Gene Signature Blood Test Can Diagnose TB and Treatment Response

MedicalResearch.com Interview with:
"Mycobacterium tuberculosis Bacteria, the Cause of TB" by NIAID is licensed under CC BY 2.0Purvesh Khatri, Ph.D.
Associate Professor
Stanford Institute for Immunity, Transplantation and Infection (ITI)
Stanford Center for Biomedical Informatics Research (BMIR)
Department of Medicine
Stanford University
Stanford, CA 94305

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We have previously described a 3-gene signature for distinguishing patients with active tuberculosis (ATB) from those with other diseases, latent mycobacterium tuberculosis (LTB) infection, and healthy controls (Sweeney et al. Lancet Respir Med 2016).

The current study in JAMA Network Open is a follow up study to validate the 3-gene signature in 3 additional independent cohorts that were prospectively collected.

Using these 3 cohorts we have now showed that the 3-gene signature

(1) can identify patients with LTB that will progress to ATB about 6 months prior to diagnosis of active tuberculosis.

(2) can identify patients with ATB in active screening, and

(3) can identify patients with ATB at diagnosis that have higher likelihood of persistent lung inflammation due to subclinical ATB at the end of treatment.  Continue reading

Trained Rats Detect TB Better Than Microscopy

MedicalResearch.com Interview with:

Howard Burditt / Reuters The rats have been used to to detect land mines in Africa.

Howard Burditt / Reuters
The rats have been used to to detect land mines in Africa.

Georgies Mgode PhD
Sokoine University of Agriculture
Pest Management Centre
African Centre of Excellence for Innovative Rodent Pest Management and Biosensor Technology Development
Morogoro, Tanzania

MedicalResearch.com: What is the background for this study?

Response: The background of this study is the APOPO and Sokoine University of Agriculture together with NIMR and NTLP interest to explore a cheap, reliable and sustainable means of addressing TB problem in high-burden countries with limited access to advanced sensitive tests. This refers to countries where to-date TB diagnosis is mainly by microscopy that is less sensitive leaving majority of patients undetected. We were driven to explore how these rats can contribute to diagnosis of TB in children that is known to be difficult and rats are known to have a better and advanced sense of smell. According to WHO ” an estimated 1 million children became ill with TB and 250 000 children died of TB in 2016 and the actual burden of TB in children is likely higher given the challenge in diagnosing childhood TB.  Continue reading

New Test for TB Can Detect Antibiotic Resistant Strains

MedicalResearch.com Interview with:

Susan E. Dorman, M.D Associate Professor of Medicine, Division of Infectious Diseases Johns Hopkins University School of Medicine, Baltimore

Dr. Dorman

Susan E. Dorman, M.D
Associate Professor of Medicine, Division of Infectious Diseases
Johns Hopkins University School of Medicine, Baltimore

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Tuberculosis, also called “TB” is one of the top 10 causes of death worldwide, according to the World Health Organization.  TB is caused by bacteria called Mycobacterium tuberculosis.  In 2015, over 10 million people became sick from TB and 1.8 million people died from TB.  This is a lot of people – diagnosing and treating TB to improve their health is important.  Because TB usually involves the lungs, it can be passed from person to person through the air, and thus, diagnosing and treating TB is critical to  reduce the spread of TB.   Drug-resistant TB — TB caused by bacteria that are resistant to commonly used TB antibiotics — is a serious problem.  In 2015 an estimated 480,000 people had multidrug-resistant TB.

We have been working to develop better, faster ways to diagnose TB and drug-resistant TB.  A new test was developed as a partnership between Rutgers University and Cepheid (Sunnyvale, CA), and development was supported by the US National Institutes of Health (NIH).  The new test was designed to detect Mycobacterium tuberculosis bacteria in sputum, and to simultaneously detect whether the bacteria are resistant to several of the main antibiotics (isoniazid, fluoroquinolones, and aminoglycosides) used to treat TB.  The test takes about two hours from sample to result.

The NEJM article describes the results of a study that was undertaken in China and South Korea to understand how well the new test works, compared against gold standard tests.

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Directly Observed Therapy Linked To Lower Mortality In Multi-Drug Resistant TB

MedicalResearch.com Interview with:
Dr. Jorge Salinas MD
Epidemic intelligence service officer
Division of Tuberculosis Elimination
Centers for Disease Control and Prevention 

MedicalResearch.com: What is the background for this study?

