Characterization of Genomic Variants Associated with Resistance to Bedaquiline and Delamanid in Naive Mycobacterium tuberculosis Clinical Strains.

The role of mutations in genes associated with phenotypic resistance to bedaquiline (BDQ) and delamanid (DLM) in Mycobacterium tuberculosis complex (MTBc) strains is poorly characterized. A clear understanding of the genetic variants' role is crucial to guide the development of molecular-based drug susceptibility testing (DST). In this work, we analyzed all mutations in candidate genomic regions associated with BDQ- and DLM-resistant phenotypes using a whole-genome sequencing (WGS) data set from a collection of 4,795 MTBc clinical isolates from six countries with a high burden of tuberculosis (TB). From WGS analysis, we identified 61 and 163 unique mutations in genomic regions potentially involved in BDQ- and DLM-resistant phenotypes, respectively. Importantly, all strains were isolated from patients who likely have never been exposed to these medicines. To characterize the role of mutations, we calculated the free energy variation upon mutations in the available protein structures of Ddn (DLM), Fgd1 (DLM), and Rv0678 (BDQ) and performed MIC assays on a subset of MTBc strains carrying mutations to assess their phenotypic effect. The combination of structural and phenotypic data allowed for cataloguing the mutations clearly associated with resistance to BDQ (n = 4) and DLM (n = 35), only two of which were previously described, as well as about a hundred genetic variants without any correlation with resistance. Significantly, these results show that both BDQ and DLM resistance-related mutations are diverse and distributed across the entire region of each gene target, which is of critical importance for the development of comprehensive molecular diagnostic tools.

Identifying research questions for HIV, tuberculosis, tuberculosis-HIV, malaria, and neglected tropical diseases through the World Health Organization guideline development process: a retrospective analysis, 2008-2018.

OBJECTIVES: World Health Organization (WHO) guidelines for health programmes and healthcare delivery are the foundation of its technical leadership in public health and essential to decision-making globally. A key function of guideline development is to identify areas in which further evidence is needed because filling these gaps will lead to future improvements in population health. The objective of this study was to examine the knowledge gaps and research questions for addressing those gaps generated through the WHO guideline development process, with the goal of informing future strategies for improving and strengthening the guideline development process. STUDY DESIGN: We did a systematic, retrospective analysis of research questions identified in the published guidelines. METHODS: We analyzed guidelines published between January 1, 2008, and December 31, 2018, by the Communicable Diseases Cluster in five disease areas: tuberculosis (TB), HIV, malaria, TB-HIV, and neglected tropical diseases (NTDs). Research questions were extracted independently by two researchers. We analyzed the distribution of research questions by disease and by topic category and did a qualitative assessment of optimum practice for research question generation during the guideline development process. RESULTS: A total of 48 guidelines were included: 26 on HIV, 1 on malaria, 11 on TB, 5 on TB/HIV, and 5 on NTDs. Overall, 36 (75%) guidelines encompassed a total of 360 explicit research questions; the remainder did not contain specific research questions. The number of research questions that focused on TB was 49, TB/HIV was 38, HIV was 250, and NTDs was 23. The number of research questions that focused on diagnosis was 43 (11.9%) of 360, prevention was 62 (17.2%), treatment was 103 (28.6%), good practice was 12 (3.3%), service delivery was 86 (23.8%), and other areas was 54 (15%). Research questions were often not formulated in a specific or actionable way and were hard to identify in the guideline. Examples of good practice identified by the review team involved the generation of specific and narrowly defined research questions, with accompanying recommendations for appropriate study design. CONCLUSIONS: The WHO must strengthen its approach to identifying and presenting research questions during the guideline development process. Ensuring access to research questions is a key next step in adding value to the guideline development process.

Multidrug-resistant tuberculosis in Uzbekistan: results of a nationwide survey, 2010 to 2011.

