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Treatment of Tuberculosis: Guidelines. 4th edition. Geneva: World Health Organization; 2010.

Treatment of Tuberculosis: Guidelines. 4th edition.

3 Standard treatment regimens

3.1. Chapter objectives

This chapter describes:

the aims of treatment;

the recommended doses of first-line anti-TB drugs for adults;

regimens for new and previously treated patients;

considerations in selecting regimens for defined patient groups;

evidence base for the selected regimens in defined patient groups.

The choice of TB regimens in special situations (pregnancy, concurrent use of oral contraceptives, liver disease, and renal failure) is covered in Chapter 8; TB treatment for persons living with HIV is discussed in Chapter 5.

3.2. Aims of treatment

The aims of treatment of tuberculosis are:

to cure the patient and restore quality of life and productivity;

to prevent death from active TB or its late effects;

to prevent relapse of TB;

to reduce transmission of TB to others;

to prevent the development and transmission of drug resistance.

3.3. Essential antituberculosis drugs

Table 3.1 shows the essential anti-TB drugs and their recommended dosages based on the patient's weight.

Table 3.1

RECOMMENDED DOSES OF FIRST-LINE ANTITUBERCULOSIS DRUGS FOR ADULTS.

The WHO-recommended formulations of anti-TB drugs and fixed-dose combinations (FDCs) of drugs appear in the WHO Model List of Essential Medicines (available at www.who.int/medicines/publications/essentialmedicines/en). The formulations and combinations of anti-TB drugs available in each country should conform to this list. (See also the WHO Model Formulary at www.who.int/selection_medicines/list/en.)

To facilitate procurement, distribution and administration of treatment to patients, the daily dosage may be standardized for three or four body weight bands – for instance 30–39 kg, 40–54 kg, 55–70 kg and over 70 kg, as is done with the Global Drug Facility patient kits. (See also reference 1.)

All anti-TB drugs should be quality-assured, and management of anti-TB drugs should be incorporated into the management of other essential medicines by the ministry of health.

Annex 1 provides additional information on the essential anti-TB drugs, including contraindications, precautions, use in pregnancy, adverse effects, and drug interactions. Intermittent dosing schedules are discussed in section 3.5.1 below.

3.3.1. Fixed-dose combinations of anti-TB drugs

While evidence on fixed-dose combinations (FDCs) of anti-TB drugs was not systematically reviewed for this fourth edition, WHO continues to recommend their use, as does Standard 8 of the ISTC (3). FDCs are thought to prevent acquisition of drug resistance due to monotherapy, which may occur with separate (“loose”) drugs. With FDCs, patients cannot be selective in the choice of drugs to ingest. Prescription errors are likely to be less frequent because dosage recommendations are more straightforward, and adjustment of dosage according to patient weight is easier. The number of tablets to ingest is smaller and may thus encourage patient adherence.

While there is ecological evidence of the benefits of FDCs in relation to drug resistance in early studies of DOTS programmes, there is limited direct evidence of improved adherence with FDCs (4). A recent multicentre trial found FDCs to have equivalent efficacy to single pills and to be more acceptable to patients (5). However, assessment of cure and relapses was based on smear microscopy and not on culture. A multicentre trial (The Union Study C) evaluating the efficacy, acceptability and toxicity of a four-drug FDC compared with loose pills given in the intensive phase of treatment has just been completed and results should soon be available. Another multicentre study including pharmacokinetic assessment is soon to be completed by WHO/TDR.

Quality assurance is essential to ensure adequate bioavailability of the component drugs of FDCs. 1 Using FDCs does not obviate the need for separate drugs for patients who develop drug toxicity or intolerance or for those with contraindications to specific component drugs.

3.3.2. Patient kits

A TB patient kit contains the full course of treatment for a single patient and thus assures the TB patient that his or her medicines will be available throughout treatment. The kit provides health workers with a container that has all required medicines in the necessary strengths and quantities. This helps limit confusion and wastage, and makes it easier to monitor the regularity of treatment; avoiding stock-outs also helps to maintain patient confidence in the health system. In addition, the patient may feel a sense of “ownership” of the patient kit and enhanced motivation to complete the full course of treatment – during visits to the health centre he or she can actually see the quantity of medicines that must be taken to achieve cure (1).

It should be noted that the TB patient kit does not eliminate the need for directly observed treatment (DOT).

