Drugs for treating infections caused by non-tubercular mycobacteria: a narrative review from the study group on mycobacteria of the Italian Society of Infectious Diseases and Tropical Medicine.

BACKGROUND: Non-tuberculous mycobacteria (NTM) are generally free-living organism, widely distributed in the environment, with sporadic potential to infect. In recent years, there has been a significant increase in the global incidence of NTM-related disease, spanning across all continents and an increased mortality after the diagnosis has been reported. The decisions on whether to treat or not and which drugs to use are complex and require a multidisciplinary approach as well as patients' involvement in the decision process. METHODS AND RESULTS: This review aims at describing the drugs used for treating NTM-associated diseases emphasizing the efficacy, tolerability, optimization strategies as well as possible drugs that might be used in case of intolerance or resistance. We also reviewed data on newer compounds highlighting the lack of randomised clinical trials for many drugs but also encouraging preliminary data for others. We also focused on non-pharmacological interventions that need to be adopted during care of individuals with NTM-associated diseases CONCLUSIONS: Despite insufficient efficacy and poor tolerability this review emphasizes the improvement in patients' care and the needs for future studies in the field of anti-NTM treatments.

Clinical standards for the diagnosis, treatment and prevention of TB infection.

BACKGROUND: Tuberculosis (TB) preventive therapy (TPT) decreases the risk of developing TB disease and its associated morbidity and mortality. The aim of these clinical standards is to guide the assessment, management of TB infection (TBI) and implementation of TPT.METHODS: A panel of global experts in the field of TB care was identified; 41 participated in a Delphi process. A 5-point Likert scale was used to score the initial standards. After rounds of revision, the document was approved with 100% agreement.RESULTS: Eight clinical standards were defined: Standard 1, all individuals belonging to at-risk groups for TB should undergo testing for TBI; Standard 2, all individual candidates for TPT (including caregivers of children) should undergo a counselling/health education session; Standard 3, testing for TBI: timing and test of choice should be optimised; Standard 4, TB disease should be excluded prior to initiation of TPT; Standard 5, all candidates for TPT should undergo a set of baseline examinations; Standard 6, all individuals initiating TPT should receive one of the recommended regimens; Standard 7, all individuals who have started TPT should be monitored; Standard 8, a TBI screening and testing register should be kept to inform the cascade of care.CONCLUSION: This is the first consensus-based set of Clinical Standards for TBI. This document guides clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage TBI.

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.

Therapeutic strategies and outcomes of MDR and pre-XDR-TB in Italy: a nationwide study.

BACKGROUND: Treatment outcomes in multidrug-resistant TB (MDR-TB) patients are suboptimal in several low-incidence countries.METHODS: The primary outcome measure was the proportion of successfully treated patients in Italy during an 18-year period. Secondary outcomes were treatment outcomes in certain drug-containing regimens and the possibility for the WHO shorter MDR-TB regimen.RESULTS: In the 191 patients included (median age at admission: 33 years; 67.5% male, following drug-resistance patterns were found: MDR-TB in 68.6%, pre-extensively drug-resistant TB (pre-XDR-TB) in 30.4% and XDR-TB in 1.1% patients. The most frequently prescribed drugs were fluoroquinolones in 84.6% cases, amikacin in 48.7%, linezolid in 34.6% and meropenem/clavulanic acid in 29.5%. The median duration of treatment was 18 months. Treatment success was achieved in 71.2% patients, of whom, 44% were cured and 27.2% completed treatment. Treatment success rates did not statistically differ between the MDR- (68.8%) and pre-XDR-TB (77.6%) groups (P = 0.26). Treatment success rates had large variability between North and South of Italy (81.3% vs. 53.3%). Only 22.5% of the cases would have been eligible for shorter MDR-TB regimensCONCLUSION: Our study highlights variability in treatment outcomes in MDR- and pre-XDR-TB patients. Study findings confirmed the potential utility of linezolid and, for patients with limited oral options, meropenem/clavulanic acid and amikacin.

Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and delamanid: Results from a large global cohort.

