Progress on diagnosis and treatment of drug-resistant tuberculosis in line with World Health Organization recommendations in six priority countries in the Western Pacific Region

Background Diagnosis and treatment of drug-resistant tuberculosis (DR-TB) have radically changed in accordance with recommendations from the World Health Organization (WHO) in the past decade, allowing rapid and simple diagnosis and shorter treatment duration with new and repurposed drugs. Methods A descriptive analysis of the status and progress of DR-TB diagnosis and treatment in six priority countries in the Western Pacific Region was conducted using information from interviews with countries and the WHO TB database. Results Over the past decade, the use of Xpert MTB/RIF has increased in the six priority countries, in parallel with implementation of national policies and algorithms to use Xpert MTB/RIF as an initial diagnostic test for TB and detection of rifampicin resistance. This has resulted in increases in the number of people diagnosed with multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB). Shorter treatment regimens with new and repurposed drugs have also been adopted for MDR/RR-TB cases, alongside a decentralized model of care, leading to improved treatment outcomes. Discussion The Western Pacific Region has achieved considerable progress in the diagnosis and treatment of DR-TB, in line with the evolving WHO recommendations in the past decade. The continued commitment of Member States is needed to address remaining challenges, such as the impact of the coronavirus disease pandemic, suboptimal management and health system issues.

Oh et al Progress on diagnosis and treatment of DR-TB in the Western Pacific Table 1

Year
Diagnosis Treatment

2013
Xpert MTB/RIF to be used as the initial diagnostic test in adults and children suspected of having MDR-TB or HIV-associated TB rather than conventional microscopy, culture and drug susceptibility testing. 3

2016
For patients with confirmed RR-TB or MDR-TB, SL-LPA may be used as the initial test to detect resistance to fluoroquinolones, instead of phenotypic culture-based drug susceptibility testing. 4 In patients with RR-TB or MDR-TB who were not previously treated with second-line drugs and in whom resistance to fluoroquinolones and second-line injectable agents was excluded or is considered highly unlikely, a shorter MDR-TB regimen of 9-12 months may be used instead of the longer regimens. 7

2017
Xpert MTB/RIF Ultra is non-inferior to the current Xpert MTB/RIF for the diagnosis of MTB and the detection of rifampicin resistance and can be used as an alternative to the latter in all settings. 5 In patients who require TB retreatment, the category II regimen should no longer be prescribed, and drug susceptibility testing should be conducted to inform the choice of treatment regimen. 11 2018 In patients with confirmed rifampicin-susceptible and isoniazid-resistant TB, treatment with rifampicin, ethambutol, pyrazinamide and levofloxacin is recommended for a duration of 6 months. 10

2019
In MDR/RR-TB patients on longer regimens, all three Group A agents and at least one Group B agent should be included, to ensure that treatment starts with at least four TB agents likely to be effective and that at least three agents are included for the rest of the treatment after bedaquiline is stopped. If only one or two Group A agents are used, both Group B agents are to be included. If the regimen cannot be composed with agents from Groups A and B alone, Group C agents are to be added. 9 Kanamycin and capreomycin are not to be included in the treatment of MDR/RR-TB patients on longer regimens. 9

2020
A shorter all-oral bedaquiline-containing regimen of 9-12 months duration is recommended in eligible patients with confirmed MDR/RR-TB who have not been exposed to treatment with second-line TB medicines used in this regimen for more than 1 month, and in whom resistance to fluoroquinolones has been excluded. 8 A treatment regimen lasting 6-9 months, composed of bedaquiline, pretomanid and linezolid (BPaL), may be used under operational research conditions in MDR-TB patients with TB that is resistant to fluoroquinolones, who have either had no previous exposure to bedaquiline and linezolid or have been exposed for no more than 2 weeks. 8