3.4. Standard regimens for defined patient groups

Standardized treatment means that all patients in a defined group receive the same treatment regimen. Standard regimens have the following advantages over individualized prescription of drugs:

errors in prescription – and thus the risk of development of drug resistance – are reduced;

estimating drug needs, purchasing, distribution and monitoring are facilitated;

staff training is facilitated;

costs are reduced;

maintaining a regular drug supply when patients move from one area to another is made easier;

outcome evaluation is convenient and results are comparable.

For assigning standard regimens, patients are grouped by the same patient registration groups used for recording and reporting, which differentiate new patients from those who have had prior treatment. Registration groups for previously treated patients are based on the outcome of their prior treatment course: failure, relapse and default (see Chapter 2).

Recommended regimens for different patient registration groups are shown in Tables 3.2, 3.3 and 3.4. More details on the evidence and judgements underlying the recommended regimens are described in Annex 2.

Table 3.2

STANDARD REGIMENS AND DOSING FREQUENCY FOR NEW TB PATIENCTS.

3.5. New patients

New patients are defined as those who have no history of prior TB treatment or who received less than 1 month of anti-TB drugs (regardless of whether their smear or culture results are positive or not) (see section 2.6).

3.5.1. New patients presumed or known to have drug-susceptible TB

New patients are presumed to have drug-susceptible TB with two exceptions:

If they have developed active TB after known contact with a patient documented to have drug-resistant TB; they are likely to have a similar drug resistance pattern to the source case (6), and DST should be carried out at the start of treatment. While DST results of the patient are awaited, a regimen based on the DST of the presumed source case should be started.

The 2-month rifampicin regimen (2HRZE/6HE) is associated with more relapses and deaths than the 6-month rifampicin regimen (2HRZE/4HR) (7). WHO therefore recommends the following for new patients presumed or known to have drug-susceptible TB. (See also Standard 8 of the ISTC (3).)

Remark a: Recommendation 1.1 also applies to extrapulmonary TB except TB of the central nervous system, bone or joint for which some expert groups suggest longer therapy (see Chapter 8).

Remark b: WHO recommends that national TB control programmes provide supervision and support for all TB patients in order to ensure completion of the full course of therapy.

Remark c: WHO recommends drug resistance surveys (or surveillance) for monitoring the impact of the treatment programme, as well as for designing standard regimens.

In terms of dosing frequency for HIV-negative patients, the systematic review found little evidence of differences in failure or relapse rates with daily or three times weekly regimens (7). However, patients receiving three times weekly dosing throughout therapy had higher rates of acquired drug resistance than patients who received drugs daily throughout treatment. In patients with pre-treatment isoniazid resistance, three times weekly dosing during the intensive phase was associated with significantly higher risks of failure and acquired drug resistance than daily dosing during the intensive phase. (Treatment regimens for TB patients living with HIV are discussed in detail in Chapter 5.)

Wherever feasible, the optimal dosing frequency for new patients with pulmonary TB is daily throughout the course of therapy

New patients with pulmonary TB may receive a daily intensive phase followed by three times weekly continuation phase [2HRZE/4(HR)₃ ] provided that each dose is directly observed

Three times weekly dosing throughout therapy [2(HRZE)₃/4(HR)₃] is another alternative to Recommendation 2.1, provided that every dose is directly observed and the patient is NOT living with HIV or living in an HIV-prevalent setting

Remark a: Treatment regimens for TB patients living with HIV or living in HIV-prevalent settings are discussed in Recommendation 4 and Chapter 5.

Remark b: In terms of dosing frequency for HIV-negative patients, the systematic review found little evidence of differences in failure or relapse rates with daily or three times weekly regimens (7). However, rates of acquired drug resistance were higher among patients receiving three times weekly dosing throughout therapy than among patients who received daily drug administration throughout treatment. Moreover, in patients with pretreatment isoniazid resistance, three times weekly dosing during the intensive phase was associated with significantly higher risks of failure and acquired drug resistance than daily dosing during the intensive phase.

There is insufficient evidence to support the efficacy of twice weekly dosing throughout therapy (7).

New patients with TB should not receive twice weekly dosing for the full course of treatment unless this is done in the context of formal research

Remark: The available evidence showed equivalent efficacy of daily intensive-phase dosing followed by two times weekly continuation phase (7). However, twice weekly dosing is not recommended on operational grounds, since missing one dose means the patient receives only half the regimen.

