The new face of an old disease: TB over 3 decades

To mark our 30th anniversary, Infectious Disease News will be examining some of the chronic conditions and infectious diseases that have impacted pediatric care over the past 3 decades.

In 1986, the CDC reported that tuberculosis cases increased in the United States for the first time since national reporting had begun in 1953: 22,725 cases compared with a record low of 22,201 cases the year before.

In the late 1980s, TB had been relegated to an afterthought in public health in the Western world. Following decades of steady decline and widespread discussion of imminent disease eradication, the deadly impact of TB in previous years had been largely forgotten — until a secondary disease emerged on the scene.

The onset of the HIV epidemic in the U.S., coupled with increases in medically underserved and immigrant populations, marked the beginning of a resurgence in TB that would last through the early 1990s. During that period, the U.S. saw more than 100,000 additional cases of TB beyond what would have been predicted based on the declines of the previous decades.

Following a renewed commitment to combating TB by numerous federal agencies and state health departments, the number of cases of TB in the U.S. decreased annually from 26,673 cases in 1992 to 9,406 in 2014. However, in 2015, the number of cases in the U.S. swung higher again — only slightly, to 9,557.

A global epidemic with domestic implications

In 2015, two-thirds of the reported cases of TB in the U.S. were among foreign-born individuals. To Jeffrey Starke, MD, professor of pediatrics at Baylor College of Medicine and director of the Children’s Tuberculosis Clinic at Texas Children’s Hospital, the persistence of TB disease among immigrant populations is unsurprising. Starke told Infectious Disease News that, consistent with estimates of the worldwide prevalence of latent TB infection (LTBI), between 20% and 30% of the 1 million people who legally immigrate to the U.S. each year are likely to be infected with TB.

Jeffrey Starke

“If we really want to eliminate TB in this country, which is our stated goal, we have to address not just TB disease but we have to address TB infection,” Starke said. Now, with a regimen for treating LTBI that requires only 12 weekly doses of isoniazid and rifapentine, as opposed to older regimens that required 9 months of daily medication, Starke said that he is hopeful that more widespread treatment of latent infection is forthcoming.

Infectious Disease News 30th Anniversary
Click to enlarge

David Cohn, MD, professor of medicine at the University of Colorado Denver and previous director of the Denver Metro Tuberculosis Clinic, also cited the inability to treat LTBI as one of the greatest failures of TB control over the past 30 years, not just in the U.S., but globally.

“Though one-third of the world population has TB infection, less than 1% of the people infected are being treated for latent TB infection,” Cohn said. “When you are an endemic country with limited budgets and limited resources, you put your resources into treatment of active disease — after that, you have no money left to treat latent infection. That is not the case in the U.S. We have more money and resources, but even here, we’re not doing a very good job.”

Since a person infected with TB often goes decades before becoming sick and contagious, it is a particularly tricky disease to control across international borders.

“You cannot control tuberculosis in the United States if you do not control it globally,” Dean Schraufnagel, MD, professor in the department of medicine at the University of Illinois at Chicago, told Infectious Disease News.

Globally, the impact of TB is immense. TB is now the single greatest infectious disease killer in the world: 10.4 million people became sick with TB disease in 2015, and in the same year, TB was responsible for 1.8 million deaths.

International efforts to combat TB since the early 1990s have led to decreasing rates of TB prevalence and mortality. Between 1990 and 2015, global TB mortality rates fell by an estimated 47% and TB prevalence fell by an estimated 40%.

“Those numbers don’t tell you about the millions and millions and millions of people who have died in that time or the millions of children who have been orphaned,” Starke said.

Evolving challenges

Two grave new challenges have entered the TB landscape in the last 30 years: TB/HIV coinfection and multi-drug-resistant TB.

Since the 1980s, HIV infection has contributed to major increases in the global incidence of TB and resulted in a massive coepidemic. An estimated 12% of the 9.6 million new TB cases in 2014 were among patients who were HIV–positive. TB is now the leading cause of death among people living with HIV: Of the 1.2 million HIV–positive people who died in 2014, 400,000 died from TB. Given the increased incidence, severity and mortality associated with TB disease among HIV–positive individuals, treatment of latent TB infection among HIV–positive individuals is considered critical.

