تعليقThis section refers to recommendations on MDR/RR-TB treatment regimens that are of longer duration than the regimens described in Sections 1 and 2.
PICO questions
The recommendations in this section address PICO questions formulated in 2018 and 2019. The questions formulated in 2018 were as follows:
PICO question 3–2018 (MDR/RR-TB, 2018): In patients with MDR/RR-TB, which individual agents are more likely to improve outcomes when forming part of a longer regimen conforming to WHO guidelines?27
PICO question 4–2018 (MDR/RR-TB, 2018): In patients with MDR/RR-TB on longer regimens composed in accordance with WHO guidelines, are outcomes safely improved with fewer or more than five effective medicines in the intensive phase?
PICO question 5–2018 (MDR/RR-TB, 2018): In patients with MDR/RR-TB on longer regimens composed in accordance with WHO guidelines, are outcomes safely improved with an intensive phase shorter or longer than 8 months?
PICO question 6–2018 (MDR/RR-TB, 2018): In patients with MDR/RR-TB on longer regimens composed in accordance with WHO guidelines, are outcomes safely improved with a total duration shorter or longer than 20 months?
PICO question 7–2018 (MDR/RR-TB, 2018): In patients with MDR/RR-TB on longer regimens composed in accordance with WHO guidelines, what is the minimum duration of treatment after culture conversion that is most likely to improve outcomes?
The two relevant PICO questions considered by the GDG for the 2020 update were as follows:
PICO question 8–2019 (MDR/RR-TB, 2019): In MDR/RR-TB patients, does a treatment regimen containing bedaquiline for more than 6 months safely improve outcomes when compared with bedaquiline for up to 6 months as part of longer regimens otherwise conforming to WHO guidelines?
PICO question 9–2019 (MDR/RR-TB, 2019): In MDR/RR-TB patients, does concurrent use of bedaquiline and delamanid safely improve outcomes when compared with other treatment regimen options otherwise conforming to WHO guidelines?
Two additional PICO questions were reviewed in 2021 as part of the GDG formed to update childhood TB guidelines (31):
PICO question 1–2021 (Childhood TB, 2021): In MDR/RR-TB patients aged below 6 years, should an all-oral treatment regimen containing bedaquiline versus other regimens conforming to WHO guidelines without bedaquiline be used?
PICO question 2–2021 (Childhood TB, 2021): In MDR/RR-TB patients aged below 3 years, should an all-oral treatment regimen containing delamanid versus other regimens conforming to WHO guidelines without delamanid be used?
Recommendations for the design of longer MDR-TB regimens have been issued by WHO for several years and have been implemented in many countries worldwide (1, 8, 11, 12). The recommendations in this section cover all forms of MDR/RR-TB; they include treatment of patients with strains resistant to rifampicin and susceptible to isoniazid (i.e. RR-TB), or with additional resistance to isoniazid (i.e. MDR-TB), or with resistance to other medicines (i.e. pre-XDR or XDR-TB). All patients with TB – children or adults – diagnosed with strains shown to be resistant to rifampicin can be placed on an MDR/RR-TB treatment regimen (12).
The likelihood of treatment success in MDR/RR-TB patients on longer regimens depends on factors related to the patient and strain of TB (e.g. severity of disease, resistance patterns and comorbidities), and access to health care (e.g. regimens with sufficient effective agents, medications of good quality, management of adverse events and patient support). Longer regimens with sufficient effective agents are known to increase the likelihood of cure and lower the risk of death in adults and children (55–58). The composition of longer regimens is governed by the selection of individual medicines considered to be effective, and by a need to combine sufficient medicines to maximize the likelihood of relapse-free cure without increasing toxicity. Regimens may be of standardized (fixed) composition or may be individualized to the patient’s needs. Longer regimens usually last 18–20 months or more; this document provides recommendations on the duration of such regimens, updated since publication of the 2011 WHO guidelines (8). In summary, in 2018, a total treatment duration of 18–20 months and a treatment duration of 15–17 months after culture conversion were suggested for most patients, with the duration being modified according to the patient’s response to therapy.
