#TB, #HIV, and viral #hepatitis #diagnostics in eastern #Europe and central #Asia: high time for integrated and people-centred services (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Tuberculosis, HIV, and viral hepatitis diagnostics in eastern Europe and central Asia: high time for integrated and people-centred services

Masoud Dara, MD  †, Soudeh Ehsani, MD, Antons Mozalevskis, MD, Elena Vovc, MD, Daniel Simões, MPH, Ana Avellon Calvo, PhD, Jordi Casabona i Barbarà, PhD, Otar Chokoshvili, MPH, Irina Felker, PhD, Sven Hoffner, PhD, Gulmira Kalmambetova, PhD, Ecatarina Noroc, MD, Natalia Shubladze, PhD, Alena Skrahina, MD, Rasim Tahirli, MD, Prof Tengiz Tsertsvadze, PhD,

Published: November 15, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30524-9

 

Summary

Globally, high rates (and in the WHO European region an increasing prevalence) of co-infection with tuberculosis and HIV and HIV and hepatitis C virus exist. In eastern European and central Asian countries, the tuberculosis, HIV, and viral hepatitis programmes, including diagnostic services, are separate vertical structures. In this Personal View, we consider underlying reasons for the poor integration for these diseases, particularly in the WHO European region, and how to address this with an initial focus on diagnostic services. In part, this low integration has reflected different diagnostic development histories, global funding sources, and sample types used for diagnosis (eg, typically sputum for tuberculosis and blood for HIV and hepatitis C). Cooperation between services improved as patients with tuberculosis needed routine testing for HIV and vice versa, but financial, infection control, and logistical barriers remain. Multidisease diagnostic platforms exist, but to be used optimally, appropriate staff training and sensible understanding of different laboratory and infection control risks needs rapid implementation. Technically these ideas are all feasible. Poor coordination between these vertical systems remains unhelpful. There is a need to increase political and operational integration of diagnostic and treatment services and bring them closer to patients.

Keywords: Public Health; European Region; TB; HIV/AIDS; Viral hepatitis.

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#Bedaquiline, #moxifloxacin, #pretomanid, and #pyrazinamide during the first 8 weeks of #treatment of patients with drug-susceptible or drug-resistant #pulmonary #TB:… (Lancet Resp Med., abstract)

[Source: The Lancet Respiratory Medicine, full page: (LINK). Abstract, edited.]

Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial

Conor D Tweed, MD, Rodney Dawson, MD, Divan A Burger, PhD, Almari Conradie, MPharm, Angela M Crook, PhD, Carl M Mendel, MD, Francesca Conradie, MBBCh, Andreas H Diacon, MD, Nyanda E Ntinginya, PhD, Daniel E Everitt, MD, Frederick Haraka, MD, Mengchun Li, MD, Christo H van Niekerk, MD, Alphonse Okwera, PhD, Mohammed S Rassool, MBChB, Klaus Reither, PhD, Modulakgotla A Sebe, MBChB, Suzanne Staples, MPhil, Ebrahim Variava, MD, Melvin Spigelman, MD

Open Access / Published: November 12, 2019 / DOI: https://doi.org/10.1016/S2213-2600(19)30366-2

 

Summary

Background

New anti-tuberculosis regimens that are shorter, simpler, and less toxic than those that are currently available are needed as part of the global effort to address the tuberculosis epidemic. We aimed to investigate the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in the first 8 weeks of treatment of pulmonary tuberculosis.

