ECDC/WHO: World TB Day - Focus On MDR & XDR Treatment Outcomes

 

Map Credit - Tuberculosis surveillance and monitoring in Europe 2014

 

# 8386

 

Next Monday (March 24th) is World TB Day, and so for the next couple of weeks we can expect to see a flurry of reports and assessments released on the global battle against this insidious disease.  The ECDC describes this year’s campaign:

 

2014 theme: MDR TB and MDR TB treatment outcomes

For World TB Day 2014, ECDC is focusing on multidrug-resistant tuberculosis (MDR TB), particularly on MDR TB treatment and treatment outcomes.

In the EU/EEA, the treatment success rates of MDR TB patients have remained stable but at a very low level: only one in every three (34%) patients in the reporting EU/EEA countries finishes MDR TB treatment successfully. More than half die, fail treatment or default (stop taking treatment).

MDR and XDR TB patients face much longer treatment, take more drugs, suffer from more side effects and treatment costs are five times higher compared to drug-susceptible TB. Only complete and successful tuberculosis treatment helps to prevent disease transmission and development of resistant strains that lead to the development of extensively drug-resistant TB (XDR TB), which is almost impossible to treat.

Merely 7 of the 21 countries reporting have maintained a mean five-year decline in MDR notification rates and the overall MDR TB treatment success rate remains far below the 70% target defined by the Framework Action Plan to Fight Tuberculosis in the European Union.

Why is MDR TB still a public health concern?

• TB is slowly declining but MDR and XDR TB pose a serious challenge in the attempt to eliminate TB across Europe, even though the number of reported MDR TB cases seem to decline slowly.
  
• In EU, only 1 in every 3 MDR TB patients has a successful treatment outcome; more than half either die, fail treatment or default (stop taking treatment). XDR TB has even worse treatment outcomes: only 1 in 4 patients finishes treatment successfully
  
• By not diagnosing and not treating patients with MDR TB early and successfully, we put their live at risk and pave the way for XDR TB
  
• Only complete and successful tuberculosis treatment helps to prevent disease transmission and development of resistant strains

 

Today the ECDC and the World Health Organization released an extensive (15mb, 218 pg) PDF report on the TB situation in Europe entitled:

 

Tuberculosis surveillance and monitoring in Europe 2014

18 Mar 2014

Available as PDF in the following languages

ENGLISH

Abstract

​The sixth report launched jointly by the European Centre for Disease Prevention and Control (ECDC) and the WHO Regional Office for Europe (WHO/Europe) indicates that, despite notable progress in the past decade, tuberculosis (TB) is still a public health concern in many countries across Europe. Of particular concern are the high rates of multidrug resistant (MDR) TB outside the European Union (EU)/European Economic Area (EEA). Meanwhile EU/EEA countries themselves have a significant number of TB cases among vulnerable population groups, such as people of foreign origin and prisoners.

An assessment of progress towards TB elimination for the four epidemiological indicators and eight core indicators defined in the report ‘Progressing towards TB elimination: A follow-up to the Framework Action Plan to Fight Tuberculosis in the European Union’ showed that none of the core indicators was achieved at EU/EEA level.

 

While progress has been made in reducing the overall incidence of Tuberculosis in Europe over the past decade, as the following press release indicates, the rise in MDR and XDR TB – and their dismal treatment outcomes -  has tempered any celebrations:

 

Tuberculosis cases down by 6% but only 1 in 3 MDR TB patients finishes treatment successfully

18 Mar 2014

​In 2012, 68 423 cases of tuberculosis (TB)  were reported in 29 EU/EEA countries according to new data published by the European Centre for Disease Prevention and Control and the WHO Regional Office for Europe ahead of World Tuberculosis Day. This results in a notification rate of 13.5 per 100 000 population and constitutes a 6% decrease compared to 2011 (72 000 cases reported), confirming the average annual decline of 5% since 2008.

The surveillance data show that the majority of EU/EEA countries report sustained low levels of TB, which means fewer than 20 TB cases per 100 000 population. In 19 of them, the number of tuberculosis patients decreased. Rates were below 10 per 100 000 population in 18 countries and below 20 in 23 countries.