2021
In people with bacteriologically confirmed pulmonary TB, low complexity automated NAATs may be used on sputum for the initial detection of resistance to isoniazid and fluoroquinolones, rather than culturebased phenotypic drug susceptibility testing. 6 • proportion of people diagnosed with MDR/RR-TB and enrolled in MDR-TB treatment in the same year (this can be more than 100% owing to cases that are enrolled in the year after they are diagnosed); • percentage of MDR/RR-TB cases tested for susceptibility to fluoroquinolones; • number of MDR/RR-TB cases treated with bedaquiline, shorter regimen and all-oral longer regimen; and • treatment outcomes for MDR/RR-TB cases started on treatment. 1,16 Information on the countries' status was obtained through interviews, supported by follow-up communication and rGLC country monitoring missions. Between July and November 2021, interviews with PMDT focal points of the national TB programmes from the six priority countries were conducted virtually using a structured questionnaire. Further information was updated after follow-up communications or subsequent rGLC country monitoring missions in 2021. Information on the countries' progress was collected from the WHO database, to which countries and areas annually report data on TB care and prevention via an electronic platform. 17 All data analyses and visualizations were conducted using the statistical software package R 4.1.1 (Comprehensive R Archive Network at https://cran.rproject.org/).

Status of DR-TB diagnosis
The six priority countries are at different stages in their uptake of WHO recommendations on diagnostic tools and algorithms for DR-TB ( Table 2). National policies and algorithms indicate universal access to drug susceptibility testing in all priority countries. Although Xpert MTB/RIF is used as an initial diagnostic test for TB and rifampicin resistance detection in all priority countries, in Cambodia and Viet Nam it does not cover the entire population. In Cambodia, Xpert MTB/RIF was used for all initial diagnostic testing in some areas; in other areas, it was limited to high-risk groups, such as previously treated cases and people living with HIV. The country aims to expand its universal use to all presumptive a few thousand residents, and from countries with a high TB burden to countries in the pre-elimination stage. 12 Five countries (China, Mongolia, Papua New Guinea, the Philippines and Viet Nam) in the region are on the WHO global list of 30 countries with a high burden of TB and multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB) for 2021-2025. 13 Countries and areas of the region have striven to adopt the changing WHO recommendations for the diagnosis and treatment of DR-TB. The regional Green Light Committee (rGLC), established in 2011 as a regional DR-TB advisory committee to WHO, has supported the scale-up of the programmatic management of DR-TB (PMDT) in countries with a high MDR/ RR-TB burden in the region. 14 This analysis provides an overview of the status and progress of DR-TB diagnosis and treatment in six priority countries in the Western Pacific Region in line with WHO recommendations.

METHODS
The Western Pacific regional framework to end TB: 2021-2030 indicates 10 priority countries in the region. 15 Six countries that are directly supported by rGLC -Cambodia, the Lao People's Democratic Republic, Mongolia, Papua New Guinea, the Philippines and Viet Nam -were selected for this descriptive analysis of the status and progress of DR-TB diagnosis and treatment using information from interviews with countries and the WHO TB database.
Indicators to assess current diagnosis and treatment processes for DR-TB were based on recommendations in the latest WHO guidelines; they included: • use of Xpert MTB/RIF, Xpert MTB/RIF Ultra (Xpert Ultra) and Xpert MTB/XDR for diagnostic tests; • use of shorter all-oral bedaquiline-containing regimens; • discontinuation of kanamycin and capreomycin for MDR/RR-TB; and • use of a bedaquiline, pretomanid and linezolid (BPaL) regimen. 6,8 Indicators to assess the progress of diagnosis and treatment for DR-TB were from the latest WHO global TB reports; they included: • percentage of TB patients tested for rifampicin resistance; Oh et al Progress on diagnosis and treatment of DR-TB in the Western Pacific Progress on diagnosis and treatment of DR-TB in the Western Pacific Oh et al Guinea) increased between 2017 and 2020, with some fluctuations (Fig. 1). The number of people diagnosed with MDR/RR-TB and the number starting on treatment per year in all countries has increased since 2010 (Fig. 2). However, in the Lao People's Democratic Republic, Mongolia and the Philippines, there was a decrease in the number of MDR/RR-TB cases diagnosed in 2020 compared with 2019. This decrease started in 2014 in Mongolia. The proportion of enrolment in treatment among diagnosed cases exceeded 80% in 2020 in Mongolia (104%) and Viet Nam (89%), whereas it was 80% or below in the Lao People's Democratic Republic (80%), Papua New Guinea (76%) and the Philippines (78%).
The percentage of MDR/RR-TB cases tested for susceptibility to fluoroquinolones in four priority countries between 2015 and 2020 (no reports from Cambodia and Papua New Guinea) varied with increased coverage in Mongolia and Viet Nam (Fig. 3).