Methods

In this multicentre, open-label, partially randomised, phase 2b trial, we prospectively recruited patients with drug-susceptible or rifampicin-resistant pulmonary tuberculosis from seven sites in South Africa, two in Tanzania, and one in Uganda. Patients aged 18 years or older with sputum smear grade 1+ or higher were eligible for enrolment, and a molecular assay (GeneXpert or MTBDRplus) was used to confirm the diagnosis of tuberculosis and to distinguish between drug-susceptible and rifampicin-resistant tuberculosis. Patients who were HIV positive with a baseline CD4 cell count of less than 100 cells per uL were excluded. Patients with drug-susceptible tuberculosis were randomly assigned (1:1:1) using numbered treatment packs with sequential allocation by the pharmacist to receive 56 days of treatment with standard tuberculosis therapy (oral isoniazid, rifampicin, pyrazinamide, and ethambutol; HRZE), or pretomanid (oral 200 mg daily) and pyrazinamide (oral 1500 mg daily) with either oral bedaquiline 400 mg daily on days 1–14 then 200 mg three times per week (BloadPaZ) or oral bedaquiline 200 mg daily (B200PaZ). Patients with rifampicin-resistant tuberculosis received 56 days of the B200PaZ regimen plus moxifloxacin 400 mg daily (BPaMZ). All treatment groups were open label, and randomisation was not stratified. Patients, trial investigators and staff, pharmacists or dispensers, laboratory staff (with the exception of the mycobacteriology laboratory staff), sponsor staff, and applicable contract research organisations were not masked. The primary efficacy outcome was daily percentage change in time to sputum culture positivity (TTP) in liquid medium over days 0–56 in the drug-susceptible tuberculosis population, based on non-linear mixed-effects regression modelling of log10 (TTP) over time. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, NCT02193776, and all patients have completed follow-up.

Findings

Between Oct 24, 2014, and Dec 15, 2015, we enrolled 180 patients with drug-susceptible tuberculosis (59 were randomly assigned to BloadPaZ, 60 to B200PaZ, and 61 to HRZE) and 60 patients with rifampicin-resistant tuberculosis. 57 patients in the BloadPaZ group, 56 in the B200PaZ group, and 59 in the HRZE group were included in the primary analysis. B200PaZ produced the highest daily percentage change in TTP (5·17% [95% Bayesian credibility interval 4·61–5·77]), followed by BloadPaZ (4·87% [4·31–5·47]) and HRZE group (4·04% [3·67–4·42]). The bactericidal activity in B200PaZ and BloadPaZ groups versus that in the HRZE group was significantly different. Higher proportions of patients in the BloadPaZ (six [10%] of 59) and B200PaZ (five [8%] of 60) groups discontinued the study drug than in the HRZE group (two [3%] of 61) because of adverse events. Liver enzyme elevations were the most common grade 3 or 4 adverse events and resulted in the withdrawal of ten patients (five [8%] in the BloadPaZ group, three [5%] in the B200PaZ group, and two [3%] in the HRZE group). Serious treatment-related adverse events affected two (3%) patients in the BloadPaZ group and one (2%) patient in the HRZE group. Seven (4%) patients with drug-susceptible tuberculosis died and four (7%) patients with rifampicin-resistant tuberculosis died. None of the deaths were considered to be related to treatment.

Interpretation

B200PaZ is a promising regimen to treat patients with drug-susceptible tuberculosis. The bactericidal activity of both these regimens suggests that they have the potential to shorten treatment, and the simplified dosing schedule of B200PaZ could improve treatment adherence in the field. However, these findings must be investigated further in a phase 3 trial assessing treatment outcomes.

Funding

TB Alliance, UK Department for International Development, Bill & Melinda Gates Foundation, US Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and the Federal Ministry for Education and Research of Germany.

Keywords: Tuberculosis; Antibiotics; Drugs Resistance; Bedaquiline; Moxifloxacin; Pretomanid; Pyrazinamide.

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Pre-detection history of #XDR #tuberculosis in #KwaZulu-Natal, South Africa (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Pre-detection history of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa

Tyler S. Brown, Lavanya Challagundla, Evan H. Baugh, Shaheed Vally Omar, Arkady Mustaev, Sara C. Auld, N. Sarita Shah, Barry N. Kreiswirth, James C. M. Brust, Kristin N. Nelson, Apurva Narechania, Natalia Kurepina, Koleka Mlisana, Richard Bonneau, Vegard Eldholm, Nazir Ismail, Sergios-Orestis Kolokotronis, D. Ashley Robinson, Neel R. Gandhi, and Barun Mathema

PNAS first published October 28, 2019 / DOI: https://doi.org/10.1073/pnas.1906636116

Edited by Erwin Schurr, McGill University, Montreal, QC, Canada, and accepted by Editorial Board Member Carl F. Nathan October 3, 2019 (received for review April 17, 2019)