Multidrug-resistant tuberculosis (MDR-TB; resistance to at least rifampicin and isoniazid) is a global public health concern. In 2010­2011, Uzbekistan, in central Asia, conducted its first countrywide survey to determine the prevalence of MDR-TB among TB patients. The proportion of MDR-TB among new and previously treated TB patients throughout the country was measured and risk factors for MDR-TB explored. A total of 1,037 patients were included. MDR-TB was detected in 165 treatment-naïve (23.2%; 95% confidence interval (CI) 17.8%­29.5%) and 207 previously treated (62.0%; 95% CI: 52.5%­70.7%) patients. In 5.3% (95% CI: 3.1%­8.4%) of MDR-TB cases, resistance to fluoroquinolones and second-line injectable drugs (extensively drug resistant TB; XDR-TB) was detected. MDR-TB was significantly associated with age under 45 years (adjusted odds ratio: 2.24; 95% CI: 1.45­3.45), imprisonment (1.93; 95% CI: 1.01­3.70), previous treatment (4.45; 95% CI: 2.66­7.43), and not owning a home (1.79; 95% CI: 1.01­3.16). MDR-TB estimates for Uzbekistan are among the highest reported in former Soviet Union countries. Efforts to diagnose, treat and prevent spread of MDR-TB need scaling up.

TB preventive treatment among pregnant women with HIV.

BACKGROUND: The WHO recommends TB preventive treatment (TPT) for people living with HIV, including pregnant women. Uptake of this policy recommendation in this subpopulation and country alignment with WHO guidance is unclear.METHODS: We conducted a policy review in 38 WHO high TB and TB-HIV burden countries to assess if the uptake of TPT policy among pregnant women living with HIV was in line with the WHO´s 2018 Updated and Consolidated Guidelines for Programmatic Management for LTBI. Data sources included TB national guidelines and HIV/AIDS/ART national guidelines, complemented by results from a previous survey on policy uptake held at the WHO.RESULTS: Uptake of WHO policy to provide TB preventive treatment among women with HIV accessing antenatal care was moderate: 64% (23 of 36 countries) explicitly recommended at least one clinical guideline or policy recommendation on screening, testing or treatment of LTBI among pregnant women living with HIV. There was considerable variation between countries on the stages in pregnancy that TPT should be provided. Two countries (5%) provided clinical monitoring recommendations for pregnant women.CONCLUSIONS: There is moderate uptake of TPT policy for pregnant women with HIV. Failure to provide TPT as part of antenatal or prevention of mother-to-child services is a missed opportunity for TB control.

WHO target product profiles for TB preventive treatment.

BACKGROUND: The WHO has developed target product profiles (TPPs) describing the most appropriate qualities for future TPT regimens to assist developers in aligning the characteristics of new treatments with programmatic requirements.METHODS: A technical consultation group was convened by the WHO to determine regimen attributes with greatest potential impact for patients (i.e., improved risk/benefit profile) and populations (i.e., reduction in transmission and TB prevalence). The group categorised regimen attributes as 'priority´ or 'desirable´; and defined for each attribute the minimum requirements and optimal targets.RESULTS: Nine priority attributes were defined, including efficacy, treatment duration, safety, drug-drug interactions, barrier to emergence of drug resistance, target population, formulation, dosage, frequency and route of administration, stability and shelf life. Regimens meeting optimal targets were characterised, for example, as having superior efficacy, treatment duration of ≤2 weeks, and improved tolerability and safety profile compared with current regimens. The four desirable attributes included regimen cost, safety in special populations, treatment adherence and need for drug susceptibility testing in the index patient.DISCUSSION: It may be difficult for a single regimen to satisfy all characteristics so regimen developers may have to consider trade-offs. Additional operational aspects may be relevant to the feasibility and public health impact of new TPT regimens.

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.

TB preventive treatment in high- and intermediate-incidence countries: research needs for scale-up.

BACKGROUND: In 2018, the WHO Member States committed to providing TB preventive treatment (TPT) to at least 30 million people by 2022. However, only 6.3 million people had initiated TPT by the end of 2019. Major knowledge gaps and research needs in diagnosis, treatment and the programmatic management of TPT (PMTPT) require to be addressed urgently.METHODS: In September 2019, a group of stakeholders involved in PMTPT in high TB burden countries met to develop an action agenda to support the global expansion of PMTPT.RESULTS: Barriers at the health system level, and priorities for research to overcome these, were identified for each step of the PMTPT cascade. The need for data on TPT financing, gaps and coverage under national health insurance schemes, as well as the need for mathematical and cost-effectiveness modelling of the impact of TPT on TB incidence and mortality were highlighted. Specific research needs were identified for high-risk populations such as household contacts of any age and people living with HIV, as well as other people at risk.CONCLUSIONS: The meeting facilitated agreement on a set of actions needed to ensure that PMTPT continues to expand to achieve the End TB Strategy targets.

