1Introduction

1.1. Chapter objectives

This chapter defines the purpose, target audience, scope and development of this fourth edition of the guidelines. It also explains why a new edition was needed and projects a date for the next revision.

1.2. Purpose of the guidelines

The principal purpose of these guidelines is to help national TB control programmes (NTPs) in setting TB treatment policy to optimize patient cure: curing patients will prevent death, relapse, acquired drug resistance, and the spread of TB in the community. Their further purpose is to guide clinicians working in both public and private sectors.

1.3. Target audience

The primary target audience for the guidelines is the managers and staff of NTPs, together with other TB service providers working in public and private health care facilities at the central and peripheral levels.

Use of the term “NTP manager” in these guidelines refers to the official within, or designated by, the ministry of health who is responsible for the TB programme or to that official's designee.

1.4. Scope

These guidelines address the treatment of active TB disease in adults. They exclude many related topics that have already been covered in detail in other publications: diagnosis, laboratory standards for smear microscopy, protocols for use of rapid drug susceptibility tests, paediatric TB, drug procurement and supply management, infection control, intensified case-finding in persons living with HIV, and isoniazid preventive therapy.

1.5. Why a new edition?

Major progress in global TB control followed the widespread implementation of the DOTS strategy. The Stop TB Strategy, launched in 2006, builds upon and enhances the achievements of DOTS (1): new objectives include universal access to patient-centred treatment, and protection of populations from TB/HIV coinfection and multidrug-resistant TB (MDR-TB). The Stop TB Strategy and the Global Plan (2) to implement the new strategy made it necessary to revise the existing guidelines (3) and develop this fourth edition.

Historically, the greatest emphasis of TB control activities has been on the most infectious patients – those who have sputum smear-positive pulmonary tuberculosis (3). This changed with the Stop TB Strategy's emphasis on universal access for all persons with TB to high-quality, patient-centred treatment (1). However, highly infectious, smear-positive patients remain the primary focus for other aspects of TB control, including contact tracing and infection control. The Patients' Charter for TB Care specifies that all TB patients have “the right to free and equitable access to TB care, from diagnosis through treatment completion” (4).

This fourth edition of the guidelines has therefore abandoned Categories I–IV, which were used to prioritize patients for treatment.¹ According to this prior categorization, smear-negative TB patients were assigned third priority and MDR-TB patients fourth priority. For treatment decisions it no longer makes sense to assign third priority to smear-negative patients given their high mortality if they are living with HIV. Equally, MDR-TB patients should not be assigned fourth priority, given their high mortality and the urgent need to prevent the spread of these deadliest TB strains.

To replace Categories I–IV, this fourth edition groups patients (and standard regimens recommended for each group) according to the likelihood of their having drug resistance. Drug resistance is a critical determinant of treatment success, and prior TB treatment confers an increased risk (5, 6). This edition uses the same patient registration groups as those used for recording and reporting, which differentiate new patients from those who have had prior treatment (7). Registration groups for previously treated patients are based on the outcome of their prior treatment course: failure, relapse, and default.

The fourth edition integrates detection and treatment of both HIV infection and MDR-TB, and thus should contribute towards achievement of the Stop TB Strategy's universal access to high-quality MDR-TB and HIV care.

With regard to HIV detection, this edition incorporates recent WHO recommendations for provider-initiated HIV testing of all persons with diagnosed or suspected TB, in all types of HIV epidemics (low-level, concentrated or generalized) (8). For treatment of TB in persons living with HIV, new recommendations on the duration of therapy and the role of intermittent regimens have emerged from systematic reviews (see Chapter 5). The new edition also includes recent WHO recommendations for DST at the start of TB therapy in all people living with HIV (9), as well as recommendations on the timing and type of antiretroviral therapy (ART) regimens (10).

New developments in MDR-TB also contributed to the need for this revision. Building on the principle of universal access to MDR-TB diagnosis and care, The MDR-TB and XDR-TB response plan 2007–2008 (11) calls for the diagnosis and treatment of MDR-TB in all countries by 2015. Even countries with low overall levels of multidrug resistance (MDR) are faced with TB patients who have been previously treated – a group that is five times more likely to have MDR-TB than new patients (see section 3.6).

In terms of ensuring universal access to MDR-TB diagnosis, this fourth edition reaffirms existing WHO recommendations (2) that all previously treated patients should have access to culture and DST at the beginning of treatment, in order to identify MDR-TB as early as possible.² It also incorporates the WHO recommendation that treatment failure be confirmed by culture and DST (9). In order to detect MDR sooner than the end of the fifth month of treatment, this edition includes the existing WHO recommendation (9) for culture and DST if patients still have smear-positive sputum at the end of the third month of treatment.