 

Significance

Epidemics of AMR pathogens are often only identified years or decades after they first evolved and distant from their place of origin. Consequently, evidence-based strategies for early containment of AMR epidemics are limited. This study employs whole-genome sequence data to reconstruct the “pre-detection” evolutionary and epidemiological history of an extensively drug-resistant Mycobacterium tuberculosis strain in KwaZulu-Natal, South Africa. We localize the geographic origin of this strain to an area hundreds of kilometers away from where the first clinical cases were reported and identify key host- and pathogen-specific factors that contributed to the rise of this important threat to global tuberculosis control. We propose that similar strategies can support the early identification and containment of AMR pathogens in the future.

 

Abstract

Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant Mycobacterium tuberculosis (Mtb) strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or public health surveillance, can inform strategies for prevention and containment. In this study, we employ whole-genome sequence (WGS) data from TB clinical isolates collected in KwaZulu-Natal, South Africa to examine the pre-detection history of a successful strain of extensively drug-resistant (XDR) TB known as LAM4/KZN, first identified in a widely reported cluster of cases in 2005. We identify marked expansion of this strain concurrent with the onset of the generalized HIV epidemic 12 y prior to 2005, localize its geographic origin to a location in northeastern KwaZulu-Natal ∼400 km away from the site of the 2005 outbreak, and use protein structural modeling to propose a mechanism for how strain-specific rpoB mutations offset fitness costs associated with rifampin resistance in LAM4/KZN. Our findings highlight the importance of HIV coinfection, high preexisting rates of drug-resistant TB, human migration, and pathoadaptive evolution in the emergence and dispersal of this critical public health threat. We propose that integrating whole-genome sequencing into routine public health surveillance can enable the early detection and local containment of AMR pathogens before they achieve widespread dispersal.

infectious disease – epidemics – tuberculosis – antimicrobial resistance – population genetics

Keywords: Antibiotics; Drugs Resistance; Rifampin; XDR-TB; Mycobacterium tuberculosis; TB; South Africa.

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Long-term #survival and cause-specific #mortality of #patients newly diagnosed with #tuberculosis in São Paulo state, #Brazil, 2010–15: a population-based, longitudinal study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Long-term survival and cause-specific mortality of patients newly diagnosed with tuberculosis in São Paulo state, Brazil, 2010–15: a population-based, longitudinal study

Otavio T Ranzani, PhD, Prof Laura C Rodrigues, PhD, Sidney Bombarda, PhD, Cátia M Minto, MSc, Prof Eliseu A Waldman, PhD, Prof Carlos R R Carvalho, PhD

Open Access / Published: October 29, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30518-3

 

Summary

Background

Long-term survival and cause-specific mortality of patients who start tuberculosis treatment is rarely described. We aimed to assess the long-term survival of these patients and evaluate the association between vulnerable conditions (social, health behaviours, and comorbidities) and cause-specific mortality in a country with a high burden of tuberculosis.

Methods

In this population-based, longitudinal study in São Paulo state, Brazil, we described the 5-year survival of patients who were newly diagnosed with tuberculosis in 2010. We included patients with newly-diagnosed tuberculosis, aged 15 years or older, and notified to the São Paulo State Tuberculosis Program in 2010. We excluded patients whose diagnosis had changed during follow-up (ie, they did not have tuberculosis) and patients who had multidrug-resistant (MDR) tuberculosis. We selected our population with tuberculosis from the dedicated electronic system TBweb. Our primary objective was to estimate the excess mortality over 5 years and within the group who survived the first year, compared with the general São Paulo state population. We also estimated the association between social vulnerability (imprisonment and homelessness), health behaviours (alcohol and drug use), and comorbidities (diabetes and mental disorders) with all-cause and cause-specific mortality. We used the competing risk analysis framework, estimating cause-specific hazard ratios (HRs) adjusted for potential confounding factors.