Evidence base and analyses
Ahead of the GDG discussion in 2018, WHO made a public call for individual MDR/RR-TB patient data, complete with results of treatment (59). IPD meta-analysis in adults and children treated with longer MDR/RR-TB regimens allows the study of useful correlates of outcome, including the regimen composition (55–57). The evidence base for the effectiveness of many of the medicines used in MDR/RR-TB regimens relies on the 2018 IPD meta-analysis. In turn, this IPD meta-analysis relies heavily on observational studies, only a few of which have employed randomized controlled designs (18); hence, the overall certainty of evidence is often graded as low or very low. The sources of data used by the GDGs to address the PICO questions in this section are summarized below.
PICO question 3–2018 (MDR/RR-TB, 2018) (choice of individual medicines)
in longer regimens, the 2018 IPD meta-analysis was used, with 13 104 records from 53 studies in 40 countries. The 2018 IPD contained datasets from preceding years and from several countries, including a large dataset from South Africa with many patients treated with bedaquiline-containing regimens. Second, to analyse adverse events resulting in permanent discontinuation of individual medicines in longer regimens, a subset of 5 450 records from 17 studies in the 2018 IPD was used, supplemented with additional information from 10 other studies that only reported adverse events for either bedaquiline (n=130), linezolid (n=508) or carbapenems (n=139).
In addition to these data, the GDG 2018 assessed unpublished results from the Phase 3 Trial 213 of delamanid (60, 61) and safety and pharmacological exposure data from unpublished paediatric studies of bedaquiline (Phase 2 TMC207-C211 and Phase 1–2 IMPAACT P1108) and delamanid (Phase 1 242–12–245, Phase 1 242–12–232, Phase 2 242–07–204 and Phase 2 242–12–233). The GDG 2018 also searched the literature for studies reporting outcomes of patients treated with agents other than those included in the 2016 guidelines (e.g. perchlozone, interferon gamma and sutezolid).
PICO question 4–2018 (MDR/RR-TB, 2018) (number of agents likely to be effective)
To analyse treatment success, treatment failure, relapse and death for the optimal number of medicines to be included in longer regimens, the data were derived from a subset of 8 957 patients in 47 studies included in the IPD used for PICO question 2–2018 (MDR/RR-TB, 2018) above. Of these, 3 570 patients in 16 studies had information on the start and end dates for individual medicines in which DST was reported, and 5 387 patients in 31 studies had information on individual medicines used in both the intensive and continuation phases of treatment, as well as DST results. This question focused on the number of agents in the intensive phase; hence, patients who did not receive an injectable agent or in whom an initial intensive phase was not defined were excluded (n=476). Patients who were designated “cured” or “treatment completed” but received less than 18 months of treatment – the minimum duration for longer regimens recommended by WHO in the past – were also excluded (n=346). In cases where DST results were available, a medicine was considered effective if results showed susceptibility, and was considered not effective if results showed resistance. Where DST results were missing, two situations existed. First, if the prevalence of resistance to that medicine was less than 10% in the same population (i.e. from the same country or study site if within one country, or overall at all sites if local data were not available), then the medicine was counted as effective. This situation applied to the following agents: cycloserine or terizidone, linezolid, clofazimine, bedaquiline, the carbapenems and delamanid. Second, if the prevalence of resistance to that medicine was more than or equal to 10% in the same population (from the same country or study site if within one country, or overall, at all sites if local data were not available), then imputed DST results were used to determine effectiveness if DST was missing. If the imputed DST result showed susceptibility, then the medicine was counted as effective; if the imputed DST result showed resistance, then the medicine was not counted as effective. This situation applied to the following agents: pyrazinamide, ethambutol, second-line injectable agents, fluoroquinolones, p-aminosalicylic acid, ethionamide and prothionamide. The following agents were not included when counting the number of medicines likely to be effective (regardless of any DST result that may have been available): isoniazid (including high-dose isoniazid), rifampicin, rifabutin, thioacetazone, amoxicillin–clavulanate and macrolide antibiotics.