Response: Because multidrug-resistant TB (MDR TB) treatment regimens are less effective, more complex, and are more likely to have side effects that are difficult to tolerate than regimens for drug-susceptible TB, patients with MDR TB are at a higher risk of dying. Directly observed therapy (a therapy by which patients meet with a healthcare worker at a regularly scheduled time and place so the healthcare worker can observe the patient taking their TB medication) is recommended to treat all forms of TB disease, including MDR TB.

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New Technology Can Quickly Detect TB and Evaluate Therapeutic Efficacy

MedicalResearch.com Interview with:

Ying Kong Ph.D. Assistant Professor University of Tennessee Health Science Center Department of Microbiology, Immunology, and Biochemistry Memphis, TN 38163

Dr. Ying Kong

Ying Kong Ph.D.
Assistant Professor
University of Tennessee Health Science Center
Department of Microbiology, Immunology, and Biochemistry
Memphis, TN 38163

MedicalResearch.com: What is the background for this study?

Response: Tuberculosis (TB) is a public health concern worldwide, with high morbidity and mortality. The causative agent of TB, M. tuberculosis, grows very slowly in culture. For research of TB, we need to quantitate bacterial numbers in order to evaluate drug and vaccine efficacy or to identify bacterial genes that are critical for survival in hosts or causing disease.

M. tuberculosis divides every ~20 hours, which is much slower than other bacteria such as E. coli and Salmonella typhimurium, which divide every 20 minutes. Conventionally, quantitation of M. tuberculosis needs to spread M. tuberculosis on agar plates and wait for four weeks to obtain visible colonies, and then to count colony forming units. For the fast-growing bacteria, it takes only 18 hours to obtain visible colonies on agar plates. We and other groups have developed fluorescent protein labeled M. tuberculosis strains in order to quantitate M. tuberculosis in real time by measuring fluorescence. In this way, we are able to estimate bacterial number right after fluorescence measurement, which only takes a few minutes. However, this technology is not a diagnostic tool for clinical use, because the M. tuberculosis strains that we used were recombinant strains transformed with fluorescent protein genes. Another imaging technology that we have developed, REF, is for diagnosis purpose, which has been described in details in our other papers (Xie H, et al. Rapid point-of-care detection of the tuberculosis pathogen using a BlaC-specific fluorogenic probe. Nat Chem. 2012 Oct;4(10):802-9. Cheng Y, et al. Fluorogenic probes with substitutions at the 2 and 7 positions of cephalosporin are highly BlaC-specific for rapid Mycobacterium tuberculosis detection. Angew Chem Int Ed Engl. 2014 Aug 25;53(35):9360-4.).

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Cures of Multidrug Resistant Tuberculosis Probably Underestimated Under Current WHO Guidelines

MedicalResearch.com Interview with:
Dr. Heinke Kunst, M.D.
Queen Mary University Hospital, London, United Kingdom

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Multidrug resistant tuberculosis (MDR-TB) has been on the increase worldwide over the past decade. Many patients who have been identified with MDR-TB live in the European region. Despite treatment with expensive second-line drug regimens, curing MDR TB remains a challenge and cure rates were thought to be very low. As part of the EU Commission funded TB-PANNET project 380 patients with MDR-TB were observed at 23 TB centers in countries of high, intermediate and low TB burden in Europe over a period of 5 years. Observation started from the time of diagnosis and lasted until one year after the end of the treatment.

The TBNET proposed new definitions for “cure” and “failure” of MDR-TB treatment based on the sputum culture status at 6 month after the initiation of therapy and whether patients were free from disease recurrence one year after the end of therapy. The researchers found that the WHO criterion for “cure” could not be applied in the majority of patients, simply because most patients who were being treated successfully were not able to produce sputum after 8 months of therapy. The TB-PANNET study showed much higher cure rates using a new definition of cure and failure of treatment for MDR TB in the European region. (61% cure rates compared to only 31% when using WHO criteria.)

The study also demonstrates that the results for “cure” from MDR-TB correlate very well with the level of drug resistance and the time to culture conversion that means the time when TB bacilli are no longer detectable in sputum. The new definitions are also independent of the total duration of treatment and can be applied to the standard 20 months MDR-TB regimen as well as to the 9-12 months shorter course MDR-TB treatment that was recently proposed by the WHO.