Tables 3.2a and 3.2b present standard treatment regimen and dosing frequency for new TB patients.

3.5.2. Settings with high levels of isoniazid resistance in new patients

When new patients with isoniazid-resistant TB start their treatment, outcomes are worse than for patients with isoniazid-susceptible TB, even with the 6-month rifampicin regimen (7). The global weighted mean of any isoniazid resistance (excluding MDR) is 7.4% in new patients (8). Thus, a significant proportion of the new TB cases in many regions of the world have a risk of poor treatment outcomes because of their pretreatment isoniazid resistance.

The following weak recommendation applies to countries where isoniazid susceptibility testing in new patients is not done (or results are not available) before the continuation phase begins.

In populations with known or suspected high levels of isoniazid resistance, new TB patients may receive HRE as therapy in the continuation phase as an acceptable alternative to HR

Given the potential benefit (9) and low risk of toxicity from ethambutol, the pressing need to prevent MDR warrants this recommendation. However, the recommendation is conditional, for the reasons explained in more detail in Annex 2. The most effective regimen for the treatment of isoniazid-resistant TB is not known. There is inadequate evidence to quantify the ability of ethambutol to “protect rifampicin” in patients with pre-treatment isoniazid resistance. The evidence for ocular toxicity from ethambutol was not systematically reviewed for this revision, but the risk of permanent blindness exists. Further research (see Annex 5) is therefore urgently needed to define the level of isoniazid resistance that would warrant the addition of ethambutol (or other drugs) to the continuation phase of the standard new patient regimen in TB programmes where isoniazid drug susceptibility testing is not done (or results are not available) before the continuation phase begins.

Daily (rather than three times weekly) intensive-phase dosing may also help to prevent acquired drug resistance in TB patients starting treatment with isoniazid resistance. The systematic review (7) found that patients with isoniazid resistance treated with a three times weekly intensive phase had significantly higher risks of failure and acquired drug resistance than those treated with daily dosing during the intensive phase.

Table 3.3 presents standard treatment regimens for new patients in settings with high isoniazid resistance.

Table 3.3

STANDARD REGIMENS FOR NEW TB PATIENTS. (in settings where the level of isoniazid resistance among new TB cases is high and isoniazid susceptibility testing is not done (or results are not available) before the continuation phase begins)

3.6. Previously treated patients and multidrug resistance

Previous TB treatment is a strong determinant of drug resistance (10), and previously treated patients comprise a significant proportion (13%) of the global TB notifications in 2007.

Of all the forms of drug resistance, it is most critical to detect multidrug resistance (MDR) because it makes regimens with first-line drugs much less effective (11) and resistance can be further amplified (12). Prompt identification of MDR and initiation of MDR treatment with second-line drugs gives a better chance of cure and prevents the development and spread of further resistance. Because of its clinical significance, MDR (rather than any drug resistance) is used to describe the retreatment patient groups below.

At the global level, 15% of previously treated patients have MDR (8), which is five times higher than the global average of 3% in new patients (Figure 3.1). Even in Africa, the WHO region thought to have the lowest level of MDR in retreatment patients, a significant proportion (6%) of retreatment patients have MDR-TB (8). 2 If their MDR is not detected and treated with second-line drugs, these patients will suffer poor outcomes and spread MDR in their communities.

Figure 3.1

WEIGHTED MEAN OF MDR-TB IN NEW AND RETREATMENT TB CASES FROM DRUG RESISTANCE SURVEYS, 1994–2007a. a Source: Anti-tuberculosis drug resistance in the world: fourth global report. Geneva, World Health Organization (2008)(8). b Data from 105 countries (more. )

WHO surveillance data from 10 countries found the level of MDR to be 32% in patients returning after defaulting or relapsing and significantly higher (49%) in patients whose prior treatment has failed (Figure 3.2). 3 Other studies show MDR levels of up to 80–90% in patients whose prior treatment courses have failed (10–16). Modelling described in Annex 2 predicts that, when a first course of treatment containing 6 months of rifampicin fails, 50–94% of patients have MDR-TB (compared with 4–56% of patients upon failure of a regimen containing 2 months of rifampicin).