Overall, the EU/EEA countries have been – and still are – successful in the fight against TB and met the target of an average five-year decline. However, they have not yet met the set targets for successful treatment of the multidrug-resistant form of tuberculosis, MDR TB.

(Continue . . . )

The Lancet : TB 2013

(From the 2011 TB Progress Report)

 

# 7025

 

 

To coincide with World TB Day, The Lancet Infectious Diseases  today has published a series of six papers (and comments) on the ongoing battle against tuberculosis, and the rising tide of of multidrug resistant (MDR) and extensively drug-resistant (XDR) TB infections around the globe.

 

Roughly 1/3rd of all new TB cases fall into the MDR-TB or XDR-TB category. Just over a year ago new alarm bells began ringing when an ahead-of-print letter to the journal Clinical Infectious Diseases announced that four cases of TDR (totally drug resistant) tuberculosis had been identified in India.

 

The term TDR-TB was quickly labeled as controversial, and poorly-defined. From the January 2012 ECDC report New drug resistant form of tuberculosis reported in India.

 

Total drug resistant TB is a relative notion and depends on the local drugs available and tested on. This term/expression should either be avoided or should be defined worldwide. The World Health Organization (WHO) has internationally-endorsed treatment recommendations for the treatment of drug-susceptible, MDR-TB and XDR-TB.

 

During this time, Maryn McKenna – Flublogia’s favorite scary disease girl – wrote extensively about these developments on her Superbug Blog:

 

Totally Resistant TB: Earliest Cases in Italy

• By Maryn McKenna January 12, 2012

India Reports Completely Drug-Resistant TB

• By Maryn McKenna January 9, 2012 

Totally Drug-Resistant TB: A Patient Is Missing

• By Maryn McKenna January 14, 2012 

 

A couple of my efforts included Resistant TB: The Limits Of Surveillance & Reporting & EID Journal: Challenges To Defining TDR-TB.

 

Recently the World Health Organization released their 2012 Global Tuberculosis Report, with the following statement regarding reports of TDR-TB.

 

“Totally drug-resistant TB” and developments in India in 2012

In December 2011, clinicians in Mumbai, India reported TB patients with what was termed “total drug resistance”.1 As a result of the intense public interest generated by this episode, in March 2012 WHO convened 40 experts to discuss its implications, whether current evidence makes it possible to define patterns of drug resistance beyond extensively drug resistance TB (XDR-TB) and if better guidance on appropriate treatment options for these patients was possible. While the group acknowledged that patients such as those described in Mumbai pose a formidable challenge to clinicians and public health authorities, no reliable definition beyond XDR-TB could be proposed.

 

Without having a better evidence base, no changes to the current guidelines on how to design treatment regimens for patients with broad patterns of resistance could be recommended. Improvements in the accuracy of drug susceptibility testing to certain drugs and the release of innovative new drugs will, however, change this position in future.

Since December 2011, several important measures have been taken by the Indian government. In Mumbai, laboratory and hospital facilities were improved, contact-tracing stepped up and efforts made to train staff on drug-resistant TB and infection control. Medical staff and funding were increased substantially. Access to second-line drugs was provided to eligible patients. National regulations governing private sales of anti-TB medication were strengthened. By the end of 2012, all 35 states in the country are expected to provide
programmatic management of drug-resistant TB. In May 2012, India made TB a notifiable disease and data collection on TB using a webbased system was initiated.2

 

 

Despite the academic debate over the definition (and existence) of TDR-TB, in January of this year - in  EID Journal: The Emergence Of `Totally Resistant TB’ - more evidence was presented suggesting that TDR-TB is either already here, or on its way.

 

In a similar vein, one of the articles appearing in the Lancet today called Drug-resistant tuberculosis: time for visionary political leadership, warns that:

 

WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis.

 

While a free registration is required, these articles are available online in their entirety. Follow the links to read:

 

Tuberculosis 2013

Published March 24, 2013

Executive summary

To commemorate World TB Day 2013, The Lancet Infectious Diseases publishes a Series of papers on tuberculosis, a disease that has long plagued human beings and was declared a global emergency in 1993 by WHO. Without concerted action from political leaders, health policy makers, funders, and others, health systems worldwide are at risk of being overwhelmed by increasing numbers of patients with treatment-resistant tuberculosis.