Subsets of the main 2018 IPD meta-analysis with 13 104 patients overall from 53 studies in 40 countries were analysed for the risk of treatment failure and relapse versus success associated with different durations in these three recommendations on the duration of treatment (see Web Annex 3 and Web Annex 4 for the GRADE tables, and Web Annex 6 for the analysis plan). Patients were followed up for relapse but numbers of patients reported with relapse were relatively small. The three IPD subsets for PICO questions 5, 6 and 7–2018 are discussed below.
PICO question 5–2018 (MDR/RR-TB, 2018) (different durations of the intensive phase)
The primary analysis used a subset of records from 3 750 patients from 42 observational studies; of these patients, 2 720 were treated with an individualized MDR-TB regimen and 1 030 were treated with standardized MDR-TB regimens. Of the 13 104 records in the main IPD, 9 354 records were excluded for the following reasons: lost to follow-up (n=2 261), died (n=2 043), did not receive an injectable (n=1 094), no information on duration of injectable (n=2 341), number of medicines likely to be effective less than five or less than four plus pyrazinamide (n=1 450) and duration of injectable longer than 20 months (n=165).
PICO question 6–2 018 (MDR/RR-TB, 2018) (on regimen duration)
The evidence to inform PICO question 6–2018 (MDR/RR-TB, 2018) was derived from a subset of 6 356 patients from 51 observational studies for the primary analysis. Of the 6 356 patients, 5 352 were treated with an individualized MDR-TB regimen and 1 004 were treated with a standardized MDR-TB regimen. Of the 13 104 records in the main IPD, 6 748 records were excluded for the following reasons: lost to follow-up (n=2 261), died (n=2 043), treatment duration not available (n=230), number of effective drugs less than five or less than four plus pyrazinamide (n=2 072), treatment duration less than 6 months (n=52) and treatment duration more than or equal to 36 months (n=90).
PICO question 7–2018 (MDR/RR-TB, 2018) (on treatment duration after culture conversion)
The analysis to address PICO question 7–2018 (MDR/RR-TB, 2018) was derived from a subset of 4 175 patients from 39 observational studies. All but three of the 4 175 patients were on individualized regimens. The reasons for exclusion of 8 929 records from the main dataset were as follows: lost to follow-up (n=2 261), died (n=2 043), treatment duration not reported (n=230), culture information not reported (n=1 945), baseline culture negative (n=754), patient never culture converted (n=426), number of effective drugs less than five or less than four plus pyrazinamide (n=1 215), treatment duration less than 6 months (n=4), treatment duration more than or equal to 36 months (n=49) and culture converted post-treatment (n=2).
PICO question 1–2019 (MDR/RR-TB, 2019) (use of bedaquiline longer than 6 months)
To analyse treatment success, failure, relapse and death for the use of bedaquiline longer than 6 months, the data were derived from the endTB observational study, with the overall dataset comprising a total of 1 094 patients from 13 countries (62).28 The data analysed to answer this question were patients from the endTB observational study cohort who received bedaquiline for at least 6 months, had started bedaquiline within the first month of the treatment episode and did not receive delamanid concomitantly with bedaquiline during treatment; among patients with treatment success, data were from those who received at least 17.5 months of treatment overall. A total of 515 patients met these criteria. The intervention group comprised 242 patients who received bedaquiline for more than 203 days29 overall, and they were compared to 273 patients who received bedaquiline for a total of 168–203 days. Additional data sources considered by the GDG 2019 included a cohort of 112 patients from Belarus treated with bedaquiline (of whom two had inadequate treatment information and were excluded), and a cohort of 123 patients from an MSF-managed clinic in Uzbekistan treated with bedaquiline (with one patient excluded due to inadequate treatment information). Of these 232 eligible patients, 65 received bedaquiline for more than 203 days and 72 received bedaquiline for 168–203 days. The primary analyses featured the endTB observational study data only.
