7.1. Chapter objectives

This chapter describes:

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the Green Light Committee – one of the sources of support to countries establishing a drug-resistant TB component and integrating it into their NTP;

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groups of drugs used to treat MDR-TB, and the principles for constructing an MDR-TB regimen;

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programmatic strategies for MDR-TB treatment – how to select the standard MDR-TB regimen (and considerations for an individualized approach once DST results are available);

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how to monitor MDR-TB patients, determine when to stop the injectable agent, and decide when treatment is completed;

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how to treat TB with resistance patterns other than MDR;

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recording and reporting of drug-resistant TB cases.

This chapter highlights key concepts for treating drug-resistant TB – preventing the development of drug resistance, and detecting it promptly when it does occur, are discussed in Chapters 3 to 6.

This chapter is intended to serve as a brief overview. Managers of NTPs who are establishing a drug-resistant component and integrating it into their programmes are strongly urged to seek expert consultation (see section 7.2 below) and to review the 2008 or subsequent editions of the WHO Guidelines for the programmatic management of drug resistant TB (1).¹ (See also Standard 12 of the ISTC (2).)

7.2. Green light Committee Initiative

In designing the country's MDR-TB treatment component and integrating it into the national programme, NTP managers are strongly encouraged to make full use of the Green Light Committee (GLC; www.who.int/tb/challenges/mdr/greenlightcommittee). The GLC is a subgroup of the MDR-TB Working Group of the Stop TB Partnership, and an advisory body of WHO that promotes access to (and monitors the use of) quality-assured, life-saving MDR-TB treatment.

Through the GLC Initiative, NTPs have access to:

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expertise in programmatic management of drug-resistant TB based on best available evidence and collective experience;

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high-quality drugs to treat drug-resistant TB at concessional prices;

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support through a wide network of technical partners;

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peer support and knowledge-sharing with other GLC-approved programmes;

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independent external monitoring and evaluation.

7.3. Groups of drugs to treat MDR-TB

For MDR treatment, anti-TB drugs are grouped according to efficacy, experience of use and drug class (Table 7.1). All the first-line anti-TB drugs are in Group 1, except streptomycin, which is classified with the other injectable agents in Group 2. All the drugs in Groups 2–5 (except streptomycin) are second-line, or reserve, drugs. The features of the drugs within each group, including cross-resistance, are discussed in more detail below. Cross-resistance means that resistance mutations (in M. tuberculosis bacteria) to one anti-TB drug may confer resistance to some or all of the members of the drug family and, less commonly, to members of different drug families (1).

Table 7.1

GROUPS OF DRUGS TO TREAT MDR-TB.

Group 1. Group 1 drugs are the most potent and best tolerated. If there is good laboratory evidence and clinical history that suggests that a drug from this group is effective, it should be used. If a Group 1 drug was used in a previous regimen that failed, its efficacy should be questioned even if the DST result suggests susceptibility. The newer rifamycins, such as rifabutin, have very high rates of cross-resistance to rifampicin.

Group 2. All patients should receive a Group 2 injectable agent if susceptibility is documented or suspected. Among aminoglycosides, kanamycin or amikacin is the first choice of an injectable agent, given the high rates of streptomycin resistance in drug-resistant TB. In addition, both these agents are inexpensive, cause less otoxicity than streptomycin, and have been used extensively for the treatment of drug-resistant TB. Amikacin and kanamycin are considered to be very similar and have a high frequency of cross-resistance. If an isolate is resistant to both streptomycin and kanamycin, or if DRS data show high rates of resistance to amikacin and kanamycin, capreomycin (a polypeptide) should be used.

Group 3. All patients should receive a Group 3 medication if the M. tuberculosis strain is susceptible or if the agent is thought to have efficacy. One of the higher generation fluoroquinolones, such as levofloxacin or moxifloxacin, is the fluoroquinolone of choice. Ciprofloxacin is no longer recommended to treat drug-susceptible or drug-resistant TB.

Group 4. Ethionamide (or protionamide) is often added to the treatment regimen because of its low cost. If cost is not a constraint, p-aminosalicylic acid (PAS) may be added first, given that the enteric-coated formulas are relatively well tolerated and that there is no cross-resistance to other agents. When two agents are needed, cycloserine can be added. Since the combination of ethionamide (or protionamide) and PAS often causes a high incidence of gastrointestinal side-effects and hypothyroidism, these agents are usually used together only when three Group 4 agents are needed: ethionamide (or protionamide), cycloserine and PAS. Terizidone can be used instead of cycloserine and is assumed to be equally efficacious.

