Vitamin D May Speed Recovery From Resistant Tuberculosis

MedicalResearch.com Interview with:

Professor Adrian Martineau, B Med Sci DTM&H MRCP PhD FRSB Clinical Professor of Respiratory Infection and Immunity Queen Mary University of London

Prof. Martineau

Professor Adrian Martineau, B Med Sci DTM&H MRCP PhD FRSB
Clinical Professor of Respiratory Infection and Immunity
Queen Mary
University of London

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

Response: The World Health Organisation estimates that 10.0 million people developed active tuberculosis in 2017, and that 1.6 million people died of this disease. Multi-drug resistant (MDR) TB is caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB drugs, causing around 500,000 cases and 150,000 deaths per year worldwide. Existing antibiotic treatments for MDR TB are lengthy, costly and often toxic due to their serious side effects.

One novel approach to treating MDR TB is to complement antibiotic treatment by using therapies that boost the immune system’s ability to kill TB bacteria. Vitamin D – the sunshine vitamin – is known to help white blood cells to make natural antibiotic substances (antimicrobial peptides) that can punch holes in the cell membranes of TB bacteria. Several clinical trials have investigated the effects of adding vitamin D to antibiotic treatment for TB.

In this study we pooled data from 8 of these studies (1850 participants) and analysed them to see if some TB patients benefited more from adding vitamin D to their treatment regimen than others. We found that vitamin D accelerated clearance of TB bacteria from the lungs of patients who had MDR TB; this benefit was not seen in patients who had ‘standard’ drug-sensitive TB. 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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T-SPOT.TB Test Demonstrates High Specificity in Screening Health Care Workers for Tuberculosis

MedicalResearch.com Interview with:

Thomas C King, MD, PhD Department of Pathology and Laboratory Medicine Chief of Pathology and Laboratory Medicine St. Vincent Hospital Worcester, MA

Dr. Thomas King

Thomas C King, MD, PhD
Department of Pathology and Laboratory Medicine
Chief of Pathology and Laboratory Medicine
St. Vincent Hospital
Worcester, MA

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

Dr. King: This landmark study provides a broad based, real world appraisal of the reliability of the T-SPOT®.TB test, an interferon gamma release assay (IGRA), based on results in screening workers in 19 U.S. hospitals. The large size of the study (more than 42,000 test results from more than 16,000 healthcare workers analyzed) provides a solid benchmark to assess performance of T-SPOT.TB in serial screening healthcare workers. In recent years, results from several studies have shown that there can be significant differences between using an IGRA and the tuberculin skin test (TST) in terms of accuracy and cost. Several studies have confirmed a risk of high false positive rates and numerous conversion/reversion rates when retesting patients with the TST.

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Researchers Discover Some Individuals Are Naturally Resistant To TB

Catherine M. Stein, PhDAssociate professor of epidemiology and biostatistics Case Western Reserve Dr. Stein is a leader of international research on resistance to Mycobacterium tuberculosis (MTB) infectionMedicalResearch.com Interview with:
Catherine M. Stein, PhD
Associate professor of epidemiology and biostatistics
Case Western Reserve
Dr. Stein is a leader of international research on resistance to Mycobacterium tuberculosis (MTB) infection

MedicalResearch: What is the background for this study? What do you hope to learn?

Dr. Stein: In a 2002 study, we began to clinically characterize people who lived in households where there were infectious tuberculosis cases. We followed them for a two-year period and noticed that approximately 9 percent of household members were resistant to Mycobacterium tuberculosis (MTB) infection, even though they were highly exposed to the organism. This finding surprised us because the prevailing notion had been that everyone living in TB-endemic settings or living with someone who has TB would become infected eventually. After several years of study, we found a substantial number of these people who do not have any evidence for MTB infection, so we wanted to do studies to learn if we could figure out why.

MedicalResearch: Is MTB resistance a new phenomenon? Do MTB resisters react to a tuberculin purified protein derivative (PPD) or a gold immunoassay but don’t develop clinical disease?

Dr. Stein: We don’t have any reason to believe that MTB-infection resistance is a new phenomenon. It’s just that no one has thought to look for it before. In terms of the PPD or gold immunoassays, MTB-resisters produce a negative response to both tests. The way gold immunoassays are done, three tubes are collected. One is a control. Another is a test for reacting to MTB. Still another is a positive control to make sure immune cells are alive. The MTB-resisters show a response to that positive control but not to MTB. It’s not that these patients don’t have an immune response. It’s just that they have no response to MTB, which means they have no previous exposure to cause their T-cells to make that response.

MedicalResearch: Are MTB-resisters immune to the newer multi-drug resistant strains of TB?

Dr. Stein: Resistance to MTB infection is independent of the drug resistance pattern of the bacteria. Thus we would expect them to resist multidrug resistant (MDR)-TB as well. There is no strong evidence that MDR-TB is more aggressive or virulent.

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QuantiFERON-TB Gold Testing For Latent TB Eliminates False Positives From BCG Vaccination

Dr. Masae Kawamura MD Director and TB Controller City and County of San Francisco Department of Health Principal investigator for the Regional TB Training and Medical Consultation CenterMedicalResearch.com Interview with:
Dr. Masae Kawamura MD
Senior Director, QuantiFERON Medical and Scientific Affairs QIAGEN

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

Dr. Kawamura:  The report in The Lancet presents the baseline phase of China’s first large-scale, multi-center prospective study of the epidemiology of latent tuberculosis infection. The comparison study of more than 21,000 patients allowed detailed analysis of demographics and risk factors, along with robust comparisons within subgroups. The study’s follow-up phase is now underway, and patients with Latent Tuberculosis Infection (LTBI) will be evaluated for rates of disease and associated risks. Generally, up to 10% of people with Latent Tuberculosis Infection will develop active, contagious Tuberculosis (TB) disease at some point.