In 1995, WHO conducted the first international survey of drug-resistant tuberculosis, of which there have now been five.

David Cohn
David Cohn

Thanks to this progress in global surveillance, Cohn said, “now we know how extensive the problem of MDR-TB is.”

In 2015, an estimated 480,000 people became ill with MDR-TB and an additional 100,000 people became ill with disease resistant to rifampicin. In other words, approximately 5% of new TB cases were caused by multidrug- or rifampicin-resistant strains. An estimated 21% of people with previously treated TB cases had multidrug- or rifampicin-resistant disease.

MDR-TB is grossly underdiagnosed, with only an estimated one quarter of drug-resistant cases detected and reported. In 2015, among those MDR-TB cases that were detected, only 50% of patients were successfully treated. In contrast, the overall treatment success rate for people newly diagnosed with TB was 86% in 2013. With new treatment regimens for MDR-TB that shorten the length of treatment from 18 to 24 months to 9 to 12 months and include drugs with fewer side effects, Cohn predicts that cure rates will improve, but, “we still have a long way to go.”

In addition to the challenges posed by MDR-TB and TB/HIV coinfection, combatting TB over the next few decades requires intensive effort in fighting childhood TB, on which there has been little progress. WHO estimated that 1 million children became sick with TB in 2015, and that 210,000 children died from the disease. “The childhood mortality rate is the same as it was before we even had chemotherapy,” Starke said.

Childhood TB functions differently from adult TB, and policies centered on adult disease are often of little help in combatting the disease in children. For example, WHO recommends diagnosing TB via microscopy of sputum, a method that will successfully identify 70% of adult TB cases while leaving most childhood cases undetected. “They set a policy that ensured the exclusion of children from tuberculosis control,” Starke said.

In 2011, the European CDC held an international meeting on childhood TB that, Starke said, felt like a major turning point in granting childhood TB the attention it requires. “I am way more optimistic that we are going to make progress over the next 5 to 10 years than I have been at any other time in the last 30.”

Advances in diagnostics, treatment, research

Cohn, Schraufnagel and Starke agreed that one area of major progress over the past 30 years is TB diagnostics. The GeneXpert MTB/RIF (Cepheid) assay, can detect the presence of TB bacteria as well as resistance to rifampicin in a sputum sample in under 2 hours.

“It is being implemented all over the world, in all parts of Africa, and not just in the big cities and not just in the big hospitals,” Cohn said.

For detecting LTBI, interferon-gamma release assays (IGRAs) represent a significant advance over TB skin tests, which had been the standard for nearly a century, because they do not require a patient to return to have the results read and lead to fewer false-positive results.

Drug development has progressed over these few decades, but slowly. Fluoroquinolones have been introduced as second-line treatments for MDR-TB. Additionally, bedaquiline and delamanid, both introduced in the past 5 years for treating highly drug-resistant disease, were the first TB drugs with a novel mechanism of action to be developed in 50 years. Rifapentine, which is related to rifampicin, was approved in 1998 and has been helpful in treating people with latent infection. Overall, though, standard treatment remains the same as 30 years ago.

“In the last 30 years, there have only been four new drugs approved for the treatment of tuberculosis,” Cohn said. “There are several more in the pipeline, but it’s been too few and it’s been too slow. In contrast, there have been over 35 new drugs or drug combinations approved for the treatment of HIV infection during the same time period.”

Over these decades, research on a new vaccine has been ongoing but without success yet. Bacillus Calmette-Guérin (BCG) vaccine, used in most high-burden countries, is nearly 100 years old and estimates of its effectiveness vary widely.

Despite setbacks, the fight against TB appears to be newly revitalized. In 2014, WHO launched the End TB Strategy, which aims to reduce TB deaths by 95% and to cut new cases by 90% between 2015 and 2035. It is an ambitious goal, but making progress toward eradicating the disease requires such ambition.

“Treatment is prevention; control is long-term elimination,” Schraufnagel said. “If we can eliminate it, we can get rid of that scourge forever. That would be enormous.” – by Sarah Kennedy

Disclosures: Cohn, Schraufnagel and Starke report no relevant financial disclosures.