Status of DR-TB treatment
The six priority countries are also at different stages in the uptake of WHO recommendations for DR-TB treatment ( Table 3). The category II regimen for retreatment cases has been discontinued in all priority countries. However, the WHO-recommended regimen for rifampicin-susceptible and isoniazid-resistant TB (Hr-TB) is used only in Cambodia, Mongolia, Papua New Guinea and Viet Nam.
Shorter injectable-containing regimens started in all priority countries between 2013 and 2017. In accordance with the 2020 update of the WHO guidelines on DR-TB treatment, 8 the shorter all-oral bedaquiline-containing regimen has been used in Cambodia, the Lao People's Democratic Republic, Mongolia, the Philippines and Viet Nam since 2020, with the shorter injectable-containing regimen being phased out accordingly.
As per the 2019 WHO consolidated guidelines on DR-TB treatment, 9 standardized longer regimens for fluoroquinolone-susceptible or fluoroquinolone-resistant MDR/RR-TB have been revised in Cambodia, Mongolia, Papua New Guinea, the Philippines and Viet Nam, prioritizing Group A drugs including bedaquiline and linezolid. Kanamycin and capreomycin were no longer included in the treatment of MDR/RR-TB patients on longer regimens in all priority countries by 2020. Among the medicines recommended for use in longer regimens, 9 the following cases nationwide by 2023. In Viet Nam, Xpert MTB/RIF is limited to high-risk groups such as people living with HIV, children and people with abnormal lesions on chest X-ray. In priority countries, the number of GeneXpert machines per 1 million population ranges from three to 12.7 nationwide.
Xpert MTB/RIF Ultra (Xpert Ultra) has been introduced in all priority countries. In Cambodia, Xpert Ultra had already replaced Xpert MTB/RIF at the time of the interview. In the other priority countries, Xpert Ultra is being used together with Xpert MTB/RIF. There are also plans to introduce Xpert MTB/XDR in 2022 in the Lao People's Democratic Republic, Papua New Guinea, the Philippines and Viet Nam.
In Cambodia, first-line line probe assays (FL-LPAs) are used to detect isoniazid resistance among rifampicinsusceptible TB cases only on an ad hoc basis. However, in Mongolia, Papua New Guinea and the Philippines, FL-LPAs are routinely used to detect isoniazid resistance among rifampicin-resistant TB cases, and in Cambodia and Viet Nam, they are used in such cases but on an ad hoc basis. Second-line line probe assays (SL-LPAs) are used as an initial test to detect fluoroquinolone resistance among confirmed MDR/RR-TB cases in all priority countries. The use of Truenat (a point-of-care rapid molecular test) for detection of TB and rifampicin resistance is planned as a pilot project in 2022 in Cambodia, the Philippines and Viet Nam.
As the use of new and repurposed drugs in shorter and longer regimens is scaled up in priority countries, phenotypic drug susceptibility testing for those drugs is conducted or planned. In the Lao People's Democratic Republic, drug susceptibility testing for linezolid is in place, and drug susceptibility testing for bedaquiline, clofazimine and delamanid is planned. In Mongolia, drug susceptibility testing for bedaquiline, linezolid and clofazimine is conducted. In Viet Nam, drug susceptibility testing for bedaquiline, linezolid, clofazimine and delamanid is conducted and drug susceptibility testing for pretomanid is planned.