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US Task Force Recommends TB Screening For Those Who Have Lived in High Risk Settings

MedicalResearch.com Interview with:

Dr. Francisco Garcí Task Force member and director Chief medical officer Pima County Department of Health Tucson, AZ

Dr. Francisco Garcia

Dr. Francisco García M.D. M.P.H.
Task Force member and
Director and Chief medical officer at
Pima County Department of Health
Tucson, AZ

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Tuberculosis infection is one of the most common infectious diseases in the world.

Although less common in the United States, many people still become infected every year and are at risk of getting sick and spreading the infection to others. We know there are effective screening tests that can detect latent tuberculosis infection before people become sick with active tuberculosis disease. Additionally, there are effective treatments to prevent people from progressing from latent tuberculosis infection to active tuberculosis disease.

Thus, for people with increased risk of contracting tuberculosis, the Task Force recommends screening for latent tuberculosis infection.

People who are considered at increased risk include those who were born in or have lived in countries where tuberculosis is highly prevalent, or who have lived in congregate settings where exposure to tuberculosis is more likely, such as homeless shelters or correctional facilities.

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Infectious Tuberculosis Can Arrive With Temporary Visa Holders in Tourism Industry

MedicalResearch.com Interview with:
Meghan Weinberg PhD
Epidemic Intelligence Service
CDC
Michigan Department of Health and Human Services

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Weinberg: Tuberculosis (TB) is a deadly disease. Once a leading killer in the United States, national, state, and local TB program efforts have dramatically reduced cases. With fewer cases occurring each year in the United States, health care providers might not consider TB when a patient has symptoms of TB disease. Every year, temporary visa holders come to the United States to work in a variety of tourist locations including amusement parks, ski lodges, national parks, and cultural or historical sites. TB testing is not required for persons entering the United States on a temporary visa.

This report documents three cases of infectious TB disease among temporary workers in the tourism industry. Increased Tuberculosis awareness is needed among employers, health care providers, and public health officials.

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Diagnosing TB in Children: Evaluating Xpert Assay

Tuberculosis creates cavities visible in x-rays like this one in the patient's right upper lobe. Wikipedia

Tuberculosis creates cavities visible in x-rays like this one in the patient’s right upper lobe Wikipedia

MedicalResearch.com Interview with:
Dr Anne K Detjen, MD

Child Lung Health Consultant
International Union Against Tuberculosis and Lung Disease

Medical Research: What is the background for this study? What are the main findings?

Dr. Detjen: The bacteriological diagnosis of tuberculosis (TB) in children is challenging due to the difficulty in obtaining specimens such as sputum and the lack of an accurate and accessible diagnostic test. In most cases, diagnosis is made on clinical grounds based on a contact history and a combination of signs and symptoms. We included 15 studies in a systematic review and meta-analysis of Xpert for the diagnosis of pulmonary TB in children.

The accuracy of Xpert for diagnosing TB in children is suboptimal, and the majority of children will still have to be diagnosed clinically. However, in settings where it replaces smear microscopy Xpert will increase the likelihood of bacteriological confirmation of TB as well as MDR TB among children. Xpert does not increase the number of confirmed TB cases among culture-negative children. We also found that smear status highly impacted Xpert results, i.e. a higher yield among smear positive compared to smear negative children. Smear positivity increases with bacillary load and might be a proxy for disease severity. Unfortunately, we were not able to assess the performance among children with different stages of disease severity since this was not classified in any of the studies included.

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New TB Screening Of Immigrants To US Has Resulted in Better Detection and Treatment Opportunities

MedicalResearch.com Interview with:
Dr.Yecai Liu

Division of Global Migration and Quarantine
Centers for Disease Control and Prevention, Atlanta, Georgia

Medical Research: What is the background for this study? What are the main findings?

Response: Since the early 1900s, immigrants and refugees applying for a visa to come to the United States undergo a medical examination that includes tuberculosis (TB) screening. In 2007, CDC began implementing the new screening guidelines, which require people suspected of having TB to receive a much more sensitive sputum culture test to confirm TB to ensure that those individuals who do have TB receive treatment before they arrive in the United States. These requirements have now been completely rolled out to all countries with U.S.-bound immigrants and refugees.