 

As new diagnostic tests, drugs, and drug regimens become available that have the potential to radically improve the detection and management of tuberculosis, the papers in the Series explore the challenges for successful implementation of these interventions.

Comments

Tuberculosis 2013 Series

John McConnell, Sally Hargreaves

Full Text | PDF

Zero deaths from tuberculosis: progress, reality, and hope

Alimuddin Zumla, Peter Kim, Markus Maeurer,Marco Schito

Full Text | PDF

Progress and challenges in childhood tuberculosis

Ben J Marais, Stephen M Graham, Markus Maeurer,Alimuddin Zumla

Full Text | PDF

Series Papers

Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test

Stephen D Lawn, Peter Mwaba, Matthew Bates, Amy Piatek, Heather Alexander, Ben J Marais, Luis E Cuevas, Timothy D Mchugh, Lynn Zijenah,Nathan Kapata, Ibrahim Abubakar, Ruth McNerney, Michael Hoelscher, Ziad A Memish, Giovanni Battista Migliori, Peter Kim, Markus Maeurer,Marco Schito, Alimuddin Zumla

Full Text | PDF

Tuberculosis biomarkers discovery: developments, needs,and challenges

Robert S Wallis, Peter S Kim, Stewart Cole, Debra Hanna, Bruno B Andrade, Markus Maeurer, Marco Schito, Alimuddin Zumla

Full Text | PDF

Tuberculosis comorbidity with communicable and non-communicable diseases: integrating health services and control efforts

Ben Marais, Knut Lönnroth, Stephen D Lawn, Giovanni B Migliori, Peter Mwaba, Philippe Glaziou, Matthew Bates, Ruth Colagiuri, Lynn Zijenah,Soumya Swaminathan, Ziad Memish, Michel Pletschette, Michael Hoelscher, Ibrahim Abubakar, Rumina Hasan, Afia Zafar, Guiseppe Pantaleo,Gill Craig, Peter Kim, Markus Maeurer, Marco Schito, Alimuddin Zumla

Full Text | PDF

Alignment of new tuberculosis drug regimens and drug susceptibility testing: a framework for action

William A Wells, Catharina C Boehme, Frank G J Cobelens, Colleen Daniels, David Dowdy, Elizabeth Gardiner, Jan Gheuens, Peter Kim, Michael E Kimerling, Barry Kreiswirth, Christian Lienhardt, Khisi Mdluli, Madhukar Pai, Mark D Perkins, Trevor Peter, Matteo Zignol,Alimuddin Zumla, Marco Schito

Full Text | PDF

Drug-resistant tuberculosis: time for visionary political leadership

Ibrahim Abubakar, Matteo Zignol, Dennis Falzon, Mario Raviglione, Lucica Ditiu, Baroness Susan Masham, Ifedayo Adetifa, Nathan Ford,Helen Cox, Stephen D Lawn, Ben Marais, Timothy D McHugh, Peter Mwaba, Matthew Bates, Marc Lipman, Lynn Zijenah, Simon Logan,Ruth McNerney, Adam Zumla, Krishna Sarda, Payam Nahid, Michael Hoelscher, Michel Pletschette, Ziad Memish, Peter Kim, Richard Hafner,Stewart Cole, Giovanni-Battista Migliori, Markus Maeurer, Marco Schito, Alimuddin Zumla

Full Text | PDF

Engaging communities in tuberculosis research

Renaud F Boulanger, Stephanie Seidel, Erica Lessem, Lee Pyne-Mercier, Sharon D Williams, Laia Ruiz Mingote, Cherise Scott, Alicia Y Chou, James V Lavery, on behalf of the Critical Path to TB Drug Regimens' Stakeholder and Community Engagement Workgroup

Full Text | PDF

EID Journal: The Emergence Of `Totally Resistant TB’

 

(From the WHO 2011 TB Progress Report)

 

# 6896

 

 

The existence of TDR-TB (Totally Drug Resistant Tuberculosis) has been fraught with controversy since the term first sprang into the headlines a little more than a year ago (see Crofsblog India: New TB strain is "totally drug-resistant" (updated)).