Progress of DR-TB diagnosis
The percentage of new and previously treated TB patients tested for rifampicin resistance in four of the priority countries (no reports from Cambodia and Papua New Culture monitoring for MDR/RR-TB patients on treatment is conducted monthly in all priority countries except for Papua New Guinea. Elective partial lung resection (lobectomy or wedge resection) alongside a recommended MDR-TB regimen is being undertaken in Mongolia and the Philippines.

Percentage of MDR/RR-TB cases tested for susceptibility to fluoroquinolones in four priority countries, 2015-2020 (no reports from Cambodia and Papua New Guinea)
PDR: People's Democratic Republic  also, the number of Xpert MTB/RIF sites and GeneXpert machines has increased, with the eligibility criteria extended to all people to be evaluated for TB. As a result, the number of people diagnosed with MDR/RR-TB and the percentage of TB patients tested for rifampicin resistance have also increased. For DR-TB treatment, shorter regimens for MDR/RR-TB treatment are used, with the shorter all-oral bedaquiline-containing regimen replacing the shorter injectable-containing regimen. New and repurposed drugs have been included in shorter or longer regimens, and kanamycin and capreomycin have been withdrawn. The model of care for MDR/RR-TB treatment is transitioning towards decentralization and increased use of ambulatory care. Consequently, the treatment outcomes for MDR/RR-TB cases have improved in these priority countries.
The rGLC has supported the scale-up of programmatic management of DR-TB in priority countries. 14 In accordance with WHO recommendations, the committee has provided technical inputs to national strategies or guidelines related to DR-TB; assisted in national capacitybuilding activities (e.g. in-person workshops or webinars); and conducted annual rGLC monitoring missions, where members of the committee and WHO staff have provided recommendations and have monitored countries' actions to previous recommendations. 14,18 Therefore, most of the new diagnostics and regimens have been implemented in a timely manner in the priority countries.
COVID-19 has impacted the diagnosis and treatment of TB and DR-TB since 2020. 19 The decrease in the number of MDR/RR-TB cases diagnosed in the Lao People's Democratic Republic, Mongolia and the Philippines in 2020 can be attributed to the decrease in TB notifications due to restricted visits to health facilities and the repurposing of TB staff and facilities for the COVID-19 response. GeneXpert machines have been repurposed for COVID-19 diagnosis; also, stockouts of cartridges and a lack of equipment maintenance may have contributed to the decrease in MDR/RR-TB diagnoses. Despite these difficulties, COVID-19 has facilitated innovations in DR-TB treatment. 20 All priority countries have expedited the transition from injectable-containing shorter or longer regimens to all-oral shorter or longer regimens, to minimize patient visits to health facilities. Hospitalization for treatment and facility-based DOT has been minimized, and community-based DOT has been facilitated in all priority countries. Also, the use of digital is facility-based DOT by health-care workers during hospitalization. Video-observed treatment (VOT) has been conducted as a pilot project in Mongolia, the Philippines and Viet Nam. MDR/RR-TB patients are treated mainly through ambulatory care in Papua New Guinea and the Philippines, whereas most patients are treated during hospitalization in the Lao People's Democratic Republic. In Mongolia, patients are hospitalized until their sputum conversion from positive to negative, and in Viet Nam, patients are hospitalized for up to 1 month. In Cambodia, patients were hospitalized for the first week for a workup and monitoring of a new regimen before the coronavirus disease (COVID-19) pandemic; however, this practice has since been restricted to ambulatory care only.

Progress of DR-TB treatment
Where data were available, the number of MDR/RR-TB cases treated with bedaquiline and the shorter regimen between 2015 and 2019 increased in all six priority countries, although there were decreases observed between 2018 and 2019 in Cambodia, the Lao People's Democratic Republic and the Philippines (Fig. 4). The use of the all-oral longer regimen increased between 2019 and 2020 in the Philippines (no report from the other countries).
Treatment outcomes for MDR/RR-TB cases started on treatment in 2014-2018 in the six priority countries differed (Fig. 5). The proportion of cases with treatment success increased in the Lao People's Democratic Republic (from 67% in 2014 to 84% in 2018) and the Philippines (from 46% in 2014 to 67% in 2018), mainly due to a reduction in the proportion of treatment failure in the Lao People's Democratic Republic and to patient loss to follow-up in the Philippines. The proportion of cases with treatment success was similar each year in Mongolia and Viet Nam, and fluctuated from year to year in Cambodia and Papua New Guinea.