To mark our 30th anniversary, Infectious Disease News will be examining some of the chronic conditions and infectious diseases that have impacted pediatric care over the past 3 decades.

In 1986, the CDC reported that tuberculosis cases increased in the United States for the first time since national reporting had begun in 1953: 22,725 cases compared with a record low of 22,201 cases the year before.

In the late 1980s, TB had been relegated to an afterthought in public health in the Western world. Following decades of steady decline and widespread discussion of imminent disease eradication, the deadly impact of TB in previous years had been largely forgotten — until a secondary disease emerged on the scene.

The onset of the HIV epidemic in the U.S., coupled with increases in medically underserved and immigrant populations, marked the beginning of a resurgence in TB that would last through the early 1990s. During that period, the U.S. saw more than 100,000 additional cases of TB beyond what would have been predicted based on the declines of the previous decades.

Following a renewed commitment to combating TB by numerous federal agencies and state health departments, the number of cases of TB in the U.S. decreased annually from 26,673 cases in 1992 to 9,406 in 2014. However, in 2015, the number of cases in the U.S. swung higher again — only slightly, to 9,557.

A global epidemic with domestic implications

In 2015, two-thirds of the reported cases of TB in the U.S. were among foreign-born individuals. To Jeffrey Starke, MD, professor of pediatrics at Baylor College of Medicine and director of the Children’s Tuberculosis Clinic at Texas Children’s Hospital, the persistence of TB disease among immigrant populations is unsurprising. Starke told Infectious Disease News that, consistent with estimates of the worldwide prevalence of latent TB infection (LTBI), between 20% and 30% of the 1 million people who legally immigrate to the U.S. each year are likely to be infected with TB.

Jeffrey Starke

“If we really want to eliminate TB in this country, which is our stated goal, we have to address not just TB disease but we have to address TB infection,” Starke said. Now, with a regimen for treating LTBI that requires only 12 weekly doses of isoniazid and rifapentine, as opposed to older regimens that required 9 months of daily medication, Starke said that he is hopeful that more widespread treatment of latent infection is forthcoming.

Infectious Disease News 30th Anniversary
Click to enlarge

David Cohn, MD, professor of medicine at the University of Colorado Denver and previous director of the Denver Metro Tuberculosis Clinic, also cited the inability to treat LTBI as one of the greatest failures of TB control over the past 30 years, not just in the U.S., but globally.

“Though one-third of the world population has TB infection, less than 1% of the people infected are being treated for latent TB infection,” Cohn said. “When you are an endemic country with limited budgets and limited resources, you put your resources into treatment of active disease — after that, you have no money left to treat latent infection. That is not the case in the U.S. We have more money and resources, but even here, we’re not doing a very good job.”

Since a person infected with TB often goes decades before becoming sick and contagious, it is a particularly tricky disease to control across international borders.

“You cannot control tuberculosis in the United States if you do not control it globally,” Dean Schraufnagel, MD, professor in the department of medicine at the University of Illinois at Chicago, told Infectious Disease News.

Globally, the impact of TB is immense. TB is now the single greatest infectious disease killer in the world: 10.4 million people became sick with TB disease in 2015, and in the same year, TB was responsible for 1.8 million deaths.

International efforts to combat TB since the early 1990s have led to decreasing rates of TB prevalence and mortality. Between 1990 and 2015, global TB mortality rates fell by an estimated 47% and TB prevalence fell by an estimated 40%.

“Those numbers don’t tell you about the millions and millions and millions of people who have died in that time or the millions of children who have been orphaned,” Starke said.

PAGE BREAK

Evolving challenges

Two grave new challenges have entered the TB landscape in the last 30 years: TB/HIV coinfection and multi-drug-resistant TB.

Since the 1980s, HIV infection has contributed to major increases in the global incidence of TB and resulted in a massive coepidemic. An estimated 12% of the 9.6 million new TB cases in 2014 were among patients who were HIV–positive. TB is now the leading cause of death among people living with HIV: Of the 1.2 million HIV–positive people who died in 2014, 400,000 died from TB. Given the increased incidence, severity and mortality associated with TB disease among HIV–positive individuals, treatment of latent TB infection among HIV–positive individuals is considered critical.