The World Health Organization (WHO) recommends countries introduce new anti-TB drugs in the treatment of multidrug-resistant tuberculosis. The aim of the study is to prospectively evaluate the effectiveness of bedaquiline (and/or delamanid)- containing regimens in a large cohort of consecutive TB patients treated globally. This observational, prospective study is based on data collected and provided by Global Tuberculosis Network (GTN) centres and analysed twice a year. All consecutive patients (including children/adolescents) treated with bedaquiline and/or delamanid were enrolled, and managed according to WHO and national guidelines. Overall, 52 centres from 29 countries/regions in all continents reported 883 patients as of January 31st 2021, 24/29 countries/regions providing data on 100% of their consecutive patients (10-80% in the remaining 5 countries). The drug-resistance pattern of the patients was severe (>30% with extensively drug-resistant -TB; median number of resistant drugs 5 (3-7) in the overall cohort and 6 (4-8) among patients with a final outcome). For the patients with a final outcome (477/883, 54.0%) the median (IQR) number of months of anti-TB treatment was 18 (13-23) (in days 553 (385-678)). The proportion of patients achieving sputum smear and culture conversion ranged from 93.4% and 92.8% respectively (whole cohort) to 89.3% and 88.8% respectively (patients with a final outcome), a median (IQR) time to sputum smear and culture conversion of 58 (30-90) days for the whole cohort and 60 (30-100) for patients with a final outcome and, respectively, of 55 (30-90) and 60 (30-90) days for culture conversion. Of 383 patients treated with bedaquiline but not delamanid, 284 (74.2%) achieved treatment success, while 25 (6.5%) died, 11 (2.9%) failed and 63 (16.5%) were lost to follow-up.

A systematic review and meta-analysis of first-line tuberculosis drug concentrations and treatment outcomes.

Low serum concentrations of first-line tuberculosis (TB) drugs have been widely reported. However, the impact of low serum concentrations on treatment outcome is less well studied. A systematic search of MEDLINE/Pubmed and the Cochrane Central Register of Controlled Trials up to 31 March 2018 was conducted for articles describing drug concentrations of first-line TB drugs and treatment outcome in adult patients with drug-susceptible TB. The search identified 3073 unique publication abstracts, which were reviewed for suitability: 21 articles were acceptable for inclusion in the qualitative analysis comprising 13 prospective observational cohorts, 4 retrospective observational cohorts, 1 case-control study and 3 randomised controlled trials. Data for meta-analysis were available for 15 studies, 13 studies of rifampicin (RMP), 10 of isoniazid (INH), 8 of pyrazinamide (PZA) and 4 of ethambutol (EMB). This meta-analysis revealed that low PZA concentration appears to increase the risk of poor outcomes (8 studies, n = 2727; RR 1.73, 95%CI 1.10-2.72), low RMP concentrations may slightly increase the risk of poor outcomes (13 studies, n = 2753; RR 1.40, 95%CI 0.91-2.16), whereas low concentrations of INH (10 studies, n = 2640; RR 1.32, 95%CI 0.66-2.63) and EMB (4 studies, n = 551; RR 1.12, 95%CI 0.41-3.05) appear to make no difference to treatment outcome. There was no significant publication bias or between-study heterogeneity in any of the analyses. The potential clinical impact of low concentrations of PZA and RMP warrants further evaluation. Also, comprehensive assessments of the complex pharmacokinetic-pharmacodynamic relationships in the treatment of TB are urgently needed.

Defining a migrant-inclusive tuberculosis research agenda to end TB.