Tuberculosis surveillance and its discontents: the ethical paradox.

In June 2017, the World Health Organization issued the Guidelines on Ethical Issues in Public Health Surveillance. Using the frame of public health ethics, the guidance declared that countries have an affirmative duty to undertake surveillance and that the global community had an obligation to support those countries whose resources limited their capacity. The centrality of TB surveillance has long been recognized as a matter of public health practice and ethics. Nevertheless, contemporary global realities make clear that TB surveillance falls far short of the goal of uniform notification. It is this reality that necessitated the paradoxical turn to research studies that require informed consent and human subjects' ethical review, the very burdens that mandated notification were designed to overcome.

The Beijing genotype is associated with young age and multidrug-resistant tuberculosis in rural Vietnam.

BACKGROUND: Associations between multidrug resistance and the Mycobacterium tuberculosis Beijing genotype have been described mainly in populations with poor tuberculosis (TB) control such as prisons and inner cities, and may reflect shared risk factors rather than a biological association. OBJECTIVE: To study the association between genotype and drug resistance among TB patients in a population with adequate TB control. SETTING: Three rural districts in Vietnam. The study was performed at the Pham Ngoc Thach Tuberculosis and Lung Disease Hospital, Ho Chi Minh City, and the Tien Giang Provincial Tuberculosis and Lung Disease Hospital, My Tho, Vietnam. METHODS: Pretreatment sputum specimens were collected for culture, drug susceptibility testing and spoligotyping of all sputum smear-positive pulmonary TB patients consecutively diagnosed over a 3-year period. RESULTS: Beijing genotype infections were observed in 614 of 1744 (35%) patients. Beijing strains were more common among female (adjusted odds ratio [aOR] 1.4, P = 0.005), young (aOR 2.8, P < 0.001) and previously treated patients (aOR 2.4, P < 0.001). The Beijing genotype was associated with any resistance (aOR 3.7, P < 0.001) and multidrug resistance (aOR 6.8, P < 0.001) among new patients, and with any resistance (aOR 2.7, P = 0.005) but not with multidrug resistance (aOR 1.4, P = 0.545) among previously treated patients. CONCLUSION: In Vietnam, Beijing genotype is associated with young age and in new patients with multidrug resistance despite adequate TB control, suggesting a biological association. This potentially undermines the effectiveness of TB control in countries where Beijing genotype infections are common.

Informed patient consent for defaulter tracing: should we obtain it?

Active default tracing is an integral part of tuberculosis (TB) programmatic control. It can be differentiated into the tracing of defaulters (patients not seen at the clinic for > or =2 months) and 'late patients' (late for their scheduled appointments). Tracing is carried out to obtain reliable information about who has truly died, transferred out or stopped treatment, and, if possible, to persuade those who have stopped treatment to resume. This is important because, unlike routine care for non-communicable diseases, TB has the potential for transmission to other members of the community, and therefore presents the issue of the rights of the individual over the rights of the community. For this reason, default or 'late patient' tracing (defined together as default tracing in this article) has been incorporated into standard practice in most TB programmes and, in many industrialised countries, it is also a part of public health legislation. In resource-poor countries with limited access to phones or e-mails, default tracing involves active home visits. In this Unresolved Issues article, we discuss the need for patient consent within both the programmatic and the research context; we describe how this subject arose during operational research training at the Research Institute of Tuberculosis in Japan; we provide comments from individuals who are experienced and skilled at international and national TB control; and finally we offer some conclusions about the way forward. This is not an easy subject, and we welcome open debate on the issue.

TB contact investigations: 12 years of experience in the National TB Programme, Morocco 1993-2004.

We reviewed data collected from 1993 to 2004 as part of the routine activities of the national tuberculosis (TB) control programme (NTP) in Morocco. More than 1 million household TB contacts were identified in approximately 200,000 investigations. On average, 77% of identified contacts were screened every year; overall prevalence was 2.5%. The proportion of TB cases identified in household contacts of registered cases was 5.6%. This was significantly higher in children under 10 years and in patients registered and diagnosed with symptomatic primary complex. Performing TB contact investigations as part of the routine activities of NTP services is feasible in low-middle-income countries.

