MDR-TB: A ‘global public health crisis’

Tuberculosis killed 1.6 million people in 2017 — more than 4,000 each day. Among its deadly attributes, TB is the leading killer of patients with HIV and the cause of one-third of all deaths related to antimicrobial resistance, according to WHO.

“Despite being preventable and curable, TB is now the world’s top infectious disease killer,” Rebecca Martin, PhD, director of the CDC’s Center for Global Health, told Infectious Disease News.

Globally, considerable action is being taken to eliminate TB, including multidrug-resistant TB, a form of the disease that is resistant at least to the powerful first-line drugs isoniazid and rifampin.

MDR-TB elimination was a focus of discussion during the United Nations General Assembly high-level meeting in September dedicated to ending the global epidemic of TB. In a political declaration signed during the meeting, heads of state promised to “reaffirm” the global commitment to ending the TB epidemic by 2030 as promised in the General Assembly’s Sustainable Development Goals and to focus on MDR-TB as an exacerbator of the epidemic and a significant challenge to tackling antimicrobial resistance. The agreement promised $13 billion a year by 2022 for TB prevention and care and $2 billion for research.

Source: UN Photo/Eskinder Debebe

“Today is a historical day in our battle with this ancient disease,” WHO Director-General Tedros Adhanom Ghebreyesus, PhD, MSc, said at the meeting. “TB knows no borders. Everyone is at risk, but it thrives where there is poverty, hunger and conflict. Enough is enough. It is time to end TB and to do that we must reach everyone with quality care.”

Infectious Disease News spoke with experts about the global effort to eliminate MDR-TB and end the TB epidemic.

‘Global public health crisis’

According to WHO’s 2018 Global Tuberculosis Report, about 1.7 billion people — 23% of the world’s population — have latent TB infection and are at risk for developing active TB during their lifetime. WHO reported that nearly 10 million people developed TB in 2017, with an estimated 1.3 million deaths occurring in HIV-negative people and 300,000 deaths in patients with HIV.

WHO has called MDR-TB a “global public health crisis” and said eliminating it will take better efforts to prevent, diagnose, and treat for patients. Among an estimated 558,000 people who developed TB resistant to rifampicin (RR-TB) in 2017 — the most effective first-line drug used for treatment — the agency reported that approximately 82% had MDR-TB. Globally, 3.6% of new cases and 17% of previously treated cases had RR-TB or MDR-TB, with the combined number of resistant infections increasing since 2016.

The report also noted that there is not a single country without TB. According to WHO, two-thirds of TBcases are in eight countries — 27% are in India alone — and just three countries carry almost half of the MDR-TB burden. Only 6% of global TB cases were in Europe and the Americas.

“TB is an old disease that was once a death sentence,” the authors of the report wrote. “Effective drug treatments ... in combination with social and economic developments [have] allowed countries in Western Europe, North America and some other parts of the world to reduce their burdens of TB disease to very low levels. For most countries, however, the ‘end’ of TB as an epidemic and major public health problem remains an aspiration rather than a reality.”

‘Hot spots’

Diagnosing and successfully treating patients with TB prevents millions of deaths each year. But there are persistent gaps in detection and treatment, and experts said the global burden of TB is not shrinking fast enough to meet goals set by WHO’s End TB Strategy, which aims to reduce deaths by 90% and new cases by 80% by 2030. Moreover, according to the WHO report, although global funding for diagnosing, preventing and treating TB has more than doubled since 2006, it continues to fall short of what is needed. Among the 119 low- and middle-income countries that reported data, funding reached $6.9 billion in 2018, well short of the estimated $10.4 billion required.

Worldwide in 2017, 6.4 million new cases of TB were reported to WHO, continuing a trend since 2013 of yearly increases in reported cases. The authors of the WHO report attributed the increases to private sector reporting in India and a rise in notifications in Indonesia.

“We need to close gaps and reach all people with TB and provide care,” Tereza Kasaeva, MD, PhD, director of the Global TB Programme, said during a news conference.

According to Martin, drug-resistant TB is more difficult to find, treat and cure. Eliminating it “will require an urgent and coordinated global response” to prevent new infections and find unreported cases, she said.

Martin said the CDC is working with ministries of health in other countries to map TB hotspots by pairing GIS software with epidemiologic data.