BACKGROUND: Pillar 3 of the End TB Strategy calls for the promotion of research and innovation at the country level to facilitate improved implementation of existing and novel interventions to end tuberculosis (TB). In an era of increasing cross-border migration, there is a specific need to integrate migration-related issues into national TB research agendas. The objective of the present review is to provide a conceptual framework to guide countries in the development and operationalization of a migrant-inclusive TB research agenda. METHODS: We conducted a literature review, complemented by expert opinion and the previous articles in this State of the Art series, to identify important themes central to migration-related TB. We categorized these themes into a framework for a migration-inclusive global TB research agenda across a comprehensive spectrum of research. We developed this conceptual framework taking into account: 1) the biomedical, social and structural determinants of TB; 2) the epidemiologic impact of the migration pathway; and 3) the feasibility of various types of research based on a country's capacity. DISCUSSION: The conceptual framework presented here is based on the key principle that migrants are not inherently different from other populations in terms of susceptibility to known TB determinants, but that they often have exacerbated or additional risks related to their country of origin and the migration process, which must be accounted for in developing comprehensive TB prevention and care strategies. A migrant-inclusive research agenda should systematically consider this wider context to have the highest impact.

Policies and practices on the programmatic management of LTBI: a survey in the African Region.

BACKGROUND: Although the management of latent tuberculous infection (LTBI) is a core component of the End TB Strategy, there is limited information about the status of implementation of such interventions in most African countries. METHODS: A web-based survey involving the 47 countries of the African Region was conducted between November 2016 and April 2017. RESULTS: The questionnaire was completed by 32/47 (68.1%) National TB Programme managers or their delegates. LTBI guidelines were available in four countries (12.5%), while 13 (40.6%) had an LTBI section in their national TB guidelines; there was no significant association with socio-economic conditions and funding allocation. LTBI diagnosis was mostly based on clinical evaluation to rule out active disease, rather than on systematic use of the tuberculin skin test. Respectively 23 (71.8%) and 17 countries (53.1%) reported providing treatment to child contacts aged <5 years and people living with the human immunodeficiency virus (PLHIV). Over two thirds of respondent countries had ongoing activities targeting at least one of the aforementioned high-risk groups. A recording and reporting system for LTBI-related data on child contacts and PLHIV was available in respectively 14 and 12 countries; 7 countries had an LTBI monitoring and evaluation plan. CONCLUSIONS: These data suggest that greater effort is needed to appropriately scale up LTBI policies in the African Region.

Effectiveness and cost-effectiveness of screening migrants for active tuberculosis and latent tuberculous infection.

With the advent of the World Health Organization End TB strategy, there has been renewed interest in screening for active tuberculosis (TB), and particularly latent tuberculous infection (LTBI). In low-incidence countries, a high proportion of TB cases are notified among migrants, which often occurs due to LTBI reactivation. We aimed to review the effectiveness and cost-effectiveness of screening migrants for active TB LTBI to inform and support the TB elimination strategy in low-incidence countries. We carried out a narrative review of English language articles published between 1 January 2000 and 31 June 2016 using the PubMed database. All studies that described the effectiveness or cost-effectiveness of active TB or LTBI screening among migrants were included. We identified 55 studies, and included 40 for the effectiveness of screening, 11 for cost-effectiveness and 4 that reported both. Screening for active TB can be effective and cost-effective depending on the setting, target group and screening approach. Pre-entry screening programmes have some impact on the epidemiology of the receiving countries. The effectiveness and cost-effectiveness of LTBI screening as predicted in mathematical models is also highly setting-specific, with best potential results achieved if screening is restricted to high-risk groups and/or to migrants from high-burden countries.

Methodological considerations for economic modelling of latent tuberculous infection screening in migrants.

Tuberculosis (TB) in migrants from endemic to low-incidence countries results mainly from the reactivation of latent tuberculous infection (LTBI). LTBI screening policies for migrants vary greatly between countries, and the evidence on the cost-effectiveness of the different approaches is weak and heterogeneous. The aim of this review was to assess the methodology used in published economic evaluations of LTBI screening among migrants to identify critical methodological options that must be considered when using modelling to determine value for money from different economic perspectives. Three electronic databases were searched and 10 articles were included. There was considerable variation across this small number of studies with regard to economic perspective, main outcomes, modelling technique, screening options and target populations considered, as well as in parameterisation of the epidemiological situation, test accuracy, efficacy, safety and programme performance. Only one study adopted a societal perspective; others adopted a health care or wider government perspective. Parameters representing the cascade of screening and treating LTBI varied widely, with some studies using highly aspirational scenarios. This review emphasises the need for a more harmonised approach for economic analysis, and better transparency in how policy options and economic perspectives influence methodological choices. Variability is justifiable for some parameters. However, sufficient data are available to standardise others. A societal perspective is ideal, but can be challenging due to limited data. Assumptions about programme performance should be based on empirical data or at least realistic assumptions. Results should be interpreted within specific contexts and policy options, with cautious generalisations.