In 1995, WHO conducted the first international survey of drug-resistant tuberculosis, of which there have now been five.

David Cohn
David Cohn

Thanks to this progress in global surveillance, Cohn said, “now we know how extensive the problem of MDR-TB is.”

In 2015, an estimated 480,000 people became ill with MDR-TB and an additional 100,000 people became ill with disease resistant to rifampicin. In other words, approximately 5% of new TB cases were caused by multidrug- or rifampicin-resistant strains. An estimated 21% of people with previously treated TB cases had multidrug- or rifampicin-resistant disease.

MDR-TB is grossly underdiagnosed, with only an estimated one quarter of drug-resistant cases detected and reported. In 2015, among those MDR-TB cases that were detected, only 50% of patients were successfully treated. In contrast, the overall treatment success rate for people newly diagnosed with TB was 86% in 2013. With new treatment regimens for MDR-TB that shorten the length of treatment from 18 to 24 months to 9 to 12 months and include drugs with fewer side effects, Cohn predicts that cure rates will improve, but, “we still have a long way to go.”

In addition to the challenges posed by MDR-TB and TB/HIV coinfection, combatting TB over the next few decades requires intensive effort in fighting childhood TB, on which there has been little progress. WHO estimated that 1 million children became sick with TB in 2015, and that 210,000 children died from the disease. “The childhood mortality rate is the same as it was before we even had chemotherapy,” Starke said.

Childhood TB functions differently from adult TB, and policies centered on adult disease are often of little help in combatting the disease in children. For example, WHO recommends diagnosing TB via microscopy of sputum, a method that will successfully identify 70% of adult TB cases while leaving most childhood cases undetected. “They set a policy that ensured the exclusion of children from tuberculosis control,” Starke said.

In 2011, the European CDC held an international meeting on childhood TB that, Starke said, felt like a major turning point in granting childhood TB the attention it requires. “I am way more optimistic that we are going to make progress over the next 5 to 10 years than I have been at any other time in the last 30.”

Advances in diagnostics, treatment, research

Cohn, Schraufnagel and Starke agreed that one area of major progress over the past 30 years is TB diagnostics. The GeneXpert MTB/RIF (Cepheid) assay, can detect the presence of TB bacteria as well as resistance to rifampicin in a sputum sample in under 2 hours.

“It is being implemented all over the world, in all parts of Africa, and not just in the big cities and not just in the big hospitals,” Cohn said.

For detecting LTBI, interferon-gamma release assays (IGRAs) represent a significant advance over TB skin tests, which had been the standard for nearly a century, because they do not require a patient to return to have the results read and lead to fewer false-positive results.

PAGE BREAK

Drug development has progressed over these few decades, but slowly. Fluoroquinolones have been introduced as second-line treatments for MDR-TB. Additionally, bedaquiline and delamanid, both introduced in the past 5 years for treating highly drug-resistant disease, were the first TB drugs with a novel mechanism of action to be developed in 50 years. Rifapentine, which is related to rifampicin, was approved in 1998 and has been helpful in treating people with latent infection. Overall, though, standard treatment remains the same as 30 years ago.

“In the last 30 years, there have only been four new drugs approved for the treatment of tuberculosis,” Cohn said. “There are several more in the pipeline, but it’s been too few and it’s been too slow. In contrast, there have been over 35 new drugs or drug combinations approved for the treatment of HIV infection during the same time period.”

Over these decades, research on a new vaccine has been ongoing but without success yet. Bacillus Calmette-Guérin (BCG) vaccine, used in most high-burden countries, is nearly 100 years old and estimates of its effectiveness vary widely.

Despite setbacks, the fight against TB appears to be newly revitalized. In 2014, WHO launched the End TB Strategy, which aims to reduce TB deaths by 95% and to cut new cases by 90% between 2015 and 2035. It is an ambitious goal, but making progress toward eradicating the disease requires such ambition.

“Treatment is prevention; control is long-term elimination,” Schraufnagel said. “If we can eliminate it, we can get rid of that scourge forever. That would be enormous.” – by Sarah Kennedy

Disclosures: Cohn, Schraufnagel and Starke report no relevant financial disclosures.

    See more from Infectious Disease News 30th Anniversary