PICO question 2–2019 (MDR/RR-TB, 2019) (use of bedaquiline and delamanid together)
To analyse treatment success, failure, relapse and death for the concurrent use of bedaquiline and delamanid, the data were derived from the same cohort of patients from the endTB observational study that informed PICO question 1–2019. However, in this dataset, only 92 patients received both medicines together for any period of time, and even fewer started bedaquiline and delamanid at the same time and within the first month of treatment (n=35). Another three patients were receiving concomitant bedaquiline and delamanid by the end of the first month of treatment, bringing the total number to 38. The remaining 57 patients started the two medicines more than 30 days apart and were therefore not included. Additional data sources comprised a cohort of 100 patients treated with bedaquiline in Mumbai, India (from an MSF-supported project), of whom 86 received some form of concomitant treatment with bedaquiline and delamanid during therapy; 62 of these 86 initiated the two medicines within 30 days of each other, and 46 of these 62 began both medicines during the first month of their treatment episode. The total intervention population therefore comprised 84 patients: 38 from the endTB observational study cohort and 46 from the Mumbai dataset. Because the data available were limited, the sources of data for the comparator populations were derived from the endTB observational study, and the datasets from Belarus, Mumbai and Uzbekistan. There were inadequate numbers of patients available in the IPD for any meaningful analyses (n=4 patients who received bedaquiline and delamanid together). The primary comparison group included 401 patients (n=302 from the endTB observational study, n=82 from the Belarus dataset, n=17 from the Uzbekistan dataset and n=0 from the Mumbai dataset). These patients initiated bedaquiline within the first month of treatment and did not receive bedaquiline beyond 6 months duration. The secondary comparison group was derived from the endTB observational study and comprised 102 patients who received delamanid within the first month of treatment and who did not receive an extended duration of delamanid. No patients in the datasets from Belarus, Mumbai or Uzbekistan received delamanid for this duration. The median duration of concurrent use of bedaquiline and delamanid among the 84 patients in the intervention group was 18.5 months (IQR: 9 months, 21 months).
Additional data presented included safety data from the DELamanId Bedaquiline for ResistAnt TubErculosis (DELIBERATE) trial (AIDS Clinical Trials Group A5343). The DELIBERATE trial is a randomized, open-label, three-arm pharmacokinetic and safety trial conducted at study sites in Peru and South Africa. Eligible patients were aged 18 years and older, with pulmonary MDR-TB (or rifampicin monoresistance) receiving treatment for MDR-TB, but without clofazimine, and with moxifloxacin replaced by levofloxacin and a baseline QTcF of less than 450 ms. In addition to the MDR-TB treatment regimen with the conditions described above, the regimens used in the three study arms comprised the addition of bedaquiline 400 mg once daily for 2 weeks, then 200 mg thrice weekly for 22 weeks; the addition of delamanid 100 mg twice daily for 24 weeks; and the addition of both bedaquiline and delamanid. The primary objective of the trial was to compare the mean change from baseline in QTcF (averaged over weeks 8–24) when bedaquiline and delamanid were co-administered with the mean change observed when each drug was administered alone.
In addition to the data reviewed for PICO questions 1–2019 and 2–2019, the GDG 2019 was provided with and reviewed data from a study in South Africa on the use of bedaquiline during pregnancy. This observational cohort study included information from 108 pregnant women with RR-TB who were recruited from one MDR/RR-TB referral hospital in South Africa between January 2013 and December 2017. As part of their MDR/RR-TB regimen, 58 women received bedaquiline; they were compared with 50 women who had no bedaquiline in their regimen. The women in this study gave birth to 109 live infants, of whom 49 had bedaquiline exposure in utero and 60 had no bedaquiline exposure in utero. Clinical assessments were carried out at 2, 6 and 12 months after birth to document infant outcomes. The main objective of the study was to document treatment, pregnancy and infant outcomes among women treated for RR-TB with second-line TB drugs during pregnancy.