“Of the 10 million cases of TB each year, approximately 36% are not diagnosed or started on treatment,” she said. “Left untreated, each person can transmit TB to nearly 15 people, and he or she is more likely to die from TB. Identifying TB hotspots — where TB infection rates are highest — is critical to ensuring diagnostic and treatment services are available where people are suffering from TB.”

Accurate data on drug-resistant TB are not easy to come by, according to Infectious Disease News Editorial Board member David Cohn, MD, professor of medicine at the University of Colorado Denver and previous director of the Denver Metro Tuberculosis Clinic.

“In 1995 at WHO, we reviewed all available literature and reports on drug resistance to anti-TB drugs, and realized how little was known, with few or no data in many countries of the world,” Cohn said.

He said surveillance surveys and efforts to strengthen laboratories that have been organized by WHO and its partners over the past 2 decades have helped fill the gaps. WHO’s recent report noted that almost half of the world’s RR-TB or MDR-TB cases are in just three countries: India (24%), China (13%) and Russia (10%).

“We now have reasonably accurate data in over 160 countries to better understand the scope of the problem — much bigger than we realized — and where the hot spots of MDR-TB are located,” Cohn said. “This has led to more focused case finding of MDR-TB in high-burden settings with improved diagnostic tools, along with better treatment interventions to save lives and decrease transmission. We are still scratching the surface to achieve global control of MDR-TB and XDR-TB, but we know where to look and how to do it.”

New treatment rankings

Identifying people with latent TB who are most likely to develop the disease is a critical step towards elimination. However, recently published findings in The Lancet Infectious Diseases confirmed the poor ability of currently available tests to predict the development of active TB, underlining the need for better tests.

In terms of treatment, Kasaeva said three things are causing gaps in treatment: underreporting of TB cases, underdiagnosis in low- and middle-income countries and a need for updates of TB-preventive treatment.

“We must seize the moment,” she said. “It is unacceptable that in the 21st century, millions lose their lives to this curable and preventable disease.”

According to the WHO report, only about 25% people with drug-resistant TB infections were treated with second-line regimens in 2017, and the global treatment success rate for these patients was barely 50%.

To help countries close treatment gaps, WHO, the Stop TB Partnership and the Global Fund to Fight AIDS, Tuberculosis and Malaria launched an initiative to detect and treat 40 million people with TB from 2018 to 2022. The initiative came on the heels of a decline in the overall success rate for TB treatment from 86% in 2013 to 82% in 2016, according to WHO data.

According to the CDC, the most important factor in preventing the spread of drug-resistant TB and the emergence of MDR-TB is for patients to complete full courses of medication exactly as prescribed. MDR-TB can also spread through exposure to infected patients in closed or crowded places such as hospitals, prisons and homeless shelters.

The Stop TB Partnership — a U.N.-run program — announced in June that it had reached an agreement with 28 manufacturers to lower the price of TB medicines delivered by the group by $31 million. Among the agreement’s effects, the group said prices for conventional MDR-TB treatment regimens would decline by up to 33%, improving access.

MDR-TB infections are resistant to at least rifampicin and isoniazid and are associated with increased mortality and worse treatment outcomes. Second-line injectables are often used to treat MDR-TB but can cause substantial toxicity, leading to the interruption of treatment and lower success rates.

In August, WHO announced changes to treatment guidelines for MDR-TB, including a new priority ranking for available medicines. It urged wider access to the highest-ranked drugs to increase treatment success, including the oral antibiotic bedaquiline, the first drug specifically developed to treat MDR-TB.

“The treatment landscape for patients with multidrug-resistant tuberculosis will be dramatically transformed for the better,” Soumya Swaminathan, MD, WHO deputy director-general for programs, said in a statement.

To prepare countries to implement the changes, WHO released a rapid communication to explain the new ranking. Karin Weyer, PhD, coordinator of laboratories, diagnostics and drug resistance for the WHO Global TB Programme, told Infectious Disease News that the rapid communication was “an early announcement of some of the major changes that will happen in WHO’s policy guidelines” for drug-resistant TB, to be released later this year.

“[It] was done to inform National TB Programme staff and other stakeholders of the main changes early on, such as which medicines are no longer recommended and which medicines should be prioritized,” Weyer said. “These have major implications for drug procurement planning and budgeting at the country level.”