Cervical Human Papillomavirus genotypes in HIV-infected women: a cross-sectional analysis of the VALHIDATE study.

INTRODUCTION: Primary-prevention by prophylactic vaccination against HPV-related cancers and HPV-based screening programs are based on HPV-type distribution in immunocompetent individuals. HIV-infected women are at high risk of invasive HPV-disease sustained by a broader range of HPV-types and have higher multi-type infection rates than immunocompetent hosts. METHODS: This is a cross-sectional analysis of High Risk HPV (HR HPV) type distribution in 805 HIV+ women (HIW) compared with a control group of 1402 immunocompetent HIV- women (SPW) enrolled in the VALHIDATE study in order to define HPV type-specific distribution according to cytology. RESULTS: HIW had a 3.8, 3.6, and 2.7 times higher risk of atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL) and high grade squamous intraepithelial lesion (HSIL) than SPW respectively. HPV-DNA prevalence was 28.4% in HIW and 11.81% in SPW (p<0.0001). The prevalence of infection increased from normal cytology to HSIL both in HIW (from 21.45% to 90.91%) and SPW (from 9.54% to 75%). The OR for women with normal cytology of having a positive HPV-DNA test result of was 2.6 times higher in HIW than in SPW. The cumulative prevalence of HPV-16/18 in HSIL is much lower in HIW (36.4±28.4) than SPW (62.5±33.5). CONCLUSIONS: A higher prevalence of infection and broader HPV type distribution were observed in HIV+ women compared to the general population. More than 60% of HSIL lesions of HIW patients are caused by single or multi-type infections from non-HPV16/18 HPVs. The potential 9v-HPV vaccine coverage could be even higher than that expected for the general population given the wide panel of HPV-types observed in the HSIL of HIV+ women.

Policies and practices on the programmatic management of latent tuberculous infection: global survey.

SETTING: Global survey among low tuberculosis (TB) burden countries, which are primary target countries for the World Health Organization (WHO) guidelines on the programmatic management of latent tuberculous infection (LTBI). OBJECTIVE: To perform a baseline assessment of policies and practices for the programmatic management of LTBI. DESIGN: Online and paper-based pre-tested questionnaire filled out by national TB programme managers or their equivalents from 108 countries. RESULTS: Of 74 respondent countries, 75.7% (56/74) had a national policy on LTBI. The majority of the countries (67/74, 90.5%) provided LTBI testing and treatment for child contacts of TB cases, while almost two thirds (49/74, 66%) reported provision of LTBI testing and treatment to people living with the human immunodeficiency virus (PLHIV). Six countries (8.1%) did not report providing LTBI management to child contacts and PLHIV. Among countries that reported both the availability of policy and practice of testing and treatment of LTBI for at-risk populations, a system for recording and reporting data was available in 62% (33/53) for child contacts and in 53% (21/40) for PLHIV. CONCLUSION: Countries need to ensure that national LTBI policies and a standardised monitoring and evaluation system are in place to promote the programmatic management of LTBI.

Active tuberculosis case finding among pregnant women: a pilot project in Burkina Faso.

Tuberculosis (TB) is a leading cause of death among women of childbearing age, and may be responsible for severe complications during pregnancy. Between August 2014 and March 2015, we conducted a pilot project to promote active TB case finding in antenatal care (ANC) clinics in the Central Region of Burkina Faso. Our results show very limited TB diagnostic practices and possible severe underdiagnosis of TB at ANC clinics, despite adequate screening practices. Integration of training and supervision of TB diagnosis and treatment into ANC services is required.

Rifampicin resistance after treatment for latent tuberculous infection: a systematic review and meta-analysis.