When reviewing evidence and formulating the recommendations, the GDG 2019 considered the need for the guidelines to also cater to key subgroups that were not well represented in the 2018 IPD meta-analysis – notably, children. Where data on children were unavailable, evidence from adults was extrapolated to children. The best available evidence was used to construct recommendations for a regimen that has high relapse-free cure rates, and that reduces the likelihood of death and the emergence of additional resistance while minimizing harms. The GDG 2019 was aware of the paediatric MDR-TB IPD meta-analysis on 975 clinically diagnosed or bacteriologically confirmed pulmonary or extrapulmonary TB cases that was used for the 2016 treatment recommendations (56). Children with XDR-TB (pre-2021 definition) were excluded from that analysis (n=36) because their treatment regimens were not considered to be comparable with those of other MDR-TB patients, and their numbers were too low to be analysed independently. No RCTs were included (or known to exist) at the time this dataset was compiled, and the overall certainty in the estimates of effect based on this evidence was judged to be very low. However, in July 2019, preliminary data from the DELIBERATE trial were made available to the GDG 2019 to partly address PICO question 9; the overall certainty in the estimates of effect for this study was judged to be low.
PICO question 1–2021 (Childhood TB, 2021) (use of bedaquiline in MDR/RR-TB patients aged below 6 years)
To answer the PICO question on the use of bedaquiline in children aged below 6 years, data from two Phase 2 trials (TMC207-C211 and IMPAACT P1108) were reviewed by the GDG 2021. TMC207-C211 is a Phase 2, open-label, single-arm study to evaluate the pharmacokinetics, safety, tolerability and anti-mycobacterial activity of bedaquiline in combination with a background regimen of MDR-TB medications for the treatment of children and adolescents aged 0–17 years who have bacteriologically confirmed or clinically diagnosed pulmonary and selected forms of extrapulmonary MDR-TB.30 IMPAACT P1108 is a Phase 1–2 dose finding modified age de-escalation study to evaluate the pharmacokinetics, safety and tolerability of bedaquiline in combination with optimized individualized MDR-TB regimens in children living with HIV and HIV-uninfected children with clinically diagnosed or confirmed pulmonary (intrathoracic) and selected forms of extrapulmonary MDR-TB.31
Data reviewed from TMC207-C211 corresponded to children aged 5–18 years and data from IMPAACT P1108 included children aged 0–6 years; therefore, the review of pharmacokinetics and safety data focused mainly on data from IMPAACT P1108. Although the sample size of the available interim data for review was small (n=12), the GDG 2021 concluded that in children aged 0–6 years, cardiac safety signals were not distinct from those reported in adults. Population pharmacokinetic models from both studies suggest that drug exposures observed in adults can be reached in most children receiving bedaquiline, although some dose modification may be necessary depending on the age and weight of the child.
In addition, data from a paediatric MDR/RR-TB IPD were analysed descriptively (24 231 records from all six WHO regions, the majority from India and South Africa). The search was conducted in April 2020. Just under 20 000 of these records were used for a matched analysis of treatment outcomes in children being treated for DR-TB. The analysis included 40 children aged below 6 years and 68 children aged 6–12 years who received bedaquiline. In the matched analysis, bedaquiline was significantly associated with shorter treatment duration and a lower aOR of injectable TB drug use. There was no statistically significant difference in successful treatment outcomes between children aged below 6 years receiving an all-oral bedaquiline-based regimen and those not receiving bedaquiline (89% vs 97%, P=0.9). Residual confounding (including confounding by indication) was thought to be likely.
A child-friendly formulation of bedaquiline (20 mg scored uncoated tablet) is being used in the Janssen C211 study to dose children aged below 5 years and will also soon be used in an updated protocol of the IMPAACT study P1108 (to date, this study has used the 100 mg formulation in all age groups). No head-to-head studies were conducted to examine the bioequivalence of the 20 mg and the 100 mg formulation of bedaquiline. Indirect bioequivalence testing showed that both tablets have the same bioavailability and can be used interchangeably at the same total dose. Findings from the bedaquiline crush study (63) also showed that the bioavailability of bedaquiline tablets suspended in water was the same as for tablets swallowed whole.