Figure 3.2

MDR IN RETREATMENT TB CASES FROM RESISTANCE SURVEYS AND SURVEILLANCE IN 10 COUNTRIES, 1997–2007a. a Source: van Gemert W et al. MDR among sub-categories of previously treated TB cases: an analysis in 12 settings. Presented at: 40th World Conference (more. )

Many factors influence the level of MDR in previously treated patients, and levels are likely to vary widely by setting. Assignment of the retreatment patient groups to medium vs high likelihood of MDR may therefore need to be modified according to country-specific data on similar groups of patients, as well as other factors discussed in section 3.8 below.

3.7. Standard regimens for previously treated patients

The Global Plan to Stop TB 2006–2015 sets a target of all previously treated patients having access to DST at the beginning of treatment by 2015 (17). The purpose is to identify MDR as early as possible so that appropriate treatment can be given. (See also Standard 11 of the ISTC (3).)

Specimens for culture and drug susceptibility testing (DST) should be obtained from all previously treated TB patients at or before the start of treatment. DST should be performed for at least isoniazid and rifampicin

The approach to the initiation of retreatment depends on the country's laboratory capacity, specifically when (or if) DST results are routinely available for the individual patient. Countries using rapid molecular-based DST (18, 19) will have results for rifampicin/isoniazid available within 1–2 days; these results can be used in deciding which regimen to start for the individual patient (section 3.7.1).

Using conventional DST methods yields results within weeks (for liquid media) or months (for solid media). Because of this delay, countries using conventional methods will need to start an empirical regimen while DST results are awaited. The choice of empirical retreatment regimens is discussed in section 3.7.2 below.

Where DST is not yet routinely available for individual retreatment patients, an interim approach could be implemented while the country is strengthening its laboratory system.

For many countries, drug resistance surveillance or surveys show that patients whose prior course of therapy has failed have a high likelihood of MDR (especially if the regimen contained 6 months of rifampicin, as described in Annex 2). Patients whose prior course of therapy has failed should therefore receive an empirical MDR regimen. Drug resistance surveillance or surveys often show that those relapsing or returning after default have a medium or low likelihood of MDR; such patients can receive the retreatment regimen of first-line drugs. However, levels of MDR in different patient registration groups vary by setting. 4

It must be noted, however, that the retreatment regimen using first-line drugs is not supported by evidence deriving from clinical trials. It was designed primarily for use in settings with low prevalence of initial drug resistance and in patients previously treated with a regimen that included rifampicin for the first 2 months (20).

The assumption that patients whose treatment has failed have a high likelihood of MDR (and relapse or defaulting patients have a medium likelihood of MDR) may need to be modified according to both the level of MDR found in these patient registration groups and the considerations discussed in section 3.8 (below).

Several other considerations (also described in section 3.8) will have an impact on the level of MDR the NTP designates as “high” in a given country. (See also Standard 12 of the ISTC (3).)

Countries will need to use a mix of approaches if they are in transition, where some areas of the country do not yet have DST results routinely available and others do, or some laboratories use rapid and others conventional DST methods.

3.7.1. Previously treated patients in settings with rapid DST

With line probe assays, MDR can be essentially confirmed 5 or excluded within 1–2 days, 6 which allows the results to guide the regimen at the start of therapy.

In settings where rapid molecular-based DST is available, the results should guide the choice of regimen

The use of rapid molecular-based tests is discussed in more detail in section 3.8.1 below.

3.7.2. Previously treated patients in settings where conventional DST results are routinely available for individual patients

Obtaining specimens for conventional culture and DST should not delay the start of therapy. Empirical regimens, often based on drug-resistance surveillance data, are used while the results of conventional DST (liquid or solid media) are awaited, and should be started promptly. 7 This is especially important if the patient is seriously ill or the disease is progressing rapidly. Placing a patient on an empiric regimen pending DST is done to avoid clinical deterioration. Also, once empiric therapy begins to render the patient less infectious, the risk of transmission to contacts decreases.

While awaiting the results of conventional DST, WHO recommends administering an empiric MDR regimen 8 for patient groups with a high likelihood of MDR, and the retreatment regimen with first line drug regimen for patient groups with medium or low likelihood of MDR (Table 3.4).

