Treatment of tuberculosis

The first objective of the treatment is to cure the patient and to prevent death from active TB.

However, the implementation of and adherence to an adequate treatment serves also to prevent relapse of TB, reduce transmission in the community, and prevent the selection and spread of drug-resistant M. tuberculosis strains [35]. The treatment of TB is based in combination therapy with bactericidal and sterilizing drugs for which the M. tuberculosis strain is susceptible during several months [35]. Drugs are associated to reduce the emergence of drug resistance and to eliminate the subpopulations of M. tuberculosis bacilli that are at different replication states [7,16]. The actively replicating subpopulation is eliminated by bactericidal drugs in the first days/weeks of treatment, reducing the patient infectiousness and increasing the chances for survival [7], whereas the slowly or non-replicating subpopulation is eliminated by sterilizing drugs in the following weeks/months, reducing the chance of relapse [10,16]. The main challenges of this long treatment are drug intolerance, toxicities, and patient compliance [10]. A strategy to ensure patient compliance is the directly observed therapy [36].

1.4.1. Treatment of drug-susceptible tuberculosis

The standard first-line regimens are assigned for defined patient groups according to the WHO guidelines [35]. For new patients presumed or known to have drug-susceptible TB, the regimen consists on a two-month intensive phase with INH, RIF, PZA, and EMB, and a four-month continuation phase with INH and RIF (2HRZE/4HR) (Table 2) [35]. Nevertheless, regimens should be adjusted appropriately upon availability of DST results [35].

Globally, the treatment outcomes in 2013 were success in 86%, failure in 1%, death in 4%, lost to follow-up in 4%, and not evaluated in 4% of new and relapse TB cases [1].

1.4.2. Treatment of drug-resistant tuberculosis

Resistance to at least INH and RIF is defined as multidrug resistance (MDR). Detection of MDR-TB is essential to implement an adequate treatment, since treatment with first-line drugs is much less effective and resistance can be further amplified [35]. It is of note that RIF-resistant TB is considered as MDR-TB for treatment purposes [15].

31 Introduction

Treatment of MDR-TB should be individually adjusted according to the DST results.

Nevertheless, a recommended empirical regimen for MDR-TB can be prescribed [15]. This regimen is composed of at least five effective drugs, from the groups recently updated by the WHO (Table 1), during the intensive phase of treatment: a FLQ from group A (LFX, MFX, GFX), a second-line injectable drug from group B (AMK, CAP, KAN, STR), at least two drugs from group C (ETO/PTO, cycloserine, linezolid, clofazimine), and PZA (group D1) (Table2) [15]. It is also recommended to strengthen the regimen with high-dose INH and/or EMB (group D1).

Agents from groups D2 and D3 may be used to complete a regimen with five effective drugs [15]. The treatment should be prolonged during at least 20 months: an intensive phase of 8 months minimum and a continuation phase of 12-18 months [15]. Nevertheless, a short-course MDR-TB regimen of 9-12 months, derived from the Bangladesh regimen, has been recently recommended by the WHO, in cases where FLQ and second-line injectable drugs are likely to be effective, among other criteria [15]. This regimen consists of an intensive phase of treatment of 4 to 6 months with GFX (or MFX), KAN, PTO, CFZ, high-dose INH, PZA, and EMB, and a continuation phase of 5 months with GFX (or MFX), CFZ, PZA, and EMB (Table2) [15].

Nevertheless, it has been recently assessed that in the European region of the WHO only 4%

of the MDR-TB cases could benefit from this regimen [37].

Second-line drugs are more toxic and expensive than first-line drugs. Minor adverse effects, which can be managed with symptomatic treatment, are common, but some severe adverse effects have also been reported [7,38]. The treatment outcomes among MDR-TB patients in 2012 were success in 50% of the cases, failure in 10%, death in 18%, and lost to follow-up or not evaluated in 22% [1]. It is of note that the treatment success rates of MDR-TB may be underestimated using the current WHO definitions [39], as outlined in a recent report that compared the treatment outcomes using the WHO definitions and the new simplified definitions proposed [40].

Resistance to at least INH and RIF (i.e. MDR), plus additional resistance to any FLQ, and at least one of the second-line injectable drugs (AMK, CAP, and KAN) is defined as extensively drug resistance (XDR). Treatment of XDR-TB should include six active drugs (or more) during the intensive phase, and four drugs during the continuation phase [21,41]. Most regimens are individually tailored based on DST results, but in general, the principles and duration for these

32

Introduction

regimens are the same as for MDR-TB [41,42]. The treatment outcomes among XDR-TB patients in 2012 were success in 26% of the cases, failure in 19%, death in 30%, and lost to follow-up or not evaluated in 25% [1].

Table 2. Summary of the recommended empirical regimens for treatment of TB. Adapted from World Health Organization, 2016 [15].

Treatment Drugs Treatment duration

Drug - An injectable (group B): AMK, CAP, KAN,

STR

- 4 months intensive phase - 5 months continuation phase - An injectable (group B): KAN

- Two drugs (group C): PTO and CFZ - High-dose INH, PZA, and EMB (group

D1)

HRZE: isoniazid, rifampicin, pyrazinamide, ethambutol; HR: isoniazid and rifampicin.

1.4.3. New treatment options

Several new or repurposed anti-TB drugs are in advanced phases of clinical development [1,42]. Bedaquiline and delamanid are the first new anti-TB drugs approved by the Food and Drug Administration in 40 years, and WHO issued policy guidance for safe and rational use of these drugs in 2013 and 2014, respectively [43,44]. Given the uncertainty on potential advantages and risks, bedaquiline or delamanid may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB. However, data on the simultaneous use of these drugs is not still available [42,44].

33 Introduction

Several trials are currently in progress to assess new treatment regimens for drug-resistant and drug-susceptible TB using different combinations and doses of anti-TB drugs [21,42].

Other strategies are also being explored, such as routes of administration, adjunct host-directed therapies for potentially enhancing immune responses, or co-administration of efflux pump inhibitors to partly restore susceptibility to anti-TB drugs [42]. Finally, in order to guarantee efficacy of treatment, adherence, adequate follow-up, and support of patients should be assured [3].

34

Introduction