World Health Organization treatment guidelines for drug-resistant tuberculosis, 2016 update

Dennis Falzon; Holger J. Schünemann; Elizabeth Harausz; Licé González-Angulo; Christian Lienhardt; Ernesto Jaramillo; Karin Weyer

doi:10.1183/13993003.02308-2016

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FIGURE 1
Choosing the treatment regimen in patients with confirmed multidrug- and rifampicin-resistant TB (MDR/RR-TB).

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TABLE 1

Certainty of the evidence and definitions

Certainty of the evidence	Definition
High (⊕⊕⊕⊕)	Further research is very unlikely to change our confidence in the estimate of effect
Moderate (⊕⊕⊕○)	Further research is likely to have an important impact on our confidence in the effect and may change the estimate
Low (⊕⊕○○)	Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low (⊕○○○)	Any estimate of effect is very uncertain

TABLE 2

What are the most important outcomes to consider when making decisions on the treatment of drug-resistant tuberculosis (TB)?

Outcomes	Mean score
Adherence to TB treatment (treatment interruption due to nonadherence)	6.8
Avoiding adverse reactions from TB drugs	7.0
Avoiding the acquisition or amplification of drug resistance	7.9
Cure or successful completion by end of treatment	9.0
Culture conversion by month 6	7.4
Death (survival) by the end of projected treatment	8.1
Treatment failure	8.7
Relapse	7.7

Members of the Guideline Development Group scored TB outcomes according to their relative priority when making decisions on drug-resistant TB treatment. They were asked to take a societal perspective in rating the outcomes. 1–3 points: not important for making recommendations on drug-resistant TB treatment; 4–6 points: important but not critical for making recommendations on drug-resistant TB treatment; 7–9 points: critical for making recommendations on drug-resistant TB treatment.

TABLE 3

General steps in designing the composition of a longer multidrug-resistant tuberculosis (MDR-TB) regimen^#

Step	Medicines
	Grouping	Options
1. Add one later-generation fluoroquinolone	A^¶	Levofloxacin (Lfx)
		Moxifloxacin (Mfx)
		Gatifloxacin (Gfx)
2. Add one second-line injectable agent	B	Amikacin (Am)
		Capreomycin (Cm)
		Kanamycin (Km)
		(Streptomycin) (S)⁺
3. Add two or more second-line agents	C^¶	Ethionamide/prothionamide (Eto/Pto)
		Cycloserine/terizidone (Cs/Trd)
		Linezolid (Lzd)
		Clofazimine (Cfz)
4. Add pyrazinamide and any other first-line agent (if they can help strengthen the regimen)	D1	Pyrazinamide (Z)
		Ethambutol (E)
		High-dose isoniazid (H^h)
5. Add bedaquiline or delamanid	D2	Bedaquiline (Bdq)^§
5. Add bedaquiline or delamanid	D2	Delamanid (Dlm)^§
6. Add any of these agents (if the regimen cannot be composed otherwise)	D3	p-aminosalicylic acid (PAS)
		Imipenem–cilastatin (Ipm-Cln)^ƒ
		Meropenem (Mpm)^ƒ
		Amoxicillin–clavulanate (Amx-Clv)^ƒ
		(Thioacetazone) (T)^##

^#: this stepwise approach guides the design of longer individualised regimens for patients who are not eligible for the World Health Organization-recommended shorter regimen (the composition of the shorter MDR-TB regimen is standardised) (see main text). The aim is to combine at least five effective agents in the intensive phase; more medicines may be included if they can safely increase the chances of cure. The choice of a medicine is based on the likelihood of its effectiveness, on reliable information on drug resistance and on the balance of expected benefits to risk. For instance, in case of nephrotoxicity or hearing loss, an injectable agent may be omitted and additional agents from Group C or D2 included. ^¶: medicines in Groups A and C are shown in decreasing order of preference for use (subject to other considerations). ⁺: streptomycin may substitute other injectable agents when the other three cannot be used; resistance to streptomycin alone does not qualify for the definition of extensively drug-resistant TB [50]. ^§: bedaquiline or delamanid may be added to the longer regimen to replace another second-line agent or to strengthen it in accordance with the interim policies [20, 21, 27]. ^ƒ: carbapenems and clavulanate are used together; clavulanate is only available in formulations combined with amoxicillin. ^##: HIV status must be tested and confirmed to be negative before thioacetazone is started.

TABLE 4

Summary of changes made by the 2016 updates to previous World Health Organization (WHO) policy on the treatment of drug-resistant tuberculosis (TB)

The priority questions which were covered by the May 2016 update of the WHO treatment guidelines for drug-resistant TB related to the composition of treatment regimens for multidrug- and rifampicin-resistant TB (MDR/RR-TB); the effectiveness and safety of shorter MDR-TB regimens; the role of elective surgery in MDR-TB management; the treatment of isoniazid-resistant and Mycobacterium bovis tuberculosis; and the impact of delays in starting treatment. From June 2016, the WHO also reviewed additional data on bedaquiline and delamanid.

The main changes in the 2016 recommendations are:

• A second-line treatment is recommended for all patients with rifampicin-resistant tuberculosis, regardless of whether isoniazid resistance is confirmed or not.

• A shorter MDR-TB treatment regimen is conditionally recommended for MDR/RR-TB patients under specific eligibility criteria.

• Recommendations for the treatment of children with MDR/RR-TB are based on a first-ever meta-analysis of individual-level paediatric patient data for treatment outcomes.

• Medicines used in the design of longer MDR-TB treatment regimens are now grouped differently, based upon current evidence on their effectiveness and safety. Clofazimine and linezolid are now considered more important MDR-TB regimen components, while p-aminosalicylic acid has been reclassified with agents used only as a last option. Clarithromycin and other macrolides are no longer included as medicines for the treatment of MDR/RR-TB. Delamanid may also be used in patients aged 6–17 years old.

• An evidence-informed recommendation on partial resection lung surgery is now included.

The evidence available on the treatment of isoniazid-resistant TB and on the delay to starting MDR-TB treatment could not address the guideline questions. There were very few published studies on the treatment of M. bovis and the regimens differed, precluding any attempt at formulating recommendations of clinical use.

The scope of the 2016 update of MDR-TB treatment policy did not include other aspects of the programmatic management of drug-resistant TB for which no substantive new evidence had emerged since the previous revision. The 2011 recommendations regarding the testing of TB patients for rifampicin resistance, the monitoring of treatment response, the duration of longer regimens, the delay in starting antiretroviral therapy in MDR-TB patients with HIV infection and models of care thus continue to apply until future evidence reviews show a need for revision. No change is made to the recommended use of bedaquiline from those of 2013 [20, 33].