Table 3.4

STANDARD REGIMENS FOR PREVIOUSLY TREATED PATIENTS. depending on the availability of routine DST to guide the therapy of individual retreatment patients

In settings where rapid molecular-based DST results are not routinely available to guide the management of individual patients, empiric treatment should be started as follows:

TB patients whose treatment has failed 9 or other patient groups with high likelihood of multidrug-resistant TB (MDR) should be started on an empirical MDR regimen

Remark a: In the absence of culture and DST results, the patient should be clinically evaluated before the MDR regimen is administered.

Remark b: Other examples of patients with high likelihood of MDR-TB are those relapsing or defaulting after their second or subsequent course of treatment. See also section 3.8.2.

TB patients returning after defaulting or relapsing from their first treatment course may receive the retreatment regimen containing first-line drugs 2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR in these patients or if such data are not available

3.7.3. Previously treated patients in settings where DST is not routinely available for individual patients

In the many countries that still lack the laboratory capacity to routinely conduct DST for each previously treated patient (or where results arrive too late to guide therapy), it is urgent to strengthen laboratory capacity. For countries without sufficient domestic funding, financial assistance is available from the Global Fund to Fight AIDS, Tuberculosis and Malaria, as well as from UNITAID or other international financing mechanisms. Technical assistance in laboratory strengthening is available from WHO, Global Laboratory Initiative and other partners.

Even though DST is not yet routinely available for individual patient management in these countries, the NTP may be able to collect or access some information on levels of MDR-TB in previously treated patients, by using data from a drug resistance survey, from a national or supranational reference laboratory, or from a referral or research centre (see section 3.8.2). These data are critical for ascertaining the level of MDR in retreatment patients. 10 For example, the results of representative drug resistance surveys may identify a group of patients among whom a very high percentage have MDR, which could justify the use of MDR regimens in all patients in the group (even if individual DST is not available) (6). The NTP manager is encouraged to obtain technical assistance from the Green Light Committee (see section 3.8.3).

If a very high level of MDR is documented in a specific group (such as patients who have failed a retreatment regimen), the NTP manager should urgently seek means to routinely obtain DST on all such patients at the start of treatment, in order to confirm or exclude MDR. If this cannot yet be achieved with any in-country laboratory, NTPs should make arrangements to send the specimens from these patients to a supranational reference or other international laboratory for DST while the country rapidly builds domestic laboratory capacity.

A country may face a short delay before a domestic or an international laboratory can perform DST on specimens from patients who are members of a group shown to have very high levels of MDR-TB. In these exceptional circumstances, an NTP may consider a short-term policy of directly starting such patients on an empirical MDR-TB regimen while awaiting confirmation of isoniazid and rifampicin resistance (last row of Table 3.4) (6). This is a temporary measure that can be implemented only if culture and DST can be arranged in the first few months of MDR treatment in each enrolled patient. It is essential to confirm the presence of MDR, and to monitor the response to treatment. (Groups of patients whose likelihood of MDR is medium or low will receive the 8-month retreatment regimen with first-line drugs.)

In settings where DST results are not yet routinely available to guide the management of individual patients, the empirical regimens will continue throughout the course of treatment

NTPs should obtain and use their country-specific drug resistance data on failure, relapse and default patient groups to determine the levels of MDR

Remark: Country-specific drug resistance data should include data stratified by type of regimen given for the patient's first course of TB treatment (i.e. 2 vs 6 months of rifampicin).

3.8. Overall considerations in selecting a country's standard regimens

National TB control programmes will need three standard regimens:

“new patient regimen”: the regimen containing 6 months of rifampicin:2HRZE/4HR 11

“retreatment regimen with first-line drugs”: 2HRZES/1HRZE/5HRE 12

To implement these regimens in the country, the NTP needs to consider the following factors:

availability of results of conventional or rapid molecular-based DST to guide management of individual patients;

level of drug resistance in the country's new and previously treated patients;

number of MDR-TB patients the programme has the capacity to enrol and treat;

the short-term risk of dying from MDR-TB due to concomitant conditions (especially HIV, discussed in Chapter 5);

availability of patient support and supervision (discussed in Chapter 6).

Many of these factors depend on available resources in the country, particularly the availability of DST and MDR-TB treatment. Because these essential elements of the Stop TB Strategy are not yet fully in place throughout the world, this chapter provides guidance on interim approaches.

Table 3.4 below presents suggestions for how the NTP manager can take account of these factors when selecting the standard regimens for defined patient groups.

