Drug-resistant tuberculosis treatment

failure/relapse/death was considered the primary indicator of regimen efficacy, whereas the lost to 
follow-up outcome was considered more indicative of feasibility and treatment adherence. Reduced 
toxicity (compared with injectable use), patient preference and programmatic simplicity were major 
perceived benefits of the shorter all-oral bedaquiline-containing regimen. Regarding generalizability, 
the GDG deliberated on whether the genetic diversity of M. tuberculosis strains in South Africa was 
globally representative, and concluded that there is a fair distribution of common strains represented 
in the country. The group also considered potential interactions in relation to HIV status and the effect 
of ART, but this was not considered a major factor given that treatment outcomes were similar in 
HIV-positive and negative individuals. The GDG agreed that results of the STREAM Stage 2 trial – a 
large-scale, multicountry Phase III trial examining a shorter all-oral bedaquiline-containing regimen 
– will provide additional important insight into the efficacy and safety of this regimen, and increase 
the certainty in the
evidence.
A clear limitation emphasized by the GDG was the lack of data on adverse events in the EDRWeb, 
with only death being accounted for. Despite the strong preference expressed by patient surveys 
and patient advocates for injectable-free regimens, the GDG could not fully ascertain all relevant 
undesirable effects, although bedaquiline-containing shorter and longer regimens seemed to be the 
equivalent for death, with a significant reduction of loss to follow-up when using shorter regimens. 
A major concern is the risk of bedaquiline resistance, which is amplified if treatment regimens are 
inadequate or treatment adherence is low (which is why adherence and adequacy should be closely 
monitored). During Stage 1 of the STREAM trial, safety of the standardized shorter regimen with 
injectables – which consists of the same medicines as the intervention regimen, except for replacement 
of the injectable with bedaquiline – was carefully assessed and was considered similar to the safety 
of the longer regimen (47). Replacement of the injectable with bedaquiline removes serious safety 
concerns related to
injectables.
The GDG also discussed data on potential costs and cost–effectiveness. Modelling of the cost–
effectiveness of the shorter all-oral bedaquiline-containing regimen showed robust cost savings 
relative to either a longer oral regimen or a short injectable-containing regimen. The use of the 
standardized shorter regimens, which included injectable agents, carried the additional costs of 
32 
In the matching algorithm, the intervention and control groups were matched according to AFB smear status, resistance to isoniazid, 
previous treatment, HIV status (antiretroviral use), gender and age. To further reduce imbalance, matching without replacement was 
employed, using a caliper width of 0.5; this required an exact match for HIV status, AFB and culture status, and propensity score match 
for age, gender, resistance to isoniazid and previous
treatment.

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Recommendations 
16
management of dose-related adverse events (e.g. nephrotoxicity and ototoxicity) associated with 
second-line injectables drugs. With the implementation of the shorter all-oral bedaquiline-containing 
shorter regimen, additional costs for electrocardiogram (ECG) monitoring had to be factored in; 
nevertheless, expenses related to quality audiometry and regular assessment of renal toxicity 
biomarkers would decrease. In addition, it was possible to achieve improved treatment outcomes 
and, more importantly, avoid lifelong disability and reduced economic losses as a result of patients’ 
ability to regain employment. The cost–effectiveness model presented to the GDG estimated that a 
9–12 all-oral regimen was both cost saving and cost effective, relative to either a longer all-oral or 
a shorter injectable-containing regimen (see Annex 2, Annex 4 and Annex 5). However, the GDG 
acknowledged that implementing the all-oral shorter regimen does not automatically and immediately 
eliminate or reduce costs. In absolute terms, looking at overall benefits and potential harms, the use 
of the all-oral shorter regimen is believed to outweigh the harms (i.e. lower risk of mortality) for most 
patients. 
Another issue was variability in how much end-users (in particular, patients) value the outcomes 
associated with the use of the all-oral bedaquiline-containing regimen. The GDG, driven by the results 
of the qualitative study on values and preferences (see Annex 2, Annex 3 and Annex 5), concurred 
that it is important to prevent the outcome of death, and to reduce the frequency and seriousness 
of adverse events, particularly those attributed to second-line injectable agents, especially hearing 
loss, nephrotoxicity and vestibular toxicity. A qualitative study on patients’ values, preferences and 
perspectives, based on interviews involving 16 former drug-resistant TB patients drawn globally from 
high burden countries, indicated that the most acceptable regimen is one that has few to no physical 
and mental health side-effects, is short and is all-oral (in that order of preference); added value was 
given to a low pill
burden.
Data on feasibility could not be retrieved to help inform these recommendations; therefore, a 
collaborative decision-making approach was used to assess the judgements of the GDG on whether 
there were specific feasibility considerations. Such considerations mostly centred on the need for DST 
to guide safe implementation of the shorter all-oral bedaquiline-containing regimen, together with 
bedaquiline resistance monitoring. The GDG emphasized the crucial need to improve laboratory 
capacity for early drug-resistant TB detection, expanded drug-resistance testing and ongoing 
monitoring of drug-resistance acquisition or
amplification.