The overall TB infection rate was 18.8% measured by QuantiFERON-TB Gold compared to 28% by the traditional tuberculin skin test (TST), a difference of over 125 million people (based on 2014 population estimates from China). Unlike the tuberculin skin test, positive rates of QuantiFERON-TB Gold were not related to prior Bacille Calmette-Guérin (BCG) vaccination, but correlated with background active TB and suspect rates, as well as known risks for TB. BCG vaccination is recommended to newborns by the World Health Organization (WHO) as a matter of TB control policy in many countries, including China.         Continue reading

Once Weekly Combination Regimen Effective For Childhood Tuberculosis

MedicalResearch.com Interview with:
Dr. Stefan Goldberg MD
Medical Officer in CDC’s Division of Tuberculosis Elimination
Clinical Research Branch

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

Dr. Goldberg: A shorter, simpler treatment regimen for children with latent TB infection can help prevent TB disease and reduce future transmission. The results from our study, a multinational, clinical trial, found that a once-weekly regimen of the anti-TB drugs rifapentine and isoniazid taken as directly observed therapy over a period of three months was safe and as effective for children (age 2-17) in preventing TB disease as the standard self-administered nine-month daily regimen of isoniazid alone. The study also showed that children are more likely to complete the shorter course of treatment, which is important given that treatment completion can be difficult. Specifically, we found that 88 percent of the trial participants on the combination regimen completed therapy while 81 percent completed the standard regimen.

The CDC’s Tuberculosis Trials Consortium (TBTC), which conducted this study, works to include children in research when their inclusion is scientifically supportable and when children also might benefit from important new tools, such as alternative treatment regimens. This study is an extension of a large, international trial among persons age 12 and older, published by TBTC in 2011, which showed the shorter, simpler regimen to be as safe and effective as standard treatment. Continue reading

Rheumatoid Arthritis: Mycobacterial Infections Relatively Common

MedicalResearch.com Interview with:
Theodore Marras, MD, FRCPC, M.Sc.
Assistant Professor, University of Toronto
Respirologist, Toronto Western Hospital
University Health Network
Toronto, ON, Canada

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

Dr. Marras: Mycobacterial infections (TB and nontuberculous mycobacteria (NTM)) are more common in patients with rheumatoid arthritis (RA). Nontuberculous mycobacteria disease was far more common than TB disease in RA patients in Ontario, Canada. Nontuberculous mycobacteria disease was also associated with increased age, COPD, asthma, and GERD. The presence of nontuberculous mycobacteria disease was associated with increased mortality.
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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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How Does Prednisone Affect TB Infections in Patients With and Without HIV?

Bongani M. Mayosi, M.B., Ch.B., D.Phil. Department of Medicine, Old Groote Schuur Hospital Cape Town, South AfricaMedicalResearch.com Interview with:
Bongani M. Mayosi, M.B., Ch.B., D.Phil.
Department of Medicine, Old Groote Schuur Hospital
Cape Town, South Africa

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

Dr. Mayosi: In those with definite or probable tuberculous pericardial effusion:

(1)       Prednisolone for 6 weeks and Mycibacterium indicus pranii  for three months had no significant effect on the combined outcome of death from all causes, cardiac tamponade requiring pericardiocentesis or constrictive pericarditis.
(2)      Both therapies were associated with an increased risk of HIV-associated malignancy.
(3)       However, use of prednisolone reduced the incidence of constrictive pericarditis and hospitalization.
(4)       The beneficial effects of prednisolone on constriction and hospitalization were similar in HIV-positive and HIV-negative patients

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New TB Combination Has Potential To Simplify and Shorten Therapy

Dr. Dan Everitt Senior Medical Officer, TB Alliance.MedicalResearch.com Interview with:
Dr. Dan Everitt
Senior Medical Officer, TB Alliance.

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

Dr. Everitt: The NC-002 trial tested a new, three-drug TB combination therapy, consisting of PA-824 (a new chemical entity), moxifloxacin (a re-purposed drug, not yet approved for TB treatment), and pyrazinamide (an existing TB drug currently used in standard TB treatment). This regimen is known as “PaMZ” and was tested in both drug-sensitive and multidrug-resistant TB (MDR-TB patients).

In the eight-week trial, PaMZ killed more bacteria than standard therapy and did so at a faster rate, showing its potential to shorten therapy to as little as four months for drug-sensitive and some forms of MDR-TB. Additionally, the trial included HIV-positive patients and a formal statistical evaluation found no effect of HIV status on the outcome of the study.
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How Best to Manage Co-Infection with Both TB and HIV?

Dr. Duncan ChandaMedicalResearch.com Interview with:
Dr. Duncan M. Chanda MD
Institute for Medical Research & Training and UNZA-UCLMS
Research and Training Project
University Teaching Hospital
Lusaka, Zambia

MedicalResearch: What are the main findings of the study?

Dr. Chanda:  The main findings are that in this cohort of relatively healthy patients, with a median CD4 of 367, ART can be delayed till the end of TB short course chemotherapy without deleterious effects. This differs from studies that looked at cohorts with very low median CD4  ( around 25-150 in most cases) in which early cART was found to reduce mortality and other AIDS defining events.

 

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