Tuberculosis screening in outpatient healthcare workers: lessons from a high-income, low TB burden country.

SETTING: Early diagnosis of latent tuberculous infection (LTBI) should be pursued in healthcare workers (HCWs). While HCWs in hospitals are screened for LTBI, HCWs in outpatient settings are usually not. In 2017, in Italy, a tuberculosis (TB) infected paediatrician working in an outpatient vaccination service infected 15 adults and nine children. The investigation involved 2490 children and 151 adults. Among children, nine were tuberculin skin test-positive, and four developed active TB. Among 123 adult contacts with longer exposure, seven were interferon-gamma release assay (IGRA) positive and none had active TB. Among 28 close contacts, eight had a positive IGRA, and three had pulmonary TB. The total outbreak cost €1 017 903.OBJECTIVE: To compare the outbreak cost with those of potential screening programme strategies.RESULTS: Regular screening of paediatric outpatient HCWs would have cost between €2592 and €11 373. Extending the screening to all outpatient HCWs (caring for adults and children) would have cost between €66 384 and €155 043. Investigating only close contacts would have cost €42 857.CONCLUSION: Each of these screening strategies would have been cost-effective compared with the outbreak investigation occurring in real life with a cut-off of 474 for the maximum number of tested outpatient HCWs needed for the screening strategy to be cost-saving.

Drug-resistant tuberculosis and HIV in Ukraine: a threatening convergence of two epidemics?

OBJECTIVE: To investigate anti-tuberculosis (TB) drug resistance rates in Donetsk Oblast, Ukraine, and to explore the association between the epidemics of human immunodeficiency virus (HIV) and multidrug-resistant TB (MDR-TB). METHODS: All consecutive newly diagnosed and previously treated patients with sputum smear-positive TB presenting to all TB units in Donetsk Oblast over 12 months were invited to take part in the study. A total of 1293 and 203 patients with TB were tested for HIV and MDR-TB in the civilian and penitentiary sectors, respectively. RESULTS: Of those enrolled for the study, 307 were HIV-positive, 379 had MDR-TB, and 97 had MDR-TB and HIV co-infection. MDR-TB rates in the civilian sector were respectively 15.5% (95%CI 13.1-17.8) and 41.5% (95%CI 36.4-46.5) in newly diagnosed and previously treated TB patients. Among prisoners, MDR-TB rates were 21.8% (95%CI 12.4-31.2) in new cases and 52.8% (95%CI 43.9-61.7) in previously treated TB cases. HIV status was significantly associated with MDR-TB (OR 1.7, 95%CI 1.3-2.3). CONCLUSIONS: High MDR-TB rates and a positive association between MDR-TB and HIV epidemics were found in Donetsk Oblast. Urgent measures to improve HIV prevention, control of drug-resistant TB and collaboration between HIV and TB control activities need to be implemented without further delay.

Alarming levels of multidrug-resistant tuberculosis in Ukraine: results from the first national survey.

SETTING: The true prevalence of multidrug-resistant tuberculosis (MDR-TB) in Ukraine is not known. Available data are a decade old and limited to only one province. OBJECTIVE: To determine the prevalence of MDR-TB among new and previously treated TB cases in Ukraine and explore the risk factors associated with drug resistance. METHODS: A total of 1550 sputum smear-positive pulmonary TB patients were recruited from 40 clusters throughout Ukraine. Sputum specimens were examined using culture, drug susceptibility testing and pncA gene sequencing. RESULTS: The proportion of MDR-TB among new and previously treated TB cases was respectively 24.1% (95%CI 20.7-27.6) and 58.1% (95%CI 52.1-64.1). More than one third (38.0%) of MDR-TB or rifampicin (RMP) resistant cases showed resistance to either a fluoroquinolone (FQ) or a second-line injectable agent or both. Resistance to pyrazinamide and FQs was low in patients with RMP-susceptible TB. Among new TB cases, the odds of MDR-TB were higher among patients who were younger, female and living in south-eastern provinces, as well as among human immunodeficiency virus-positive patients who belonged to a low socio-economic group. CONCLUSIONS: Our study showed that the burden of MDR-TB in Ukraine was much greater than previously assumed. Urgent actions are needed to prevent further spread of drug-resistant TB in Ukraine.