The story concerned at least 12 patients treated at an Indian hospital that had been diagnosed with `TDR-TB’. 

 

Not - as has been seen in the past - MDR-TB (multi-drug resistant tuberculosis), and XDR-TB (extensively drug resistant Tuberculosis), but tuberculosis that was supposedly resistant to all known drugs.

 

Varyingly resistant forms of TB have come about primarily as the result of incomplete, irregular, or inappropriate treatment and management of infected patients. Patient compliance for long-term treatment has consistently been a major obstacle.

 

Until now – as difficult as treatment might have been - there has always been some combination of antibiotics that could be used to treat even the most resistant of TB cases.

 

The emergence of a totally resistant form of the disease would be a game-changer, and so these reports began to set off alarm bells around the world.

 

A few days later, in ECDC Comment On Drug Resistant TB In India, we saw calls to avoid using the term TDR-TB until it could be better defined. 

 

From the ECDC report New drug resistant form of tuberculosis reported in India.

 

Total drug resistant TB is a relative notion and depends on the local drugs available and tested on. This term/expression should either be avoided or should be defined worldwide. The World Health Organization (WHO) has internationally-endorsed treatment recommendations for the treatment of drug-susceptible, MDR-TB and XDR-TB.

 

During this time, Maryn McKenna – Flublogia’s favorite scary disease girl – wrote extensively about these developments on her Superbug Blog:

 

Totally Resistant TB: Earliest Cases in Italy

• By Maryn McKenna January 12, 2012

India Reports Completely Drug-Resistant TB

• By Maryn McKenna January 9, 2012 

Totally Drug-Resistant TB: A Patient Is Missing

• By Maryn McKenna January 14, 2012 

 

That same week, in Resistant TB: The Limits Of Surveillance & Reporting, I wrote about the World Health Organization’s initial response to these reports (they did not currently recognize TDR-TB due to reasons stated in their TDR-TB FAQ), along with an article in the Indian Express suggesting that TDR-TB cases may be more widespread than reported. 

 

By the end of January, India’s government was denying the existence of untreatable TB in their country (see Referral: McKenna On India’s Denial Of TDR-TB), a response not dissimilar to their denials of NDM-1.

 

In March of 2012, the World Health Organization  released a statement on the supposed TDR-TB, titled  More evidence and better diagnostics needed before redefining severe forms of drug-resistant TB says WHO.

 

The `TDR-TB’  story simmered quietly for the next few months, that is, until October of 2012, when in EID Journal: Challenges To Defining TDR-TB we looked at an EID Journal article called:

NOTE: Corrected Link

 

Challenges and Controversies in Defining Totally Drug-Resistant Tuberculosis

Peter Cegielski , Paul Nunn, Ekaterina V. Kurbatova, Karin Weyer, Tracy L. Dalton, Douglas F. Wares, Michael F. Iademarco, Kenneth G. Castro, and Mario Raviglione

(Excerpt)

Susceptibility tests for several drugs are poorly reproducible. Few laboratories can test all drugs, and there is no consensus list of all anti-TB drugs. Many drugs are used off-label for highly drug resistant TB, and new drugs formulated to combat resistant strains would render the proposed category obsolete. Labeling TB strains as totally drug resistant might lead providers to think infected patients are untreatable. These challenges must be addressed before defining a new category for highly drug-resistant TB

 

All of which brings us to a new EID Journal article (abstract reparagraphed for readability), published yesterday, called:

 

Emergence and Spread of Extensively and Totally Drug-Resistant Tuberculosis, South Africa

Marisa Klopper, Robin Mark Warren, Cindy Hayes, Nicolaas Claudius Gey van Pittius, Elizabeth Maria Streicher, Borna Müller, Frederick Adriaan Sirgel, Mamisa Chabula-Nxiweni, Ebrahim Hoosain, Gerrit Coetzee, Paul David van Helden, Thomas Calldo Victor, and André Phillip Trollip

Abstract

Factors driving the increase in drug-resistant tuberculosis (TB) in the Eastern Cape Province, South Africa, are not understood. Using a convenience sample of 309 drug-susceptible and 342 multidrug-resistant (MDR) TB isolates, collected July 2008–July 2009, we characterized them by spoligotyping, DNA fingerprinting, insertion site mapping, and targeted DNA sequencing.

