection, diagnosis and cure)
-Collapse of the health infrastructure in countries experiencing severe economic crisis and civil unrest.
The impact of the HIV pandemic.
"The most cost-effective public health measure for the control of tuberculosis is identification and cure of infectious TB cases, i.e. patients with smear positive (the TB bacillus visible through a microscope in a sputum sample) pulmonary TB. Nevertheless, NTP's (National Treatment Programs) provide the identification and cure for all patients with TB. These guidelines cover the treatment of patients, both adults and children, with smear positive pulmonary TB, smear negative pulmonary TB and extrapulmonary TB.
Treatment of TB is the cornerstone of any NTP. The modern treatment strategy is based on standardized short-course chemotherapy regimens and proper case management to ensure completion of treatment and cure. Standardized treatment is a component of the TB control control policy package, set out in the WHO's expanded framework for effective tuberculosis control, and of the internationally recommended strategy for TB control known as DOTS. Success of the treatment strategy depends on the commitment to the policy package in its entirety. The emphasis is on placing the patient at the centre of TB control activities, the health system begin responsible for facilitaiting access to treatment and ensuring drug intake.
The DOTS strategy provides the TB patient withg all the necessary requirements for cure.".
"The essentails needed to control TB, based on diagnosis and treatment of infectious cases and incorporating the essentail management tools, were developed and packaged as the DOTS strategy in the early 1990's.
Countries applying DOTS on a wide scale have witnessed remarkable results. Transmission has declined in several countries; in Peru, for example, incidence has dropped by approxiamtely 6% per year over the last decade. Mortality has fallen: in China some 30 000 deaths have been averted each year in districts implementing DOTS. Drug resistance has decreased: in New York in the 1990's the revelance of TB drug resistance fell by 75% following intensive interventions to improve pateint management and TB transmission.".
"What determines a case definition?
-Site of disease.
-Severity of TB disease
-History of previous treatment of TB.
-Tuberculosis suspect: Any person who presents with symptoms or signs suggestive of TB, in particular cough of long duration.
- Case of tuberculosis: A patient in whom TB has been bacteriologically confirmed by a clinician.
- Definite case of tuberculosis: A pateint with postive culutre for mycobacterium tuberculosis complex. (In countries where culture is not routinely available, a patient with two putum smears positive for acide fast bacilli (AFB) is alos considered a definite case.".
"Treamtent regimens have an initial(or intensive) pahse pasting 2 months and a continuation phase lasting 4 to 6 months. During the intial phase, normally consisting of isoniazide, rifampicin, pyrazinamide and ethambutol, the tubercol bacilli are killed rapidly. Infectious patients quickly become non-infectious (within appoximately two weeks); symptoms abate. The vast majority of patients with sputum smear-positive TB become smear-negative within two months. During the continuation pahse, fewer drugs are necessary but for a longer time. The sterilizing effect of the drugs eliminates the remaining bacilli and prevents subsequent relapse.".
MANAGEMENT OF CHRONIC AND MULTI-DRUG RESISTANT CASES:
"CHRONIC: A patient with TB who is sputum-postive at the end of the standard re-treatment regimen with essential anti-tuberculosis drugs.
MDR-TB: A patient who has active tuberculosis with bacilli resistant at least to both rifampicin and isoniazid.
Chronic cases and MDR-TB cases are noy synonymous. MDR-TB can rarely be observed in new cases; it is mosre frequent in re-treatment cases, expecially in faliure cases. MDR-TB is one of the main cuases of faliure to a Category 1 (see above) treatment regimen in patients treated under strict observation.
Chronic patients probably have MDR-TB because they have proviously received at least two full course of treatment with essential antituberculosis drugs. The aim of treatment of chronic and MDR-TB cases are similar to those of all cases with TB. However, MDR-TB patients respond poorly to short-course chemotherapy and need to be treated intensively and for up to 24 months with a regimen based on reserve antituberculosis drugs.