PICO question 2–2021 (Childhood TB, 2021) (use of delamanid in MDR/RR-TB patients aged below 3 years)
To answer the PICO question on the use of delamanid in children aged below 3 years, data were reviewed by the GDG 2021 from a Phase 1, open-label, age de-escalation trial designed to assess the pharmacokinetics, safety and tolerability of delamanid administered twice daily for 10 days in children with MDR/RR-TB on treatment with an optimized background regimen (protocol 242–12–232)32 and from the corresponding open-label extension study (protocol 242–12–233).33 Data from cohorts 1 (age 12–17 years), 2 (age 6–11 years), 3 (age 3–5 years) and 4 (age 0–2 years) for both protocols were reviewed. Exposures in the 0–2-year age group were lower than those of children aged 3 years and older, necessitating a modelling or simulation approach to dosing. No cardiac safety signals distinct from those reported in adults were observed in children aged 0–2 years. However, consideration of these findings should take into account that children had lower drug exposures than adults. Pharmacodynamic simulations suggested that clinically meaningful changes in QT (i.e. prolongation) would be unlikely in children aged below 3 years, even if higher doses were used to reach drug exposures comparable to those achieved in adults.
CNS effects (paraesthesia, tremors, anxiety, depression and insomnia) were included in the delamanid label for both adults and children as important potential safety concerns for the drug. In March 2021, the study sponsor released a statement of intent to modify the labelling to include hallucinations as an adverse reaction. This new safety signal has been more prevalent among children than adults, with 15 reports in 14 children aged 2–16 years in India, the Philippines, South Africa, Tajikistan and Ukraine. Children experiencing this safety signal included some with extensively resistant forms of TB (MDR/XDR-TB) treated with delamanid under programmatic conditions (12 reports) and children enrolled in a clinical trial studying delamanid for TB prevention (3 reports). Seven of the 15 reports were for children also receiving cycloserine (under programmatic conditions). The GDG noted the importance of side-effects involving the CNS in young children, considering their dynamic brain development.
In addition to data from the trials, data from a paediatric DR-TB IPD were analysed descriptively (24 231 records from all six WHO regions, the majority from India and South Africa). The search was conducted in April 2020. Just under 20 000 of these records were used for a matched analysis of treatment outcomes in children being treated for DR-TB. The paediatric DR-TB IPD included only seven children aged below 3 years treated with delamanid, 14 children aged 3–6 years and 69 children aged 6–12 years. All 21 children aged below 6 years were successfully treated. The number of children was insufficient for a matched analysis.
27 Given that few trials or other studies have made head-to-head comparisons of MDR-TB medicines at different dosage regimens, it is not expected that guidance on dosage adjustment will be affected by the findings of the systematic review.
28 These countries are Armenia, Bangladesh, Belarus, the Democratic People’s Republic of Korea, Ethiopia, Georgia, Indonesia, Kazakhstan, Kenya, Lesotho, Myanmar, Pakistan and Peru.
29 203 days was chosen as a cut-off as the intermodal trough of bedaquiline use for all patients in the endTB observational study was 203 days; the cut-off was not 6 months exactly, but 203 days.
30 Pharmacokinetic study to evaluate anti-mycobacterial activity of TMC207 in combination with background regimen (BR) of multidrug resistant tuberculosis (MDR-TB) medications for treatment of children/adolescents pulmonary MDR-TB (https://clinicaltrials.gov/ct2/show/NCT02354014, accessed 21 January 2022).
31 P1108. A Phase I/II, open-label, single arm study to evaluate the pharmacokinetics, safety and tolerability of bedaquiline (BDQ) in combination with optimized individualized multidrug-resistant tuberculosis (MDR-TB) therapy in HIV-infected and HIV-uninfected infants, children and adolescents with MDR-TB disease (https://www.impaactnetwork.org/studies/p1108, accessed 21 January 2022).
32 Pharmacokinetic and safety trial to determine the appropriate dose for pediatric patients with multidrug resistant tuberculosis (https://clinicaltrials.gov/ct2/show/NCT01856634, accessed 21 January 2022).
33 A 6-month safety, efficacy, and pharmacokinetic (PK) trial of delamanid in pediatric participants with multidrug resistant tuberculosis (MDR-TB) (https://clinicaltrials.gov/ct2/show/NCT01859923, accessed 21 January 2022).