 

Analysis of molecular-based data showed diverse genetic backgrounds among drug-sensitive and MDR TB sensu stricto isolates in contrast to restricted genetic backgrounds among pre–extensively drug-resistant (pre-XDR) TB and XDR TB isolates.

 

Second-line drug resistance was significantly associated with the atypical Beijing genotype. DNA fingerprinting and sequencing demonstrated that the pre-XDR and XDR atypical Beijing isolates evolved from a common progenitor; 85% and 92%, respectively, were clustered, indicating transmission.

 

Ninety-three percent of atypical XDR Beijing isolates had mutations that confer resistance to 10 anti-TB drugs, and some isolates also were resistant to para-aminosalicylic acid.

 

These findings suggest the emergence of totally drug-resistant TB.

 

 

For those unfamiliar with para-aminosalicylic acid (PAS), it’s an older drug discovered in 1944, and one of the first drugs to effectively treat TB.  Its use as a first-line drug treatment was discontinued when newer antibiotics – like Rifampin - became available.

 

PAS is still used in treating XDR-TB although its value is limited and there are problems with toxicity.

 

Whether we should label them XDR-TB or TDR-TB may be debatable, but what is not is that we continue to see an erosion in our arsenal of effective drugs as new, resistant forms of TB emerge and spread.

 

As reported in last week’s MMWR, getting the best drugs to treat resistant TB can be difficult, even here in the United States (Interruptions in Supplies of Second-Line Antituberculosis Drugs — United States, 2005–2012).

 

Semantics aside, if you are unlucky enough to be infected by one of these resistant TB strains - and no effective drug is available to you  – then the fine distinction over whether it is XDR or TDR TB is of little practical consequence to you.

EID Journal: XDR-TB/HIV Treatment Outcomes

(From the 2011 TB Progress Report)

 

# 6828

 

 

Despite great advances made against tuberculosis since the introduction of antibiotics in the 1940s, in recent years we’ve seen the rise of new drug resistant strains of this killer disease; MDR-TB (Multi-drug Resistant Tuberculosis) and XDR-TB (Extensively Drug Resistant Tuberculosis).

 

Although the numbers have decreased in recent years, in 2010 1.4 million deaths were attributed TB, and it remains one of the three greatest causes of death of women (ages 14-44) in the world.

 

In 2009, the NIH had this to say about the global spread of the disease, including the fact that about 1 in 5 active cases of TB are also co-infected with HIV.

 

Today, one-third of the world’s population is thought to be infected with Mycobacterium tuberculosis (Mtb), the microbe that causes TB.

 

An estimated 13.7 million people have the active form of the disease. In 2007, approximately 9.27 million people developed TB, of whom 1.37 million were HIV positive, and 1.75 million died, including 456,000 individuals co-infected with HIV.

 

And in 2010, the World Health Organization announced:

 

Drug-resistant tuberculosis now at record levels

18 MARCH 2010 | GENEVA | WASHINGTON DC -- In some areas of the world, one in four people with tuberculosis (TB) becomes ill with a form of the disease that can no longer be treated with standard drugs regimens, a World Health Organization (WHO) report says.

 

Also from the World Health Organization:

 

Tuberculosis and HIV

 

The risk of developing tuberculosis (TB) is estimated to be between 20-37 times greater in people living with HIV than among those without HIV infection. In 2010, there were 8.8 million new cases of TB, of which 1.1 million were among people living with HIV.

In response to demands from countries, WHO recommends 12 TB/HIV collaborative activities, including the Three I's for HIV/TB. The WHO HIV/AIDS and TB Departments and their partners, including community groups, work collaboratively on joint HIV/TB advocacy, policy development and implementation in countries.

The Three I’s

• Intensified TB case finding
• Isoniazid preventive therapy
• Infection control for TB.

 

While the incidence of co-infection with XDR-TB and HIV is rising, little is known about the effectiveness of treatment of these patients.

 

We’ve some new research, appearing in the CDC’s EID Journal, indicating that among a small cohort of patients followed in South Africa over 2 years – disappointingly - only 22% were cured or successfully completed treatment.

