Drug-resistant tuberculosis treatment

Box 2. Inclusion criteria for the Nix-TB study, which used the BPaL regimen 

---

WHO consolidated 
guidelines 
on
tuberculosis: 
drug-resistant tuberculosis treatment
43
Patients were followed up for a period of up to 24 months after completion of treatment. The primary 
outcome measure was the incidence of bacteriological failure, relapse or clinical failure (including 
TB-related deaths) through follow-up until 6 months after the end of treatment. Secondary outcome 
measures comprised: 
• 
incidence of bacteriological failure or relapse or clinical failure through follow-up until 24 months 
after the end of treatment (as a confirmatory analysis); 
• 
time to sputum culture conversion to negative status through the treatment period; 
• 
the proportion of subjects with sputum culture conversion to negative status at 4, 6, 8, 12, 16 and 
26 or 39 weeks; 
• 
linezolid dosing (actual) and efficacy; 
• 
change from baseline in TB symptoms; 
• 
change from baseline in patient reported health status; and 
• 
change from baseline in
weight.
The Nix-TB study regimen comprised pretomanid administered at 200 mg once daily, bedaquiline 
administered at 400 mg once daily for the first 2 weeks of treatment (days 1–14) and then 200 mg 
three times a week thereafter, and linezolid commenced at 1200 mg per day (additional information 
on linezolid dosing is included in 
Section 4.5
) (89). Close microbiological, clinical and adverse event 
monitoring were features of the Nix-TB study (89). 
The evidence to inform PICO question 10 was derived from the Nix-TB study, and included information 
on 108 patients. The total study population was 109 patients, but one patient withdrew informed 
consent to participate in the study; this person was included in safety analyses but not in the analyses 
for effectiveness. These data were compared to a subset of data from the IPD, which overall included 
13 273 individual patient records from 55 different studies or centres in 38 countries. For the primary 
analyses, the comparator group included patients from the IPD on longer treatment regimens (with 
a mean duration of treatment of 21.0–25.5 months), who received both bedaquiline and linezolid as 
part of the regimen (no patients received pretomanid in the IPD). This comparison group included data 
of 456 patients reported from Belarus, India, France, Russian Federation and South Africa, and from 
one study in a group of countries.
49
The intervention and comparison groups were matched exactly 
for XDR, MDR and fluoroquinolone resistance, and for HIV status, with propensity score matching 
for the variables of age, sex, baseline culture result, extent of disease (determined by baseline AFB 
smear or chest X-ray findings of cavitation or bilateral disease if the AFB smear result was missing) 
and country income level (using the World Bank Atlas method (91)). Treatment outcomes used in 
these analyses comprised the investigator-defined outcomes for the intervention group (i.e. for the 
Nix-TB study) and those largely based on WHO definitions
50
for the comparator group (i.e. for the 
patients included in the IPD). To allow an equal opportunity for treatment outcomes to occur from 
49 
China, Philippines, Republic of Korea, Russian Federation, Thailand.
50 
These treatment outcomes conform to the definitions outlined in the paper by Laserson K.F. et al. (2005) (93) or in the WHO publication: 
Definitions and reporting framework for tuberculosis – 2013 revision (94).
7. Chest X-ray picture (taken within a year prior to screening) consistent with pulmonary 
TB in the opinion of the investigator. 
8. Being of non-childbearing potential or using effective methods of birth control, as 
defined in the protocol. 
Twenty exclusion criteria are listed in the protocol; they relate to medical history, 
specific medical treatments and laboratory abnormalities. For a complete list of the 
exclusion criteria, please see the protocol, available at: https://clinicaltrials.gov/ct2/
show/NCT02333799 .

---

Recommendations 
44
the start of treatment when comparing the two groups, all outcomes were included from the start of 
treatment to 24 months after the start of treatment. Thus, in the intervention group, these outcomes 
occurred after completion of treatment and in the comparator group the outcomes were end-of-
treatment outcomes (because patients in the IPD received a longer regimen and were not followed 
up after completion of treatment). Three other comparator groups from the IPD included patients on 
longer treatment regimens who received one of the following: a regimen that included bedaquiline, 
a regimen that included linezolid, or a regimen that included neither bedaquiline nor linezolid. The 
GDG’s initial intention was to assess the intervention regimen against all three comparison groups; 
however, during their deliberations, the panel agreed that the judgements should be based on the 
comparison group who received bedaquiline and linezolid as part of their regimen, because these 
patients most closely resemble patients who would receive currently recommended longer regimens 
composed with medicines from Groups A, B and C. However, a direct comparison of BPaL with all-
oral longer regimens constructed according to the most recent WHO recommendations issued in 
March 2019 was not possible, because these regimens may have only been in use since mid-2019, so 
treatment outcomes for these patients are not yet available. Based on an assessment of the certainty 
of the evidence, carried out using predefined criteria and documented in GRADEpro, the certainty 
of the evidence was rated as very
low.
Additional data reviewed by the GDG relevant to PICO question 10 were a cost–effectiveness 
analysis, a study on the acceptability and likelihood of implementation of the BPaL regimen, modelled 
pharmacokinetic data based on the development of a pharmacokinetic toxicodynamic model, and a 
summary review of preclinical and early clinical data on pretomanid. The cost–effectiveness analysis, 
acceptability study and modelled pharmacokinetic studies were conducted along with the Nix-TB 
study and were sponsored by TB Alliance. 
The aims of the cost–effectiveness study were twofold: 
• 
to estimate the cost–effectiveness of a new regimen (BPaL) compared with the standard of care 
at a given price; and 
• 
to estimate the maximum drug price at which the BPaL regimen could be considered cost effective 
or cost neutral in each setting. 
There were two patient populations: XDR-TB patients; and XDR-TB patients combined with MDR-TB 
patients who failed treatment or who were treatment intolerant. The comparison treatment regimen 
was the standard of care in Georgia, the Philippines and South Africa, and the main outcome of 
interest was the incremental cost per disability adjusted life year (DALY) averted. A health service 
perspective was taken. 
The objective of the acceptability study was to assess the acceptability and likelihood of implementation 
of the BPaL regimen as anticipated by key stakeholders based on a number of criteria including 
perceived benefits and challenges of implementation of BPaL and also longer individualized treatment 
regimens and other practical requirements of implementation. The study was a mixed-methods, 
multicountry, cross-sectional study conducted in 2018–2019 among stakeholders in Indonesia, 
Kyrgyzstan and Nigeria. A total of 188 participants offered their views; they included caregivers, 
programmatic stakeholders (including national and international programmatic stakeholders and 
patient advocacy groups), and public and private laboratory stakeholders. 
Additional evidence presented included modelled pharmacokinetic data based on the development of a 
pharmacokinetic toxicodynamic model designed to quantify the relationship between pharmacokinetic 
features of linezolid and toxicity as part of a 6-month BPaL regimen. Modelled data from 88 patients 
who received linezolid as part of the Nix-TB study were presented. This patient population included 
information on seven patients who had died. A total of 21 individuals from the Nix-TB study were 
excluded from these analyses – 16 because they had incomplete dosing histories (i.e. they were 
receiving ongoing treatment at the time of analysis) and five because they had an unverifiable 
dosing
history.

---

WHO consolidated 
guidelines 
on
tuberculosis: 
drug-resistant tuberculosis treatment
45
Additionally, the GDG was presented with an independent summary review of the preclinical and early 
clinical data on pretomanid. This review included background information, preclinical data and early 
phase clinical data detailing safety and efficacy, including data submitted to the United States Food 
and Drug Administration (US FDA) as part of the original new drug application or as supplemental 
information.