Chapters 2–5 of this new edition discuss the critical role of the identification of Mycobacterium tuberculosis and of DST. This is in contrast to the previous edition, which relied almost exclusively on smear microscopy for case definition, assignment of standard regimens, and monitoring of treatment response. Line probe assays can identify MDR-TB within hours and liquid media can do so within weeks (rather than months when solid media are used) (12). These techniques should be introduced in line with comprehensive, country-specific plans for laboratory capacity strengthening.

To move towards universal access to MDR-TB treatment, the fourth edition includes a new recommendation for every country to include an MDR regimen in its standard regimens. This is essential while awaiting DST results for patients with a high likelihood of MDR (such as those whose prior treatment with a 6-month rifampicin regimen has failed), and for patients in whom resistance to isoniazid and rifampicin is confirmed. With the availability of funding from international financial partners,³ lack of resources for MDR-TB treatment is no longer an acceptable rationale for providing the 8-month retreatment regimen with first-line drugs (formerly called the “Category II regimen”) to patients with a high likelihood of MDR; this regimen is ineffective in treating MDR-TB and may result in amplification of drug resistance (5, 13).

Use of rapid DST methods will eventually render the 8-month retreatment regimen of first-line drugs obsolete. In the meantime, the regimen is retained in this fourth edition in only two circumstances. In countries with access to routine DST using conventional methods, the 8-month retreatment regimen with first-line drugs is recommended while awaiting DST results from patients who have relapsed or are returning after default (if country-specific data show they have a medium likelihood of MDR-TB, or if such data are unavailable). In countries that do not yet have DST routinely available at the start of treatment for all previously treated patients (see section 3.7.3), the 8-month retreatment regimen with first-line drugs will be used for the duration of treatment on an interim basis until laboratory capacity is available.

In principle, MDR treatment should be introduced only in well-performing DOTS programmes. Before focusing on curing MDR-TB cases, it is critical to “turn off the tap”, i.e. to strengthen poor programmes so that they stop giving rise to MDR-TB. Following this principle, the 2004 revision of the treatment chapter⁴ listed adequate performance of a country's overall TB programme as a requirement for the use of MDR regimens in patients with a high likelihood of MDR. This is no longer a prerequisite in the fourth edition. In some countries with limited DOTS coverage, there may be an appropriate setting for an MDR pilot project that, once established, can provide a model and an impetus for the expansion of basic DOTS into more areas. In most countries, however, conditions for initiating an MDR component in most NTPs are not met until the overall NTP has the essential elements of DOTS firmly in place.

1.6. Methodology

Development of the fourth edition of the guidelines followed new WHO procedures. WHO defined the scope of revision and convened a guidelines group of external experts. All members of the group completed a Declaration for the Conflict of Interest; there were no conflicts declared. With input from the Guidelines Group, WHO identified seven key questions on the treatment of TB (see Annex 2) covering the following topics:

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duration of rifampicin in new patients;

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dosing frequency in new patients;

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initial regimen for new TB patients in countries with high levels of isoniazid resistance;

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TB treatment in persons living with HIV;

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sputum monitoring during TB treatment;

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treatment extension;

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retreatment.

Systematic literature reviews were conducted for each question and the evidence was synthesized⁵ (see Annex 2).

Input from the Guidelines Group to the revision of guidelines was made by e-mail, in conference calls and at a 3-day meeting (21–23 October 2008) during which the final treatment recommendations were established once consensus had been reached by the Guidelines Group. The recommendations are based on the quality of the evidence, values, and costs, as well as judgements about trade-offs between benefits and harm.

The group graded the strength of each recommendation, reflecting the degree of confidence that the desirable effects of adherence to a recommendation outweigh the undesirable effects. Although the degree of confidence is necessarily a continuum, three categories are used – strong, conditional and weak. The quality of the evidence was assessed according to the GRADE methodology (14).

Moderate/low quality of evidence means that the estimate of effect of the intervention is very uncertain and further research is likely to have an important impact on confidence in the estimate. For high-quality evidence, by contrast, further research is unlikely to change confidence in the estimate of effect.

A strong recommendation means that the desirable effects of adherence to the recommendation clearly outweigh the undesirable effects. Strong recommendations use the words “should” or “should not”. No alternatives are listed.

A conditional recommendation means that the desirable effects of adherence to the recommendation probably outweigh the undesirable effects, but the trade-offs are uncertain. Reasons for lack of certainty include:

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high-quality evidence to support the recommendation is lacking;

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benefits of implementing the recommendation are small;

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benefits may not justify the costs;

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it was not possible to arrive at precise estimates of benefit.

A weak recommendation means that there is insufficient evidence; the recommendation is therefore based on field application and expert opinion.