From 2007 through 2012, half of the 3.2 million arrivals of immigrants and refugees to the United States were screened for TB by the new screening guidelines. Out of more than 4,000 TB cases diagnosed by the new screening guidelines during this period, nearly 2,200 were smear-negative and culture positive. These cases would likely have been missed under the previous screening requirements. The results of this study showed that the updated overseas screening guidelines led to a roughly one-third decrease in the annual number of TB cases among foreign-born persons within their first year in the United States.

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Cancer Drug May Overcome Physiological Resistance To Tuberculosis Medications

Rakesh K. Jain, Ph.D. A.W.Cook Professor of Tumor Biology Director, E.L. Steele Laboratory Department of Radiation Oncology Harvard Medical School and Massachusetts General Hospital Boston, MA    02114MedicalResearch.com Interview with:
Rakesh K. Jain, Ph.D.

A.W.Cook Professor of Tumor Biology
Director, E.L. Steele Laboratory
Department of Radiation Oncology
Harvard Medical School and
Massachusetts General Hospital Boston, MA    02114

Medical Research: What are the primary findings of this study and why are they important?

Dr. Jain: Pulmonary granulomas are the hallmark of the Tuberculosis (TB) infection, yet it is not fully understood how these structures contribute to disease progression and treatment resistance. In this study, we applied our insight in tumor biology – gained over three decades – to explore and exploit the similarities between vasculature (blood vessel network) in solid cancerous tumors and TB pulmonary granulomas. We demonstrate for the first time that TB granulomas have abnormal vasculature. This abnormality provides a mechanism for the observation that TB granulomas are often hypoxic (have low oxygen conditions) and have differential distribution of anti-TB drugs. We showed that bevacizumab, a widely prescribed anti-VEGF antibody for cancer and eye diseases, is able to create more structurally and functionally normal granuloma vasculature and improve small molecule delivery. This study suggests that vasculature normalization in combination with anti-TB drugs has the potential to enhance treatment in patients with TB.

Tuberculosis (TB) is a global scourge that is responsible for nearly 2 million deaths annually. Due to the inability of currently available treatment regimens to eradicate this devastating disease, it is clear that new treatment strategies are urgently needed. Unlike many researchers in the TB field, we do not seek to discover new therapeutics that target bacterial resistance; instead, we strive to overcome physiological resistance to treatment resulting from abnormalities in the granuloma vasculature that impair drug delivery and create hypoxia that impairs efficacy of drugs and immune system. By using an FDA-approved drug, our study has the potential to be rapidly translated into the clinic.

Medical Research: Has any association previously been made between the vascular structure of TB granulomas and the challenges of treating TB – both the fact that treatment takes so long and the development of multidrug resistance?

Dr. Jain: Our study is the first to implicate a specific facet of the granuloma – the abnormal vasculature – as a potential contributor to disease progression and treatment resistance. Granuloma hypoxia is known to negatively affect the local immune system while conferring resistance to some of the TB drugs. Our collaborators have shown that different anti-TB drugs have differential abilities to penetrate the granuloma structure, especially to the interior granuloma regions where the TB bacteria are found in greatest numbers. Our study is the first to provide evidence that by modulating the granuloma vasculature, hypoxia can be alleviated and drug delivery can be improved.

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Hypertension Medication May Enhance Tuberculosis Treatment

Shashank Gupta, Ph.D. Center for Tuberculosis Research Department of Medicine, JHU, Baltimore, Maryland, USAMedicalResearch.com Interview with:
Shashank Gupta, Ph.D.

Center for Tuberculosis Research
Department of Medicine, JHU, Baltimore, Maryland, USA

Medical Research: What is the background for this study? What are the main findings?

Dr. Gupta: Verapamil is an efflux pump inhibitor drug that has been used to treat hypertension and other cardiac conditions in patients. Adding verapamil to standard tuberculosis (TB) treatment accelerates both the killing activity of the regimen in mouse model. We have recently shown in vitro that supplementing bedaquiline with verapamil profoundly decreases the MIC of bedaquiline in the wild type strain M. tuberculosis H37Rv, and also in drug-susceptible and drug-resistant clinical isolates. The MIC of another anti-mycobacterial drug clofazimine against M. tuberculosis H37Rv also decreased significantly in the presence of verapamil.

