Resistance to tuberculosis (TB) drugs is a formidable obstacle to effective TB care and prevention globally. Multidrug-resistant TB (MDR-TB) is multifactorial and fuelled by improper treatment of patients, poor management of supply and quality of drugs, and airborne transmission of bacteria in public places. Case management becomes difficult and the challenge is compounded by catastrophic economic and social costs that patients incur while seeking help and on treatment.

In 2006, MDR-TB strains with additional resistance to second-line drugs were described as extensively drug-resistant TB (XDR-TB) strains, further compromising treatment options available to patients infected with these strains. Since then, clinicians in some settings have reported patients infected with strains in which virtually all treatment options have been exhausted. This rapidly evolving landscape is a clarion call to policy-makers and practitioners to respond with improvements in care delivery and introduction of innovative tools and approaches. In 2009, the 62nd World Health Assembly urged WHO Member States to provide universal access to care for drug-resistant TB patients. In that resolution, it was acknowledged that national TB programme managers, clinicians, nurses, all care providers and affected people themselves need guidance on how best to bring together different elements of health systems and services needed to effectively address the MDR-TB challenge. Therefore, this Handbook has been developed for the purpose of describing ways to implement established WHO policies relevant for the management of MDR-TB. These WHO policy recommendations have been produced using the GRADE methodology for evidence assessment, as adopted by WHO in 2008.