Conditional and weak recommendations use the word “may”. Alternatives are listed for several of the conditional recommendations.

Table 1.1 shows how strong and conditional recommendations differ in terms both of wording and of the factors used to judge their strength. Strong and conditional recommendations also have different implications for policy-makers, patients, and health care providers; these are summarized in the table.

A plan for implementing and evaluating the strong recommendations is outlined in Annex 4. To address the gaps in the evidence critical for decision-making, the Guidelines Group developed a series of questions as a basis for future research; these are detailed in Annex 5. Members of the Guidelines Group are listed in Annex 6.

The recommendations that address the seven key questions appear in the context of guidance on standard treatment (Chapter 3), monitoring (Chapter 4) and HIV (Chapter 5). Areas outside the scope of those questions have been updated with current references and WHO TB policies but were not the subject of systematic literature reviews or of new recommendations by the Guidelines Group.

The draft guidelines were circulated to the external review group (whose members are listed in Annex 6), made up of NTP managers from high-burden countries, members of the WHO Strategic, Technical and Advisory Group on TB (STAG-TB), six regional TB Advisers and TB medical officers working in high-burden countries.

Comments received from the external review group were appropriately addressed and the few disagreements between the external reviewers and the Guidelines Group were resolved by e-mail consultation.

1.7. International Standards for Tuberculosis Care

The International Standards for Tuberculosis Care (ISTC) (15) describe a widely accepted level of TB care that all practitioners should seek to achieve. Cross-referencing the applicable ISTC standards in this new edition should help providers in both public and private sectors to ensure their implementation.

1.8. Expiry date

The WHO Stop TB Department will review and update these guidelines after 3–5 years or as needed when new evidence, treatment regimens or diagnostic tests become available.

References

1.

Raviglione MC, Uplekar MW. WHO's new stop TB strategy. Lancet. 2006;367:952–955. [PubMed: 16546550]

2.

The global plan to stop TB, 2006–2015. Geneva: World Health Organization; 2006. (WHO/HTM/STB/2006.35)

3.

Treatment of tuberculosis: guidelines for national programmes. 3rd ed. Geneva: World Health Organization; 2003. (WHO/CDS/TB/2003.313)

4.

Patients' charter for tuberculosis care: patients' rights and responsibilities. Geneva: World Care Council; 2006. (available at: www​.who.int/tb/publications​/2006/patients_charter.pdf). [PubMed: 19588856]

5.

Espinal MA, et al. Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. Journal of the American Medical Association. 2000;283:2537–2545. [PubMed: 10815117]

6.

Aziz MA, et al. Epidemiology of antituberculosis drug resistance (the Global Project on Anti-tuberculosis Drug Resistance Surveillance): an updated analysis. Lancet. 2006;368:2142–2154. [PubMed: 17174706]

7.

Revised TB recording and reporting forms and registers – version 2006. Geneva: World Health Organization; 2006. (WHO/HTM/TB/2006.373; available at: www​.who.int/tb/dots/r_and_r_forms​/en/index.html)

8.

Guidance on provider-initiated HIV testing and counselling in health facilities. Geneva: World Health Organization; 2007.

9.

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

10.

Antiretroviral therapy for HIV infection in adults and adolescents in resource-limited settings: recommendations for a public health approach. Geneva: World Health Organization; 2006.

11.

The global MDR-TB & XDR-TB response plan 2007–2008. Geneva: World Health Organization; 2007. (WHO/HTM/TB/2007.387)

12.

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)

13.

Espinal MA. Time to abandon the standard retreatment regimen with first-line drugs for failures of standard treatment. International Journal of Tuberculosis and Lung Disease. 2003;7:607–608. [PubMed: 12870678]

14.

Guyatt GH, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. British Medical Journal. 2008;336:924–926. [PMC free article: PMC2335261] [PubMed: 18436948]

15.

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

Footnotes

1

Also, the original one-to-one correspondence between patient group and treatment regimens was lost as Categories I–IV were redefined over the years. The same treatment regimen came to be recommended for patients in Categories I and III; after 2004, different treatment regimens were recommended for patients in Category II depending on factors such as programme performance and drug resistance.

2

This recommendation is consistent with the International Standards for Tuberculosis Care and resolutions endorsed by the World Health Assembly in 2007 which call for universal access to DST by 2015.

3

Such as UNITAID and the Global Fund to Fight AIDS, Tuberculosis and Malaria.

4

Treatment of tuberculosis: guidelines for national programmes, 3rd ed. Chapter 4, Standard treatment regimens, was revised in June 2004 and the new version was posted on the WHO web site.

5

At the time of publication of this fourth edition, evidence gathered through some of the systematic reviews had not been published.