DR-TB diagnosis and treatment in the Western Pacific
Region have changed drastically over the past decade. As shown by the six priority countries, national policies and algorithms now recommend Xpert MTB/RIF as an initial diagnostic test for TB and rifampicin resistance detection; Oh et al Progress on diagnosis and treatment of DR-TB in the Western Pacific that there may be an insufficient number of laboratories for SL-LPA for nationwide coverage. For example, in the Philippines, a large country, there was only one laboratory functional for SL-LPA between 2020 and 2021 from among three designated laboratories, because one facility was repurposed for COVID-19 testing and another had never started SL-LPA testing. It has been reported from the field that SL-LPA may be underused in areas where Xpert MTB/RIF-confirmed RR-TB patients are initiated on MDR-TB treatment without SL-LPA testing against national guidelines. There may also be missing data on SL-LPA results during the recording and reporting process. With the Lao People's Democratic Republic, Papua New Guinea, the Philippines and Viet Nam soon to introduce Xpert MTB/XDR, a new landscape of drug susceptibility testing for fluoroquinolones is expected.
Due to the underuse of FL-LPA and regimens for Hr-TB in most priority countries, diagnosis and treatment of Hr-TB remain limited in the region. FL-LPA or the soon-to-be-introduced Xpert MTB/XDR should be further used to detect isoniazid resistance in cases of rifampicin-technology such as VOT was accelerated in three priority countries during the pandemic. This analysis shows that there is still a gap in enrolment in treatment for cases diagnosed with MDR/RR-TB in some priority countries. Programme staff in the field have reported that this might be due to several factors, including death or loss to follow-up of cases before treatment commencement; significant delay in diagnosis due to the long turnaround time of SL-LPA or phenotypic drug susceptibility testing results; and delay in treatment due to health system challenges including drug supply interruption, stockouts or insufficient staff capacities, or inaccuracies in recording and reporting from paper-based systems. There should be a focus on addressing these factors for more timely patient treatment enrolment in those countries.
Although SL-LPA has been successfully promoted as initial drug susceptibility testing for fluoroquinolones in all priority countries, for various reasons, coverage is suboptimal in some of these countries. One issue is Although attempts were made to refer to official documents, some answers were provided based on memory. Notwithstanding these limitations, this analysis provides a comprehensive and practical insight into the progress of PMDT in these six priority countries in the region.
In conclusion, these six priority countries in the Western Pacific Region, in collaboration with the rGLC, have achieved considerable progress in the diagnosis and treatment of DR-TB in line with the evolving WHO recommendations over the past decade. Automated nucleic acid amplification tests and shorter all-oral regimens containing new and repurposed drugs are now used for DR-TB diagnosis and treatment in the region, leading to reductions in the case-detection gap and enhanced treatment outcomes. However, several challenges remain, particularly the impact of the COVID-19 pandemic, suboptimal patient management and health system issues.
susceptible TB (at least among retreatment cases), given the high rate of isoniazid resistance in some countries. Moreover, the regimen for Hr-TB should be implemented in more of the priority countries.
There was static and fluctuating MDR/RR-TB treatment success in some priority countries, despite the roll-out of shorter regimens. Although they are shorter, these regimens do not guarantee improved treatment outcomes because they still require clinical management, strong patient support and monitoring systems to ensure patient adherence to treatment. In those countries, expansion of shorter regimens should be reinforced by optimal management and supportive health systems for improved treatment outcomes.
Our analysis has several limitations. First, there were no reported data for some indicators for certain years or from particular countries in the WHO database, impeding a complete analysis. Second, there is a possibility of re-PDR: People's Democratic Republic