Multi-drug resistant TB is a major cause of a faliure for the individual pateints concerned. Management of chronic cases becomes an objective for an NTP when the DOTS strategy is fully implemented. Full implementation of DOTS is the best prevention against chronic disease and extension of MDR-TB.".
"The main priority for TB control is the identification and cure of sputum smear-positive pulmonary TB cases. The decision to use regimens incorporating reserve antituberculosis drugs shoudl based on:
-The availability of financial resources for reserved drugs;
- The capacity of the NTP to maintain patients on regular treatment;
- Laboratories that can perfrom high quality drug susceptibility testing;
- Prevention of uncontrolled use of reserve drugs;
- Special registration of chronic and MDR-TB cases and expert commitees for decisions on treatment and monitoring;
- Special cohort analysis.".
"Without an effective organizational framework, such as the one suggested in the DOTS strategy and without knowledge of the operational requirements of treatment with reserve regimens, the chances of success will be minimal.
Treatment of chronic and MDR-TB cases with reserve drugs is more expensive and more toxic than treatment with essential drugs. Many programmes will therefore choose hospitalization, at least for the initial portion of therapy. However, hospitalization entails increased risk of nosocomial transmission of MDR-TB to both staff and patients, especially those infected with HIV. After tolerance of the drug regiemn has been ascertained and the patient's cooperation has been secured, the patient can be started on ambulatory treatment. Programmes with strong hom-based care cnetres may choose to have ambulatory treatment from the outset. Ambulatory treatment reduces the risk of MDR-TB transmission in hospitals, which often lack adequate infection control capacity.
Management of chronic and MDR-TB cases with reserve drugs can be done in different ways. If standardized regimens are used, feasibility of their administration under the aegis of the NTP is conditional on a strong NTP that is successfully applying the DOTS strategy. Advantages of standard regimens include potential reduction of costs compared with invidualized regimens, reduction of errors in prescrription, easier estimation of drug needs, purchasing, distribution, and monitoring, facilitation of staff training, and facilitation of a regular drug supply when patients move from one area to another.
Centres of excellence, to which patients are referred for treatment, could utilize individualized regimens tailored to the drug suscepibility pattern of the patient. Referral to such facilities may also be the best option for patients whose cooperation is not easy to chieve, such as individuals suffering alcoholism or drug dependance, prisoners, and homeless persons. Special efforts are needed to persuade such patients to somplete the long and arduous treatment regimens required. The advantages of individualized regimens include treatment according to the susceptibility pattern and, probably, higher cure rates. This approach may, however, be more costly than standardized regimens in terms of tthe drugs involved, n laboratory capability and in the training required to administer a variety of treatment regimens.
Use of standardized or individualized treatment regimens is currently the subject of operations studies to assess the feasibility and cost-effectiveness of using drugs under aegis the NTP in resource-limited countries. Evidence from Peru shows that the use of standardized regimens at the country level may be feasible and cost-effective.".
The treatment regimen should include at least 4 drugs , including an injectable agent and fluoroquine in the initial phase, and at least 3 of the most active and best-tolerated drugs in the continuation phase. And initial phse of at least 6 months should be followed by a continuation phase of 12-18 months.
While drug susceptibility testing may not be available in some resource-limited settings, all efforts shoudl be made to obtain an accurate essentail drug susceptibility testing profile of pateints failing short-course chemotherapy and of chronic disease in order to confirm the presence of MDR-TB. Programmes planning to implement the use of reserve drugs in a standardized regimen but unable to perform susceptibility testing should set up relationshops with suprnational laboratories until such facilities can be established locally.
Standradized regimens are the choice in settings where susceptibility testing of reserve drugs is not available. However, drug susceptibility testing is recommended in patients who fail the standardized regimen and, when possible, these cases should be referred to specialized centres for individualized treatment.
Use of regimens tailored to the susceptibility pattern of reserve drugs requires highly specialized laboratory and microbiological follow-up facilites that are not yet available in most resource-limited countries.".