Group 5. Group 5 drugs are not recommended by WHO for routine use in drug-resistant TB treatment because their contribution to the efficacy of multidrug regimens is unclear. They can be used in cases where it is impossible to design adequate regimens with the medicines from Groups 1–4, such as in patients with XDR-TB. They should be used in consultation with an expert in the treatment of drug-resistant TB.

7.4. General principles in designing an MDR-TB treatment regimen

The general principles in Table 7.2 apply whether an NTP manager is selecting an empirical or standard MDR-TB regimen for the country² or a clinician is constructing a regimen for an individual patient. These principles also apply to XDR-TB cases. (Individual patient-specific information, which is part of the clinician's evaluation of each patient before starting the MDR regimen, is given in parentheses in the table.)

Table 7.2

GENERAL PRINCIPLES FOR DESIGNING MDR-TB TREATMENT REGIMENS.

Treatment regimens should consist of at least four drugs with either certain, or almost certain, effectiveness. Where evidence about the effectiveness of a certain drug is unclear, the drug can be part of the regimen but it should not be depended upon for success. Often, more than four drugs may be started if the susceptibility pattern is unknown or the effectiveness of one or more agents is questionable.

Susceptibility testing for isoniazid, rifampicin, the fluoroquinolones, and the injectable agents is fairly reliable. For other agents it is less reliable, and basing individualized treatments on DST for these agents should be avoided. The clinical effectiveness or ineffectiveness of a drug cannot be predicted by DST with 100% certainty.

Each dose in an MDR regimen is given as DOT throughout the treatment. See reference 1 for detailed information on each drug, including adverse effects, contraindications, monitoring, and dosing based on weight bands.

7.5. Programmatic strategies for treatment of MDR-TB

Programmatic approaches to MDR-TB treatment depend in part on the type of laboratory method used to confirm MDR (see Figure 7.1). Once MDR-TB is confirmed (by either type of laboratory method), patients can be treated with:

Figure 7.1

DIAGRAM OF MDR TREATMENT STRATEGIES DEPENDING ON LABORATORY METHOD TO CONFIRM MDR.

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a standard MDR regimen (standardized approach); or

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an individually tailored regimen, based on DST of additional drugs.

For NTPs using conventional DST methods, there is often a delay of months before results are available to confirm or exclude MDR. These countries need to consider MDR treatment at two stages: when MDR is suspected but laboratory confirmation is pending, and once MDR is confirmed. While awaiting results, patients who are highly likely to have MDR-TB (such as those whose prior treatment has failed) need an empirical MDR regimen. If MDR is confirmed, this regimen may be continued, or it may be tailored on the basis of susceptibility to drugs other than isoniazid and rifampicin, as discussed in section 7.7.

NTPs using rapid molecular-based DST will be able to confirm MDR-TB within 1–2 days,³ and then can initiate treatment with a standard MDR regimen immediately, or may tailor the regimen later when DST results for second-line drugs become available, as discussed in section 7.7.

Standardized and individualized approaches each have advantages. Standard MDR-TB regimens (5) make it easier to estimate drug needs, to order, manage and distribute drug stocks, and to train personnel in the treatment of MDR-TB patients. Even when standard regimens are used throughout treatment, patients experiencing severe adverse effects will need to have their MDR treatment individualized. Thus all programmes need some capacity to individualize treatment.

Changing to an individualized regimen (once DST results are available for additional drugs beyond isoniazid and rifampicin) is advantageous because it:

• Allows clinicians to design a regimen with knowledge of resistance to particular injectables and fluoroquinolones, which is especially important if patients have received second-line drugs in the past. This knowledge helps in avoiding the use of toxic and expensive drugs to which the patient's M. tuberculosis is found to be resistant.
• Allows clinicians to tailor the regimen in settings with high rates of resistance to second-line drugs where it may be difficult to find a standard regimen that is appropriate for all patients.
• Provides flexibility if patients experience adverse effects related to one drug.

In some settings, individualized regimens may achieve higher cure rates than standard MDR regimens (6).