3.8.1. Availability of DST results to guide management of individual patients: conventional and rapid methods

Ideally, DST is done for all patients at the start of treatment, so that the most appropriate therapy for each individual can be determined. However, the goal of universal access to DST has not yet been realized for most of the world's TB patients. While countries are expanding laboratory capacity and implementing new rapid tests (see below), WHO recommends that sputum specimens for testing susceptibility to isoniazid and rifampicin be obtained from the following patient groups at the start of treatment:

All previously treated patients (17, 21, 22). The highest levels of MDR are found in patients whose prior course of therapy has failed (6).

All persons living with HIV who are diagnosed with active TB, especially if they live in areas of moderate or high MDR prevalence. It is essential to detect MDR as soon as possible in persons living with HIV, given their high risk of mortality should they have MDR-TB. Some programmes recommend DST for HIV-infected TB patients with CD4 counts below 200 cells/mm 3 (6).

In addition to the indications listed above for DST at the start of treatment (or re-treatment), WHO recommends that DST be performing during treatment in the following situation:

New and previously treated patients who remain sputum smear-positive at the end of the intensive phase should submit another specimen for smear microscopy the following month. If that specimen is also smear-positive, culture and DST should be undertaken (see Recommendation 5.3 in Chapter 4). This will allow a result to be available earlier than the fifth month of treatment.

Comprehensive systems for managing the quality of laboratory services, including internal quality control and external quality assurance, are mandatory. Laboratories should follow standardized protocols for good laboratory practice, technical procedures and biosafety, in compliance with international standards (6). Documentary proof of sustained technical proficiency in DST is essential, and links with supranational TB reference laboratories to ensure DST quality are strongly encouraged. It is also important that appropriate specimens be obtained and rapidly transported to the laboratory. Because laboratory errors or discrepant results may occur, the clinical situation must be taken into account in interpreting the results of in vitro DST.

Conventional DST

WHO has endorsed the use of liquid culture and rapid species identification as preferable to solid culture-based methods alone. Liquid culture and rapid species identification should be based on a country-specific comprehensive plan for laboratory capacity strengthening and implemented in a step-wise manner. Liquid systems are more sensitive for detecting mycobacteria and may increase the case yield by 10% compared with solid media. Liquid systems may also yield DST results in as little as 10 days, compared with 28–42 days using conventional solid media. 13

Longer delays in receiving DST results mean longer empirical treatment, which has significant disadvantages:

With empirical use of the retreatment regimen with first-line drugs, patients whose DST eventually confirms MDR will have been inadequately treated while awaiting DST results. Consequences could include continued spread of MDR and amplification of resistance to include ethambutol.

With empirical use of MDR regimens, patients whose DST eventually rules out MDR will have been exposed to toxic drugs they did not need while awaiting DST results. Consequences could include adverse drug effects and an increased risk of defaulting from treatment.

Rapid DST

In contrast to conventional methods, molecular-amplification assays such as line probe assays allow detection of rifampicin resistance (alone or in combination with isoniazid) within days of sputum specimens being obtained from the patient (and can also be used on cultures obtained from rapid liquid culture systems). Patients with MDR-TB can avoid delays in starting an MDR regimen, and TB patients without MDR will avoid unnecessary second-line drug treatment. WHO strongly encourages the use of rapid molecular (and culture-based) DST in smear-positive persons living with HIV (6).

WHO recommends that ministries of health decide on line probe assays for rapid detection of MDR-TB within the context of country plans for appropriate management of MDR-TB patients; plans should also include the development of country-specific screening algorithms and timely access to quality-assured second-line anti-TB drugs (24).

Line probe assays have been adequately validated in direct testing of sputum smear-positive specimens, as well as on isolates of M. tuberculosis complex grown from smear-negative and smear-positive specimens. Direct use of line probe assays on smear-negative clinical specimens is not recommended. Adoption of line probe assays does not eliminate the need for conventional culture and DST capability; culture remains necessary for definitive diagnosis of TB in smear-negative patients, while conventional DST is required to determine drug susceptibility to drugs other than rifampicin and isoniazid. Additional guidance on selecting and implementing rapid drug susceptibility tests can be found on the WHO web site at: www.who.int/tb/features_archive/mdrtb_rapid_tests/en/index.html

3.8.2. Level of drug resistance in the country's new and previously treated patients

Countries reporting approximately half the world's TB cases have conducted at least one drug resistance survey since 1994 (8). These results, together with estimates of MDR-TB levels in all countries, are available on the WHO web site at: www.who.int/tb/features_archive/drsreport_launch_26feb08/en/index.html

New patients

Drug resistance information is critical for managing new patients and selecting the country's standard regimen for new patients:

If country data (or WHO estimates) show that more than 3% of new patients have MDR, DST should be obtained at the start of therapy for all new patients (see section 3.8.1).