Findings

In 2010, there were 19 252 notifications of tuberculosis cases. We excluded 550 cases as patients were younger than 15 years, 556 cases that were not tuberculosis, 2597 retreatments, and 48 cases of MDR tuberculosis, resulting in a final cohort of 15 501 patients with tuberculosis. Over a period of 5 years from tuberculosis diagnosis, 2660 (17%) of 15 501 patients died. Compared with the source population, matched by age, sex, and calendar year, the standardised mortality ratio was 6·47 (95% CI 6·22–6·73) over 5 years and 3·93 (3·71–4·17) among those who survived the first year. 1197 (45%) of 2660 deaths were due to infection. Homelessness and alcohol and drug use were associated with death from infection (adjusted cause-specific HR 1·60, 95% CI 1·39–1·85), cardiovascular (1·43, 1·06–1·95), and external or ill-defined causes of death (1·80, 1·37–2·36). Diabetes was associated with deaths from cardiovascular causes (1·70, 1·23–2·35).

Interpretation

Patients newly diagnosed with tuberculosis were at a higher risk of death than were the source population, even after tuberculosis treatment. Post-tuberculosis sequelae and vulnerability are associated with excess mortality and must be addressed to mitigate the tuberculosis burden worldwide.

Funding

Wellcome Trust.

Keywords: Tuberculosis; Antibiotics; Drugs Resistance; Society; Poverty; Brazil.

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#Prevalence of #Tuberculosis in #Children After Natural #Disasters, Bohol, #Philippines (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 10—October 2019 / Research

Prevalence of Tuberculosis in Children After Natural Disasters, Bohol, Philippines

Kristy O. Murray, Nina T. Castillo-Carandang, Anna M. Mandalakas, Andrea T. Cruz, Lauren M. Leining, Salvacion R. Gatchalian  , and on behalf of the PEER Health Bohol Pediatric Study Team

Author affiliations: Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA (K.O. Murray, A.M. Mandalakas, A.T. Cruz, L.M. Leining); University of the Philippines, Manila, Philippines (N.T. Castillo-Carandang, S.R. Gatchalian)

 

Abstract

In 2013, a severe earthquake and typhoon affected Bohol, Philippines. To assess the postdisaster risk for emergence of Mycobacterium tuberculosis infection in children, we conducted a cross-sectional multistage cluster study to estimate the prevalence of tuberculin skin test (TST) positivity and tuberculosis (TB) in children from 200 villages in heavily affected and less affected disaster areas. Of the 5,476 children we enrolled, 355 were TST-positive (weighted prevalence 6.4%); 16 children had active TB. Fourteen (7%) villages had >20% TST-positive prevalence. Although prevalence did not differ significantly between heavily affected and less affected areas, living in a shelter with >25 persons approached significance. TST positivity was independently associated with older age, prior TB treatment, known contact with a person with TB, and living on a geographically isolated island. We found a high TST-positive prevalence, suggesting that national programs should consider the differential vulnerability of children and the role of geographically isolated communities in TB emergence.

Keywords: Environmental disasters; Tuberculosis; Philippines; Pediatrics.

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Targeting innate #immunity for #tuberculosis #vaccination (J Clin Invest., abstract)

[Source: Journal of Clinical Investigation, full page: (LINK). Abstract, edited.]

Targeting innate immunity for tuberculosis vaccination

Shabaana A. Khader, Maziar Divangahi, Willem Hanekom, Philip C. Hill, Markus Maeurer, Karen W. Makar, Katrin D. Mayer-Barber, Musa M. Mhlanga, Elisa Nemes, Larry S. Schlesinger, Reinout van Crevel, Ramakrishna Vankalayapati, Ramnik J. Xavier, Mihai G. Netea, and on behalf of the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group

First published September 3, 2019

 

Abstract

Vaccine development against tuberculosis (TB) is based on the induction of adaptive immune responses endowed with long-term memory against mycobacterial antigens. Memory B and T cells initiate a rapid and robust immune response upon encounter with Mycobacterium tuberculosis, thus achieving long-lasting protection against infection. Recent studies have shown, however, that innate immune cell populations such as myeloid cells and NK cells also undergo functional adaptation after infection or vaccination, a de facto innate immune memory that is also termed trained immunity. Experimental and epidemiological data have shown that induction of trained immunity contributes to the beneficial heterologous effects of vaccines such as bacille Calmette-Guérin (BCG), the licensed TB vaccine. Moreover, increasing evidence argues that trained immunity also contributes to the anti-TB effects of BCG vaccination. An interaction among immunological signals, metabolic rewiring, and epigenetic reprogramming underlies the molecular mechanisms mediating trained immunity in myeloid cells and their bone marrow progenitors. Future studies are warranted to explore the untapped potential of trained immunity to develop a future generation of TB vaccines that would combine innate and adaptive immune memory induction.