Contents

• Abbreviations and acronyms
• Acknowledgements
• Foreword
• Executive summary
• Methods and process for developing the Handbook
• PART 1. PREVENTION AND DRUG-RESISTANT TB DIAGNOSIS, TREATMENT AND CARE
  • 1. Prevention of drug-resistant tuberculosis
    • 1.1 Introduction
    • 1.2 Causes of drug-resistant TB
    • 1.3 Interventions to prevent drug-resistant TB
    • References
  • 2. Monitoring the detection, enrolment and treatment outcomes of drug-resistant TB patients
    • 2.1 Introduction
    • 2.2 Implementing an effective information system
    • 2.3 Definitions for cases and treatment outcomes
    • 2.4 Registration of information on drug-resistant TB cases
    • 2.5 Minimum indicators for monitoring drug-resistant TB programmes
    • 2.6 Using indicators to monitor programme performance
    • References
  • 3. Laboratory
    • 3.1 Introduction and general considerations
    • 3.2 General definitions for laboratory and DST
    • 3.3 Essential laboratory services and infrastructure
    • 3.4 Organization of the TB laboratory network
    • 3.5 Specimen collection and transport of infectious substances
    • 3.6 Mycobacteriology laboratory services for drug-resistant TB programmes
    • 3.7 Rational use of DST in drug-resistant TB programmes
    • 3.8 Testing and reporting: turnaround time
    • 3.9 Laboratory biosafety
    • 3.10 Quality assurance
    • References
  • 4. Case finding for drug-resistant TB
    • 4.1 Background
    • 4.2 Epidemiological data and drug resistance surveillance
    • 4.3 High-risk groups and targeted DST
    • 4.4 Recommendations regarding conventional and molecular DST for drug-resistant TB detection
    • 4.5 Presumptive MDR-TB when rapid genotypic DST is not available
    • 4.6 Diagnosing XDR-TB
    • 4.7 Management of specimens and results
    • 4.8 Drug-resistant TB case finding in paediatric patients
    • 4.9 Drug-resistant TB case finding among extrapulmonary TB patients
    • 4.10 Drug-resistant TB case finding in HIV-infected patients
    • References
  • 5. Treatment strategies for MDR-TB and XDR-TB
    • 5.1 Introduction
    • 5.2 Essential assessments prior to designing a programmatic treatment strategy
    • 5.3 Definitions of terms used to describe treatment strategies
    • 5.4 Classes of anti-TB drugs
    • 5.5 Standard code for TB treatment regimens
    • 5.6 Role of drug susceptibility testing
    • 5.7 Designing and administrating an MDR regimen
    • 5.8 Designing a treatment strategy for the drug-resistant TB component of the TB programme
    • 5.9 Duration of the intensive phase (length of use of injectable drugs)
    • 5.10 Total duration of treatment
    • 5.11 Extrapulmonary and central nervous system drug-resistant TB
    • 5.12 Surgery in treatment of drug-resistant TB
    • 5.13 Adjuvant therapies in drug-resistant TB treatment
    • 5.14 Nutritional support
    • 5.15 Treatment of XDR-TB
    • References
  • 6. Mono- and poly-resistant strains (drug-resistant TB other than MDR-TB)
    • 6.1 Introduction
    • 6.2 Treatment of patients with mono- and poly-resistant TB
    • 6.3 Registration and reporting of patients with mono- and poly-resistant TB
    • References
  • 7. Treatment of drug-resistant TB in special conditions and situations
    • 7.1 Introduction
    • 7.2 Pregnancy
    • 7.3 Breastfeeding
    • 7.4 Contraception
    • 7.5 Children
    • 7.6 Diabetes mellitus
    • 7.7 Renal insufficiency
    • 7.8 Liver disorders
    • 7.9 Seizure disorders
    • 7.10 Psychiatric disorders
    • 7.11 Substance dependence
    • 7.12 HIV-infected patients
    • References
  • 8. Drug-resistant TB and HIV
    • 8.1 General considerations
    • 8.2 Drug-resistant TB and HIV collaborative activities
    • 8.3 Clinical features and diagnosis of drug-resistant TB in HIV-infected patients
    • 8.4 Drug-resistant TB and HIV cotreatment
    • References
  • 9. Initiating treatment
    • 9.1 Introduction
    • 9.2 Flow of patients into treatment
    • 9.3 Initial evaluation and pretreatment screening
    • 9.4 Preparing the patient for treatment and education
    • References
  • 10. Monitoring treatment response
    • 10.1 Introduction
    • 10.2 Monitoring the progress of treatment
    • 10.3 Assessment of patients when treatment failure is suspected
    • 10.4 Indications for suspending treatment
    • 10.5 Follow-up after successful completion of MDR-TB treatment
    • References
  • 11. Management of adverse effects and pharmacovigilance
    • 11.1 Introduction
    • 11.2 Monitoring for adverse effects during treatment
    • 11.3 Management of adverse effects
    • 11.4 Pharmacovigilance in programmatic management of drug-resistant TB
    • References
  • 12. Patient-centred care, social support and adherence to treatment
    • 12.1 Introduction
    • 12.2 Patient-centred care and its role in directly observed therapy (DOT)
    • 12.3 Social support in MDR-TB management
    • 12.4 Planning and managing social support for MDR-TB patients
    • 12.5 Adherence monitoring and the follow-up of the nonadherent patient
    • References
  • 13. Palliative and end-of-life care
    • 13.1 Introduction
    • 13.2 Approach to suspending therapy
    • 13.3 Palliative and end-of-life care for patients in whom all the possibilities of treatment have failed
    • 13.4 Infection control measures and domicile considerations for the end-of-life MDR-TB patient
    • Reference
  • 14. Drug resistance and infection control
    • 14.1 Introduction
    • 14.2 The WHO global TB infection control policy
    • 14.2 Impact of effective treatment on TB transmission
    • References
  • 15. Management of contacts of MDR-TB patients
    • 15.1 Introduction
    • 15.2 Diagnosis and treatment of contacts with active MDR-TB
    • 15.3 Management of latent TB infection in close contacts of MDR-TB patients
    • References
• PART 2. PROGRAMMATIC MANAGEMENT OF DRUG-RESISTANT TB
  • 16. The global response to drug-resistant TB
    • 16.1 Introduction
    • 16.2 Global epidemiology and the magnitude of the drug-resistant TB problem
    • 16.3 The strategy to prevent, diagnose and treat TB and the Global Plan to Stop TB 2011–2015
    • 16.4 The WHO response to MDR-TB and the new framework to support scale up to universal access to quality MDR-TB management
    • References
  • 17. Managerial aspects of the programmatic management of drug-resistant TB
    • 17.1 Introduction
    • 17.2 Management structure of the PMDT
    • 17.3 Supervisory support to facilities implementing PMDT
    • 17.4 Planning the scale-up of PMDT integrated into the NTP
    • 17.5 Contributing to health system strengthening
    • 17.6 Engaging all care providers
    • References
  • 18. Models for delivering MDR-TB treatment and care
    • 18.1 Introduction
    • 18.2 Hospital-based model of MDR-TB treatment and care
    • 18.3 Clinic-based model of MDR-TB treatment and care
    • 18.4 Community-based model of MDR-TB treatment and care
    • 18.5 Deciding which model is best for a particular situation
    • References
  • 19. Community engagement to support universal access to diagnosis, care and treatment of drug-resistant TB
    • 19.1 Introduction
    • 19.2 Community-based TB activities
    • 19.3 Community health workers and community volunteers
    • 19.4 Integrating drug-resistant TB into community based work
    • 19.5 Creating an enabling environment for community engagement
    • 19.6 Monitoring and evaluation of community engagement
    • References
  • 20. Managing medicines for drug-resistant TB
    • 20.1 Introduction
    • 20.2 Selection of anti-TB drugs for programmatic management of drug-resistant TB
    • 20.3 Quantification and procurement
    • 20.4 Drug distribution, storage and ordering
    • 20.5 Rational medicine use and adherence
    • 20.6 Global Drug Facility
    • 20.7 Registration, importation and market control of MDR-TB medicines
    • References
  • 21. Ethics in programmatic management of MDR-TB
    • 21.1 Introduction
    • 21.2 Key ethical principles in response to the TB and drug-resistant TB epidemic
    • References
  • 22. Use of drugs under development and preapproval by national drug regulatory authorities
    • 22.1 Introduction
    • 22.2 General considerations and definitions
    • 22.3 Supporting patients to benefit from CU and EA programmes: Steps for NTPs to set up programmes to enable access to drugs in the preapproval period
    • References
• PART 3 Anti-TB drug information sheets
• PART 4 Forms for drug-resistant TB programmes
• PART 5 – ANNEXES
  • ANNEX 1 Suggestions for further reading and available training materials and tools
  • ANNEX 2 Weight-based dosing for adults
  • ANNEX 3 Weight-based dosing for children
  • ANNEX 4 “How-to” guide on the use of bedaquiline for MDR-TB treatment
  • ANNEX 5 Online MDR-TB indicators
  • ANNEX 6 Schedule of clinical and laboratory follow up
  • ANNEX 7 Management of electrolyte disturbances
  • ANNEX 8 Management strategy for hearing loss
  • ANNEX 9 “How-to” guide for forecasting drugs needs and tools for quantification and forecasting
  • ANNEX 10 Reinforcing the parameters of observational studies for MDR-TB patients on treatment
  • ANNEX 11 Indicators for monitoring drug-resistant TB programmes

This book is a companion handbook to existing WHO policy guidance on the management of multidrug-resistant tuberculosis, including the WHO guidelines for the programmatic management of drug-resistant tuberculosis and the WHO interim policy guidance on the use of bedaquiline in the treatment of in compliance with the process for evidence gathering, assessment and formulation of recommendations, as outlined in the WHO Handbook for Guideline Development (version March 2010; available at http://apps​.who.int/iris​/bitstream/10665​/75146/1/9789241548441_eng.pdf).

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.