Many countries have a high level of isoniazid resistance in new patients but do not have drug susceptibility results for isoniazid by the time of the continuation phase. In these countries, the NTP may select an isoniazid/rifampicin/ethambutol continuation phase for the standard regimen to be used for all new patients, as discussed in section 3.5.2.

Previously treated patients

As discussed in section 3.6 above, the NTP needs to review country-specific data to verify, or modify, the assignment of failure patients to high likelihood of MDR (Table 3.4) and patients returning after relapse or default to medium or low likelihood of MDR. Boxes 3.1, 3.2 and 3.3 provide examples of how these data may be used.

BOX 3.1

AN EXAMPLE OF REASSIGNING PATIENT GROUPS BASED ON COUNTRY-SPECIFIC DRUG RESISTANCE SURVEY RESULTS. In Country A, a nationwide survey of all previously treated patients showed the following levels of MDR in patients: Because relapsing patients have nearly (more. )

BOX 3.2

AN EXAMPLE OF ASSIGNING THE PATIENT GROUP WITH THE HIGHEST MDR LEVELS TO RECEIVE EMPIRICAL MDR TREATMENT, AND LATER ADDING A PATIENT GROUP WITH THE NEXT HIGHEST MDR LEVELS, DURING SCALE-UP OF MDR-TB TREATMENT. Based on a special survey in one province, (more. )

BOX 3.3

AN EXAMPLE OF WEIGHING THE HARMS AND BENEFITS OF EMPIRICAL MDR TREATMENT IN A SETTING OF HIGH HIV PREVALENCE. In Country C, 80% of all TB patients are living with HIV, and 30% of relapse patients have MDR. While the country is planning to implement rapid (more. )

While WHO recommends that DST be performed on all previously treated cases (22), systems that will yield this critical information are not yet in place in most countries. Until countries have finished establishing the needed laboratory and surveillance capacity, information on the level of MDR in previously treated patients is available from a few other sources.

The Global Drug Resistance Surveillance project includes actual and estimated levels of MDR in previously treated patients as a whole, although sample sizes were usually too small to yield very precise estimates (8). Moreover, only 10 countries have measured MDR levels in subgroups of previously treated patients since 1994 (Figure 3.2).

Alternative sources of data are in-country laboratories, supranational reference laboratories, hospitals, treatment centres and research projects. The results must be interpreted with caution, as they represent only those patients who have accessed the specific services and those institutions where the testing is done. For example, the level of MDR found in a hospital-based survey in a capital city accepting referrals of the most difficult cases is likely to be higher than the level that would be found in unselected patients in a remote area.

Note on other patient-specific risk factors for MDR

By assigning registration groups of previously treated patients to high and medium likelihood of MDR, Table 3.4 incorporates Standard 11 of the ISTC (3). This standard recommends that an assessment of the likelihood of drug resistance be obtained for all patients at the start of treatment.

The most critical patient-specific risk factor for MDR-TB is prior TB treatment (13, 14).

Known contact with a proven MDR case is another important determinant and can be ascertained by TB programmes at the time of patient registration. Other TB patients observed to have elevated MDR levels in certain settings are those (6):

treated in a programme that operates poorly;

with a history of using anti-TB drugs of poor or unknown quality;

who remain sputum smear-positive at month 2 or 3 of treatment (see Chapter 4);

whose private-sector treatment has failed;

exposed in institutions with an MDR outbreak or a high prevalence of MDR (such as certain prisons or mines);

with co-morbid conditions associated with malabsorption or rapid-transit diarrhoea;

living with HIV (in some settings);

whose prior course of therapy included rifampicin throughout (Annex 2);

have type 2 diabetes mellitus (25).

NTPs may be able to collect samples for DST from some of the patient groups listed above to determine their levels of MDR.