SETTING: Treatment for latent tuberculous infection (LTBI) reduces the risk of tuberculosis (TB) disease. Shorter, rifamycin-containing regimens have been shown to be as effective as 6 months of isoniazid and superior with regard to safety and completion rate. It is unknown whether preventive therapy with rifamycins increases resistance to the drugs used. OBJECTIVE: To determine whether treatment for LTBI with rifamycin-containing regimens leads to significant development of resistance against rifamycins. DESIGN: Systematic review and meta-analysis. RESULTS: We included six randomised-controlled trials of rifamycin-containing regimens for LTBI treatment that reported drug resistance. There was no statistically significant increased risk of rifamycin resistance after LTBI treatment with rifamycin-containing regimens compared to non-rifamycin-containing regimens (RR 3.45, 95%CI 0.72-16.56; P = 0.12) or placebo (RR 0.20, 95%CI 0.02-1.66; P = 0.13). CONCLUSION: Preventive treatment with rifamycin-containing regimens does not significantly increase rifamycin resistance. Programmatic management of LTBI requires the creation of sound surveillance systems to monitor drug resistance.

Major differences in organization and availability of health care and medicines for HIV/TB coinfected patients across Europe.

OBJECTIVES: The aim of the study was to investigate the organization and delivery of HIV and tuberculosis (TB) health care and to analyse potential differences between treatment centres in Eastern (EE) and Western Europe (WE). METHODS: Thirty-eight European HIV and TB treatment centres participating in the TB:HIV study within EuroCoord completed a survey on health care management for coinfected patients in 2013 (EE: 17 respondents; WE:21; 76% of all TB:HIV centres). Descriptive statistics were obtained for regional comparisons. The reported data on health care strategies were compared with actual clinical practice at patient level via data derived from the TB:HIV study. RESULTS: Respondent centres in EE comprised: Belarus (n = 3), Estonia (1), Georgia (1), Latvia (1), Lithuania (1), Poland (4), Romania (1), the Russian Federation (4) and Ukraine (1); those in WE comprised: Belgium (1), Denmark (1), France (1), Italy (7), Spain (2), Switzerland (1) and UK (8). Compared with WE, treatment of HIV and TB in EE are less often located at the same site (47% in EE versus 100% in WE; P < 0.001) and less often provided by the same doctors (41% versus 90%, respectively; P = 0.002), whereas regular screening of HIV-infected patients for TB (80% versus 40%, respectively; P = 0.037) and directly observed treatment (88% versus 20%, respectively; P < 0.001) were more common in EE. The reported availability of rifabutin and second- and third-line anti-TB drugs was lower, and opioid substitution therapy (OST) was available at fewer centres in EE compared with WE (53% versus 100%, respectively; P < 0.001). CONCLUSIONS: Major differences exist between EE and WE in relation to the organization and delivery of health care for HIV/TB-coinfected patients and the availability of anti-TB drugs and OST. Significant discrepancies between reported and actual clinical practices were found in EE.

The impact of Xpert® MTB/RIF depends on service coordination: experience in Burkina Faso.

Translating the potential of Xpert(®) MTB/RIF into more effective tuberculosis (TB) care and control in low-income settings is challenged by operational issues. We report the experience in introducing this technology in Burkina Faso through a centralised approach. Xpert was successfully integrated into the diagnostic algorithm of multidrug-resistant TB cases. However, barriers to Xpert use for the diagnosis of TB in vulnerable populations, such as persons living with human immunodeficiency virus infection and children, were observed, mainly due to lack of coordination between services. Lessons learnt can be exploited to optimise the roll-out of this technology at country level.

Latent tuberculous infection: ethical considerations in formulating public health policy.

There is increasing interest in the introduction of public health policies relating to latent tuberculous infection (LTBI). However, there has been little previous systematic engagement with LTBI from an ethical perspective. This article offers a general overview of ethical issues in relation to LTBI, with particular focus on those aspects relevant to the development and implementation of public health policy. Key characteristics of LTBI are discussed from an ethical perspective, with examples of challenging situations for policy makers.