Improving the quality of cohort analysis by incorporating treatment outcomes of 'transferred in' TB cases.

Treatment outcomes of patients with tuberculosis (TB) who move between TB units ('transferred out') are often not incorporated in the annual cohort analysis. Experience from Morocco shows that using a simple method, the outcomes of these patients, notified as 'transferred in' cases, can be easily taken into account when compiling the annual report on treatment outcomes. With this method the treatment success rate increased in Morocco by a median of 5.8% (range 5.0-6.7), indicating that the country reached the global target of curing at least 85% of the new smear-positive TB cases detected during the period 1995-2003.

Source of retreatment cases under the revised national TB control programme in Rajasthan, India, 2003.

BACKGROUND: Three years after state-wide DOTS coverage and achievement of global targets for detection and cure, the proportion of sputum-positive retreatment cases remained high in the north Indian state of Rajasthan. AIM: To determine source, accuracy of categorisation and treatment outcomes in Category II sputum-positive retreatment cases registered from January to March 2003 in five districts of Rajasthan. MATERIAL AND METHODS: Two hundred consecutive Category II sputum-positive retreatment cases were identified from the tuberculosis register and interviewed using a semi-structured questionnaire. RESULTS: Categorisation was correct in 195 (97.5%) of retreatment cases interviewed. Treatment after default (TAD) comprised 84.6% (165/195) of interviewees, with 13.3% (n = 26) relapses and 2.1% (n = 4) failure cases. Of the TAD cases, 84.8% (n = 140) had defaulted from previous treatment in the private sector. Only 6.1% (n = 10) had defaulted from Category II DOTS treatment. The most unfavourable treatment outcome seen amongst interviewees was default, as also described in the national data. CONCLUSION: TADs constituted the majority of interviewed retreatment cases (84.6%), and were overwhelmingly being generated by irregular treatment in the private sector. Further involvement of the private sector in the DOTS programme in Rajasthan is needed to stop the creation of further retreatment cases.

Results of cohort analysis by category of tuberculosis retreatment cases in Morocco from 1996 to 2003.

OBJECTIVE: To analyse treatment outcomes by subcategory of tuberculosis (TB) retreatment cases. METHODS: All TB patients treated with the Category II regimen from 1996 to 2003 in Morocco were enrolled in this retrospective study. For each cohort, the retreatment outcome data were analysed as a whole and by the following sub-categories: 1) cases who relapsed after one course of anti-tuberculosis treatment; 2) cases who failed the Category I regimen; and 3) cases who interrupted one course of anti-tuberculosis treatment. RESULTS: The study population included 14 635 retreatment patients, among whom 81.7% were TB relapse cases, 5.2% had failed the Category I regimen and 13.1% were defaulters. The average treatment success rates were respectively 74.8% (range 71.8-76.6), 58.0% (range 52.4-74.0) and 51.4% (range 46.4-55.6) among relapse, failure and default cases. Failure and default rates were significantly higher (P < 0.001) among patients who failed Category I treatment and among those who defaulted, respectively. CONCLUSIONS: TB cases who fail the Category I regimen should systematically receive drug susceptibility testing, while defaulters should be given support to improve treatment adherence. Stratified cohort analysis by subcategory of retreatment has been shown to be useful for evaluating the performance of TB control programmes.

Sputum smear microscopy result: a predictor for drug-resistant tuberculosis?

Until countries establish capacity for continuous surveillance systems, representative surveys of tuberculosis (TB) patients continue to improve our understanding of the burden of drug-resistant TB and help ensure appropriate allocation of resources. Although the available data are limited, the current recommendation of restricting surveys to sputum smear-positive patients is justified, given the greatly simplified logistics and only limited evidence in specific settings of an association between drug resistance and sputum smear status. Nonetheless, the relationship between drug resistance and sputum smear microscopy results may vary according to the setting and population under study. With the increasing availability and use of molecular diagnostics and the drive for universal drug susceptibility testing under the World Health Organization's End TB Strategy, substantially more data on drug resistance in the whole TB patient population should become available in the near future.