 

A few excerpts ( reparagraphed for readability), but follow the link to read the entire study:

 

 

Treatment Outcomes for Extensively Drug-Resistant Tuberculosis and HIV Co-infection

Max R. O’Donnell , Nesri Padayatchi, Charlotte Kvasnovsky, Lise Werner, Iqbal Master, and C. Robert Horsburgh

Abstract

High mortality rates have been reported for patients co-infected with extensively drug-resistant tuberculosis (XDR-TB) and HIV, but treatment outcomes have not been reported. We report treatment outcomes for adult XDR TB patients in KwaZulu-Natal Province, South Africa. Initial data were obtained retrospectively, and outcomes were obtained prospectively during 24 months of treatment.

 

A total of 114 XDR TB patients were treated (median 6 drugs, range 3–9 drugs); 82 (73%) were HIV positive and 50 (61%) were receiving antiretroviral therapy. After receiving treatment for 24 months, 48 (42%) of 114 patients died, 25 (22%) were cured or successfully completed treatment, 19 (17%) withdrew from the study, and 22 (19%) showed treatment failure.

 

A higher number of deaths occurred among HIV-positive patients not receiving antiretroviral therapy and among patients who did not show sputum culture conversion. Culture conversion was a major predictor of survival but was poorly predictive (51%) of successful treatment outcome.

 

Discussion

The main findings of our study were a high mortality rate (42%) and a low rate of successful treatment outcomes (22%) for XDR TB patients after completion of 24 months of treatment in a setting with a high incidence of HIV.

 

All deaths in this cohort occurred in the first 12 months after start of treatment. Predictors of deaths in this cohort included TB-specific (TB culture conversion) and HIV-specific (ART use) factors. Consistent with findings in other studies of treatment of drug-resistant TB/HIV, HIV was not independently associated with death (12,13,20).

 

Although HIV was not independently associated with death, use of ART among HIV-infected patients was associated with improved survival.

 

Sex appeared to modify the association between death and HIV because female sex was associated with higher survival rates among HIV-negative XDR TB patients but with higher death rates in women co-infected with HIV than in men co-infected with HIV.

 

However, this finding was not significant in all strata. TB culture conversion was a useful predictor of survival and treatment outcome. However, it was not sufficiently sensitive in this cohort to be a surrogate for successful TB treatment outcome, given the number of patients who ultimately showed treatment failure (n = 7), defaulted (n = 7), or died (n = 4) after TB culture conversion.

 

 

The authors conclude by saying:

 

Although not addressed by our study, improvements in treatment outcomes for patients co-infected with MDR TB and HIV will require changes in HIV- and TB-related factors. For HIV, these include more rapid HIV testing for early initiation of ART, appropriate monitoring of CD4 T-cell counts, HIV virus load testing, appropriate opportunistic infection prophylaxis, and improvement in ART adherence.

 

Although not addressed by our study, we recommend that for TB these improvements include widespread implementation of rapid diagnostics, particularly for smear-negative disease; early drug susceptibility testing for first-line and second line agents; improvement in adherence for second-line TB drugs; development of more effective anti-TB drugs and regimens; and guidance of drug selection by timely and ongoing drug susceptibility testing.

 

 

While often overshadowed by other issues, the HIV AIDS epidemic (exacerbated by TB) in South Africa (and much of Sub-Saharan Africa) continues to devastate the populace.

 

The UNAIDS website lists the following grim statistics for South Africa, a country that has seen more than a 10 year-drop in life expectancy since HIV began to spread in the 1980s:

 

HIV AND AIDS ESTIMATES (2011)

Number of people living with HIV

5,600,000 [5,300,000 - 5,900,000]

 

Adults aged 15 to 49 prevalence rate

17.30% [16.60% - 18.10%]

 

Adults aged 15 and up living with HIV

5,100,000 [4,900,000 - 5,400,000]

 

Women aged 15 and up living with HIV

2,900,000 [2,700,000 - 3,000,000]

 

Children aged 0 to 14 living with HIV

460,000 [410,000 - 520,000]

 

Deaths due to AIDS

270,000 [240,000 - 300,000]

 

Orphans due to AIDS aged 0 to 17

2,100,000 [2,000,000 - 2,300,000]