Keywords: Tuberculosis; Vaccines.

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#Effectiveness of pre-entry active #tuberculosis and post-entry latent tuberculosis #screening in new entrants to the #UK: a retrospective, population-based cohort study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Effectiveness of pre-entry active tuberculosis and post-entry latent tuberculosis screening in new entrants to the UK: a retrospective, population-based cohort study

Luis C Berrocal-Almanza, PhD, Ross Harris, MSc, Maeve K Lalor, PhD, Morris C Muzyamba, PhD, John Were, MPH, Anne-Marie O’Connell, MSc, Adil Mirza, MSc, Prof Onn-Min Kon, MD, Prof Ajit Lalvani, DM  †, Dominik Zenner, MD †

Published: August 27, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30260-9

 

Summary

Background

Evaluating interventions that might lead to a reduction in tuberculosis in high-income countries with a low incidence of the disease is key to accelerate progress towards its elimination. In such countries, migrants are known to contribute a large proportion of tuberculosis cases to the burden. We assessed the effectiveness of screening for active tuberculosis before entry to the UK and for latent tuberculosis infection (LTBI) post-entry for reduction of tuberculosis in new-entrant migrants to the UK. Additionally, we investigated the effect of access to primary care on tuberculosis incidence in this population.

Methods

We did a retrospective, population-based cohort study of migrants from 66 countries who were negative for active tuberculosis at pre-entry screening between Jan 1, 2011, and Dec 31, 2014, and eligible for LTBI screening. We used record linkage to track their first contact with primary care, uptake of LTBI screening, and development of active tuberculosis in England, Wales, and Northern Ireland. To assess the effectiveness of the pre-entry screening programme, we identified a control group of migrants who were not screened for active tuberculosis using the specific code for new entrants to the UK registering in primary care within the National Health Service patient registration data system. Our primary outcome was development of active tuberculosis notified to the National Enhanced Tuberculosis Surveillance System.

Findings

Our cohort comprised 224 234 migrants who were screened for active tuberculosis before entry to the UK and a control group of 118 738 migrants who were not. 103 990 (50%) migrants who were screened for active tuberculosis registered in primary care; all individuals in the control group were registered in primary care. 1828 tuberculosis cases were identified during the cohort time, of which 31 were prevalent. There were 26 incident active tuberculosis cases in migrants with no evidence of primary care registration, and 1771 cases in the entire cohort of migrants who registered in primary care (n=222 728), giving an incidence rate of 174 (95% CI 166–182) per 100 000 person-years. 672 (1%) of 103 990 migrants who were screened for active tuberculosis went on to develop tuberculosis compared with 1099 (1%) of 118 738 not screened for active tuberculosis (incidence rate ratio [IRR] 1·49, 95% CI 1·33–1·67; p<0·0001). 2451 (1%) of the 222 728 migrants registered in primary care were screened for LTBI, of whom 421 (17%) tested positive and 1961 (80%) tested negative; none developed active tuberculosis within the observed time period. Migrants settling in the least deprived areas had a decreased risk of developing tuberculosis (IRR 0·74, 95% CI 0·62–0·89; p=0·002), and time from UK arrival to primary care registration of 1 year or longer was associated with increased risk of active tuberculosis (2·96, 2·59–3·38; p<0·0001).

Interpretation

Pre-entry tuberculosis screening, early primary care registration, and LTBI screening are strongly and independently associated with a lower tuberculosis incidence in new-entrant migrants.

Funding

National Institute for Health Research (NIHR) Health Protection Research Unit in Respiratory Infections and NIHR Imperial Biomedical Research Centre.

Keywords: Tuberculosis; Migrants; UK.

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