Bedaquiline is the first drug to be approved by the USFDA in last forty years for the treatment of multidrug-resistant tuberculosis (MDR-TB). Bedaquiline usage in patients presents several safety concerns including increased mortality and hepatic-related adverse drug reactions. Bedaquiline also prolongs the QT interval in patients, which is a measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle. In a phase 2 trial involving patients with advanced MDR-TB, a significantly higher number of participants receiving bedaquiline died than those receiving placebo although the causes of mortality were not directly attributable to the drug. Thus strategies to reduce the human dose of bedaquiline while retaining antibacterial activity may be valuable. We hypothesized verapamil may potentiate the killing of M. tuberculosis by bedaquiline and accelerate clearance of mycobacteria that in an in vivo infection model. Shortening treatment regimens and reducing the required doses may be a promising strategy to reduce the incidence of bedaquiline-related adverse effects and thereby improve MDR-TB treatment outcomes.

In this study, we investigated the effect of verapamil on the activity of bedaquiline against M. tuberculosis in a mouse model of TB infection. In addition to investigating the effects of verapamil on the full human bioequivalent dose of bedaquiline (25 mg/kg), we also used a sub-optimal dose of bedaquiline (12.5 mg/kg) daily, with or without verapamil to test if verapamil may potentiate the activity of bedaquiline. We have also determined if verapamil can protect bedaquiline monotherapy from the development of resistance.

Using mouse model of tuberculosis, we have shown lower doses of bedaquiline together with verapamil have the same antibacterial effect as the higher toxic doses. A lower dose of bedaquiline will cause no or less severe side effects. Verapamil also protected bedaquiline against the development of resistant mutants of the bacteria in the animals. Continue reading

Tuberculosis: Moxifloxacin Likely To Be Cornerstone Of New Treatment Regimen

MedicalResearch.com Interview with:
Stephen H. Gillespie, M.D., D.Sc University of St. Andrews Medical School, St. Andrews Stephen H. Gillespie, M.D., D.Sc
University of St. Andrews Medical School, St. Andrews

Medical Research: What are the main findings of the study?

Dr. Gillespie: REMox TB was a pioneering trial that has shown that a large-scale trial can be run efficiently in resource-poor settings with a high TB burden, adhere to the highest standards of good clinical trial practices, and deliver a clear, unequivocal result. REMoxTB was among the most rigorous Tuberculosis drug trials ever conducted in the modern era of TB treatment and among the largest ever conducted for a new TB treatment. It enrolled 1,931 patients at 50 sites in nine countries, mostly in Africa and Asia. Previously, there were thought to be regional differences in way in which patients’ response to treatment across the world but we showed that a rigorous approach to trial conduct there was no evidence for that difference.

The study confirmed that daily moxifloxacin was safe over four months of therapy and the moxifloxacin containing arms were more bactericidal initially. Despite its substantial anti-TB activity it did not prove possible to shorten therapy to four months.  .

These findings, with the safety of moxifloxacin, and its activity against TB, support the continued clinical testing of moxifloxacin as a component of other novel regimens.
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New Drug Bedaquiline Effective Against Multidrug-Resistant Tuberculosis

Medical Research Interview with:
Brian Dannemann, MD, FACP
Senior Director, JNJ Pharmaceutical Research and Development
Titusville, NJ 08560

MedicalResearch: What are the main findings of the study?

Dr. Dannemann : The final investigational 120-week results from the TMC207-C208 Phase 2 study demonstrated that bedaquiline (SIRTURO®) showed nearly twice an many patients in the bedaquiline group as in the placebo group were cured on the basis of the World Health Organization (WHO) outcome definitions for Multidrug-Resistant Tuberculosis which was statistically significant (38 of 66 patients  [58%] and 21 of 66 patients [32%] respectively; p = 0.003).
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Childhood Tuberculosis Likely Under-diagnosed and Under-reported

Pete Dodd (BA, BSc, MMath, PhD) Research associate in health economic modelling Health Economics and Decision Science ScHARR Regent Court SheffieldMedicalResearch.com Interview with:
Pete Dodd (BA, BSc, MMath, PhD)
Research associate in health economic modelling
Health Economics and Decision Science
ScHARR
Regent Court Sheffield

Medical Research: What are the main findings of the study?

Dr. Dodd: We found that over 650,000 children under the age of 15 developed tuberculosis in the 22 highest burden countries in 2010, with around 7.6 million becoming infected with the bacillus and more than 50 million harboring latent infection.
Our work points to a much larger gap between notifications and incidence in children compared to adults.
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