7.6. Selection of the country's standard MDR-TB regimen

A country's standard MDR regimen can be used while confirmation of MDR is awaited (i.e. empirically) or once MDR is confirmed. In selecting the standard MDR regimen, NTP managers are strongly urged to seek expert consultation (see section 7.2 above) and to review planned regimens (1). The discussion below provides a general overview only.

The standard MDR regimen is constructed using the principles outlined in section 7.5 and Table 7.2. To identify the drugs that are likely to be effective, the NTP manager needs to gather information about the level of MDR in the patients to be treated, as well as the pattern of resistance to other Group 1 drugs, injectable agents (Group 2) and fluoroquinolones (Group 3). Ideally, drug resistance data will be available from patients who have similar histories of previous treatment to the patients who will actually be treated. The data should:

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include a large enough number of patients to give confidence in the results;

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be based on reliable laboratory methods for DST;

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accurately describe the patients' treatment history to distinguish between those in whom the first or subsequent treatment failed, those who have relapsed, and those who are returning after defaulting.

As described in section 3.8.2, the NTP manager should access any drug resistance surveys or available surveillance data. If data show very different drug resistance patterns across groups of previously treated patients, there may need to be more than one standard MDR regimen.

The NTP manager also needs to assess the use and quality of anti-TB drugs in the country. The following information, if available, will be helpful:

• Current and past NTP standard regimens for new and previously treated patients.
• History of drug availability and sales in pharmacies. Some second line anti-TB drugs may have been used only rarely and will probably be effective in MDR regimens. Those that have been used extensively are highly likely to be ineffective.
• Quality assurance of drugs used within and outside the NTP.

Box 7.1 provides an example of how to design a standard regimen.

Box 7.1

EXAMPLE. Survey data from 93 consecutively enrolled relapsed patients from a resource-constrained area show that 11% have MDR-TB. Of these MDR-TB cases, 45% are resistant to ethambutol and 29% are resistant to streptomycin. Resistance to other drugs is (more...)

7.7. Selection of individualized MDR-TB regimens

Individually designed regimens are based on the patient's history of past drug use and on DST of isoniazid, rifampicin, the second-line injectable agents and a fluoroquinolone. Every effort should be made to supplement the patient's memory of treatment with objective records from previous health care providers. A detailed clinical history can help suggest which drugs are likely to be ineffective. Although resistance can develop in less than 1 month, if a patient has used a drug for more than 1 month with persistently positive smears or cultures, the strain should – as a general rule – be considered as “probably resistant” to that drug, even if DST results indicate that it is susceptible.

DST results should complement, rather than invalidate, other sources of data on the likely effectiveness of a specific drug. For example, if a history of prior anti-TB drug use suggests that a drug is likely to be ineffective, that drug should not be relied on as one of the four core drugs in the regimen, even if DST shows the strain to be susceptible. Alternatively, if the patient has never taken a particular drug and resistance to that drug is extremely uncommon in the community, DST results that indicate resistance may be the result case of a laboratory error or of the limited specificity of DST for some second-line drugs.⁴

Another important limitation is the turnaround time for DST results: the patient may have already received months of treatment by the time DST results become available from the laboratory. The possibility of further acquired resistance developing during this time must be considered. If there is a high probability of acquired resistance to a particular drug after collection of the specimen for DST, that drug should not be counted as one of the four drugs in the core regimen (but can be included as an adjunctive agent).

7.8. Monitoring the MDR-TB patient

Close monitoring is essential during treatment of MDR-TB patients. To assess treatment response, sputum smears and cultures should be performed monthly until smear and culture conversion. (Conversion is defined as two consecutive negative smears and cultures taken 30 days apart.) After conversion, the minimum frequency recommended for bacteriological monitoring is monthly for smears and quarterly for cultures. Monitoring of MDR-TB patients by a clinician should be at least monthly until sputum conversion, then every 2–3 months. Each patient's weight should be monitored monthly.

Second-line drugs have many more adverse effects than the first-line anti-TB drugs, but management of these adverse effects is possible even in resource-poor settings. At every DOT and clinician encounter, the patient should be screened for side-effects of medication. It is also essential for patients to be aware of possible side-effects and to have access to clinical and laboratory services to help detect side-effects, and medications to treat adverse effects when they occur. For more details on patient monitoring, see reference 1. Timely and intensive monitoring for, and management of, adverse effects caused by second-line drugs are essential for MDR-TB treatment.