"The management of chronic and MDR-TB cases require operational organization that allows integration with the NTP. An expert commitee of TB specialists, public health specialists and laboratory specialists should be appointed to screen requests from general health facilites for access to treatment with reserve drugs. The commitee could be national, or several regional commiteess can be constituted. This is very important, since cental level NTP staff do not usually have time to be looking into these issues - their most important priority is the management of new cases to prevent the development of chronic and MDR-TB.
A register of the chronic cases and MDR-TB identified should be created, for follow-up and treatment outcome and the end of treatment.
Some countries have created a special unit under the aegis of the NTP to coordinate meetins of the special commitee, for data management and analysis, to solve problems, to oversea delivery of reserve drugs and for other operational activites. This unit is an appendage of the NTP. The minimum persoanl requirements are a project coordinator (who respnds to the NTP manager), a nurse, a medical coordinator and a data manager.
Coordination with the laboratory is vital. Usually only one reference laboratory capable of susceptibility testing of essential drugs (to confirm MDR) is available. It is therefore important that the reference laboratory works in close coodination with the special unit.".
"A standardized re-treatment regimen should include at least 4 drugs never used by the patient, including an injectible (capreomycin, amikacin or kanamycin) and a fluoroquinolone. Treatment should be given daily and directly observed. Bacteriologoical results (smear and, if possible culute) should be monitored. Pyrazinamide and ethambutol can included in the regimen because of the lower probability or resistnace than to other essential drugs. However, in chronic cases that have received multpile treatments, using ethambutol and pyraziniamide, it is doubtful whether these drugs remain active, and including them may offer little advantage. And initial phase of at least 6 months should be followed by a continuation pahse of 12-18 months with at lest 3 of the most active and best tolerated drugs.
"If the results of susceptibility test for essentail and reserve drugs are available and the full range of reserve drugs is available, the treatment regimen may be tailored according the susceptibility pattern. Designing a regimen will depend on several factors, such as the drugs to which the strain of M. tuberculosis is resistant. The same principles - at least 4 drugs never used, including an injectable and fluroroquinilone, and an initial pahse of at least 6 months followed by a continuation phase of 12-18 months - apply.
Treatment regimens with reserve antituberculosis drugs remain much more expensive than regimens with essentail antituberculosis drugs. In countries with limited financial resources, health facilites and staff, the provision of regimens with reserve drugs may be an acceptible drains on resrouces. It would irrational for any country to divert resources to regimens with reserve drugs is a large proportion of new infectious cases remain untreated or ineffectively treated and short-course chemotherapy with drugs has not reached its full therapeutic potential. (italics mine) A large requirement for resrve drugs reflects porr-quliaty implmentation of short-course treatment.
Furthermore, since there is poor toleranace to some other reserved drugs and their efficacy is limited, the best strategy to prevent chronic cases (and MDR-TB) is through full implementation of the DOTS strategy and standardized short-course regimens Category I and II.
Access to spcially priced, quality assured reserve drugs can be possible through the Green Light Commitee (GLC). In addition the GLC offers technical assistance a regular monitoring mechanism for projects. Programmes considering the use of reserve drugs should strongly conside using the GLC mechanism to help ensure that all parameters are in place to guarantee successful outcomes.".
Now, the reason I wrote all this down was to provide at least some sense of just how serious MDR-TB actaully is, and just how complicated tuberculosis treatment becomes when the stantdard treatment for Phases I-IV fails to work and the bacillus begins to becoe drug resistant. Son one imagine just how difficult it would be in so-called 'resource-limited', with prgrams which are already struggling to achieve the basics in primary care.".
So, just to sum up:
"MDR-TB describes strains of tuberculosis that are resistant to at least the two first line drugs - isoniazid and rifampicin. XDR-TB, or Extensive Drug Resistant TB (also referred to as Extreme Drug Resistance) is MDR-TB that is also resistant to three or more of the six classes of second-line drugs, as well.">
And remember, in many of these case the patient is also suffering from HIV.