3.8.3. Number of MDR-TB patients the programme has the capacity to enrol

The Green Light Committee (GLC) Initiative helps countries to gain access to quality-assured second-line drugs 14 at considerably less than market prices. The GLC provides countries with high-level expertise in setting up and running MDR-TB programmes, integrated with routine TB control activities. Information about the GLC application process can be found online at: www.who.int/tb/challenges/mdr/greenlightcommittee/en/index.html

Projects intending to treat fewer than 50 patients can use a fast-track option to minimize the time required for the GLC application process. Countries with limited domestic resources for MDR detection and treatment can apply to the Global Fund to Fight AIDS, Tuberculosis and Malaria or other donors for funding.

As sufficient funding becomes available, countries will provide universal access to MDR-TB treatment. The stage of implementation has a bearing on the level of MDR that the country will use to define “high”, “medium” and “low” likelihood of MDR.

At the beginning of an MDR programme, when the availability of MDR treatment is very limited, the NTP may chose to include only the very highest risk patients in the “high likelihood of MDR” group for empirical MDR treatment while DST results are awaited. As the programme is scaled up, the NTP manager can include more patients who need MDR treatment. Thus, there are no absolute thresholds for low, moderate, or high likelihood or levels of MDR: NTP managers will define them for their own country and will need to redefine them as progress is made towards universal access to MDR-TB treatment.

3.8.4. Short-term risk of death from MDR-TB

Clinicians faced with a very ill TB patient suspected of having MDR-TB will initiate an MDR regimen while DST results are pending, even if the likelihood of MDR may be intermediate rather than high. The clinician judges that the risk of toxicity of the MDR regimen is outweighed by the possible life-saving benefit of the MDR regimen.

Similar judgements apply to regimen decisions at the level of the NTP. If previously treated patients as a group have frequent concomitant conditions (such as HIV) that increase the risk of short-term death from MDR-TB, the NTP will want to recommend an empirical MDR regimen for more retreatment patients while DST results are awaited. (WHO also recommends the use of rapid molecular-based tests in smear-positive persons found to be living with HIV, as well as culture-based DST to determine additional drug susceptibility (6).)

3.8.5. Availability of patient support and supervision

The availability of good quality patient support and supervision is essential to implementation of the regimens recommended in this chapter. The importance of the capacity of TB programmes to provide patient-centred care is discussed in Chapter 6.

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Footnotes

Of 46 countries in Africa, 6 have reported drug resistance data since 2002; 22 countries (representing 72% of the region's cases) have reported data since 1994 (5, p. 90).

These are the only 10 countries that reported drug resistance surveillance data by subcategory of retreatment cases since 1997.

If drug resistance surveys show that patients relapsing or returning after default have high levels of MDR, they will need an MDR regimen instead. Similarly, if the country data show that levels of MDR are low in patients who failed their previous treatment, the NTP may decide to administer retreatment regimens with first-line drugs. See section 3.8 for further details.

Line probe assays detect resistance to rifampicin alone or in combination with isoniazid resistance. Overall high accuracy for detection of MDR is retained when rifampicin resistance alone is used as a marker for MDR (19).

From sputum samples or from bacterial cultures derived from those specimens.

In some individual patients who have been treated multiple times, waiting to start treatment until DST results are available may be prudent provided that the patients are clinically stable and transmission to contacts is prevented. In most countries, however, adequate infection control measures are not yet in place.

Guidance on designing a country's standard MDR regimen is provided in Chapter 7 of this document, and in Chapter 7 of Guidelines for the programmatic management of drug-resistant TB (6).

Failures in a well-run NTP should be infrequent in the absence of MDR-TB. If they do occur, they are due either to MDR-TB or to programme factors such as poor DOT or poor drug quality. If drug resistance data from failure patients are available and these show low or medium levels of MDR, patients should receive the retreatment regimen outlined in 7.3.2, and every effort should be made to address the underlying programmatic issues.

This information is also needed to determine the patterns of MDR, so that a standard MDR regimen can be chosen for empirical treatment of patients with high likelihood of having MDR.

With or without ethambutol in the continuation phase (see section 3.5.2).

Countries with rapid molecular-based DST will not need this regimen.

If second-line drugs are used, the NTP must ensure that they are quality-assured and can be provided by DOT throughout the entire 18–24 months it takes to treat MDR TB. In addition, laboratory capacity to monitor response to treatment and a system for detecting and treating adverse reactions must be in place.

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