7.9. Duration of treatment for MDR-TB

In MDR-TB treatment, the intensive phase is defined by the duration of treatment with the injectable agent. The injectable agent should be continued for a minimum of 6 months, and for at least 4 months after the patient first becomes and remains smear- or culture-negative. Review of the patient's cultures, smears, X-rays and clinical status may also aid in deciding whether or not to continue an injectable agent longer than the above recommendation, particularly in the case of patients for whom the susceptibility pattern is unknown, effectiveness of one or more agents is questionable, or extensive or bilateral pulmonary disease is present.

Culture conversion also determines the overall duration of MDR treatment. These guidelines recommend continuing therapy for a minimum of 18 months after culture conversion. Extension of therapy to 24 months may be indicated in chronic cases with extensive pulmonary damage.

7.10. Treating TB with resistance patterns other than MDR

Cases with drug resistance patterns other than MDR will be detected by DST. The design of regimens for mono- and poly-resistant cases of TB is recommended for programmes with good infrastructure that are capable of treating MDR-TB. Individually designed treatments for mono- and poly-resistance are often determined by a review panel that meets periodically. The panel reviews treatment history, DST patterns and the possibility of strains of M. tuberculosis having acquired new resistance, and then determines the regimen. For suggested regimens according to the pattern of drug resistance, see reference 1.

It is essential to remember that the DST result reflects the bacterial population at the time the sputum was collected and not necessarily the bacterial population in the patient at the time the result is reported. During the interval between collection of the specimen and receipt of the results, the M. tuberculosis bacteria may have acquired further resistance if the patient was being treated with the functional equivalent of only one drug for a significant period of time (usually considered to be 1 month or more). Depending on the drugs concerned, resistance sometimes develops if the patient was receiving the functional equivalent of two drugs. For example, pyrazinamide is not considered a good companion drug to prevent resistance (1, 9). If a patient was functionally receiving only rifampicin and pyrazinamide in the initial phase (because of resistance to isoniazid and ethambutol), resistance to rifampicin may develop.

7.11. Recording and reporting drug-resistant TB cases, evaluation of outcomes

Recording and reporting activities assist in the management of individual patients and enable managers to evaluate and improve the treatment outcomes of the programme as a whole. A system other than the standard one for drug-susceptible TB is recommended for drug-resistant TB cases. For registration of patients with drug resistance and for reporting treatment outcome for MDR patients, the reader is referred to reference 1.

References

1.

Guidelines for the programmatic management of drug-resistant tuberculosis: emergency update 2008. Geneva: World Health Organization; 2008. (WHO/HTM/TB/2008.402)

2.

International Standards for Tuberculosis Care (ISTC). 2nd ed. The Hague: Tuberculosis Coalition for Technical Assistance; 2009.

3.

Molecular line probe assays for rapid screening of patients at risk of MDR-TB: policy statement. Geneva: World Health Organization; 2008. (available at: www​.who.int/tb/features_archive​/policy_statement.pdf.

4.

Sam IC, et al. Mycobacterium tuberculosis and rifampin resistance, United Kingdom. Emerging Infectious Diseases. 2006;12:752–759. [PMC free article: PMC3374436] [PubMed: 16704831]

5.

Suarez PG, et al. Feasibility and cost-effectiveness of standardized second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet. 2002;359:1980–1989. [PubMed: 12076553]

6.

Resch SC, et al. Cost-effectiveness of treating multidrug-resistant tuberculosis. PLoS Medicine. 2006;3(7):e241. [PMC free article: PMC1483913] [PubMed: 16796403]

7.

Keshavjee S, et al. Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet. 2008;372:1403–1409. [PubMed: 18723218]

8.

Mitnick CD, et al. Comprehensive treatment of extensively drug-resistant tuberculosis. New England Journal of Medicine. 2008;359:563–574. [PMC free article: PMC2673722] [PubMed: 18687637]

9.

Mitchison DA. Basic mechanisms of chemotherapy. Chest. 1979;76(6 Suppl.):771–781. [PubMed: 92392]

Footnotes

1

Tat publication also provides in-depth guidance on the many facets of MDR-TB management, including management of side-effects and indications for surgery.

2

Programmatic strategies for MDR-TB treatment (standardized or individualized approaches) are described in section 7.5.

3

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 (3, 4).

4

Since a fluoroquinolone and an injectable agent form the backbone of MDR treatment, they should be used even if the patient's M. tuberculosis demonstrates resistance to all available drugs in these two classes (7, 8).