Longer MDR-TB regimens were broken down into three groups, with Group A medicines levofloxacin/moxifloxacin, bedaquiline and linezolid being prioritized. Medicines in Group B include clofazimine and cycloserine/terizidone. When agents from Group A and Group B cannot be used, WHO said drugs from Group C — including ethambutol, delamanid, pyrazinamide, imipenem-cilastatin, meropenem, amikacin (streptomycin), ethionamide/prothionamide and p-aminosalicylic acid — can also be included to complete the regimen

Officials said kanamycin and capreomycin are no longer recommended because, when used in longer regimens, they carry an increased risk for treatment failure and relapse.

The new guidelines prioritize oral drugs, such as bedaquiline, over injectables. Study findings recently published in Clinical Infectious Diseases support substituting bedaquiline for second-line injectables in treatment of MDR-TB. Researchers reported improved patient outcomes at 12 months compared with patients who remained on second-line injectables.

“Bedaquiline is now established as an important drug for drug-resistant TB,” Sean Wasserman, MBChB, MMed, infectious disease physician and research fellow at University of Cape Town in South Africa, and co-author of the bedaquiline study, told Infectious Disease News. “Data from the South African national TB program recently showed that its use is associated with a mortality benefit and a number of other observational studies — including ours — demonstrate improved outcomes with its use. The ability to safely and effectively replace injectables in [drug-resistant TB] treatment is a major advance.”

In response to the new priority ranking, Doctors Without Borders urged bedaquiline maker Johnson & Johnson to make the drug more affordable, especially in low- and middle-income countries. An executive from Johnson & Johnson told Infectious Disease News that the company would offer a reduced price of $400 for a 6-month treatment of bedaquiline to eligible programs and nongovernmental organizations procuring the drug through the Stop TB Partnership.

In addition to prioritizing bedaquiline, WHO recommends minimizing injectables as much as possible.

“The two key changes are treatment without the inconvenience of daily painful injections for most patients and combining drugs that are safer and more effective when given together,” Weyer said. “These changes are expected to make it easier for patients to stay on treatment and also provide new choices for clinicians in prescribing optimal MDR-TB treatment regimens.

“More emphasis is also placed on the need for clinicians to provide patients with adequate information on their treatment so that patients can make informed choices, and on active TB drug safety monitoring and management to quickly identify and manage drug adverse effects and provide alternative options for patients who are not responding well to their treatment.”

Finding and treating more patients successfully is pivotal to limiting the spread of drug-resistant TB and preventing additional drug resistance, Weyer explained. According to WHO, treatment success for MDR-TB remains low, around 55%. Only 139,114 of the estimated 558,000 people who developed RR-TB or MDR-TB in 2017 were treated with a second-line regimen.

“WHO has advocated for many years that prevention, diagnosis and treatment for all people with drug-resistant TB should be a priority to address the global public health crisis of MDR-TB,” Weyer said. “The changes in MDR-TB treatment, together with accelerated efforts to diagnose MDR-TB and design optimal treatment regimens based on drug susceptibility testing results, will be key drivers in confronting this crisis.”

In 2016, more than 9,200 cases of TB were reported in the United States from all 50 states, but MDR-TB is rare, with only 96 cases being reported. Still, in 2015, the Obama administration released the White House National Action Plan to Combat Multidrug-Resistant Tuberculosis, the goals of which are to strengthen domestic capacity to combat MDR-TB, improve international capacity and collaboration to combat MDR-TB, and accelerate basic and applied research and development to combat MDR TB.

Sluggish pipeline

Finding novel treatments for TB is complicated by a sluggish drug pipeline, according to Cohn, who said the time it takes to develop and license new medicines is too long. This is compounded by inadequate funding for clinical trial networks.

“It’s way better than it was 20 years ago,” Cohn said, “but it’s still not enough.”

According to the WHO report, the TB drug development pipeline is “progressing, but slowly,” with only 20 drugs, several treatment regimens and 12 vaccine candidates in clinical trials. It said funding for TB research peaked in 2016 at $724 million, still well short of the estimated $2 billion that is required.

One success story, Cohn said, was the development, licensing and rapid endorsement by WHO of the GeneXpert MTB/RIF (Cepheid) assay to rapidly diagnose TB and RR-TB, which he has called the biggest breakthrough for TB diagnosis in decades. The molecular test provides a rapid and sensitive method for diagnosing active TB as well as organisms that are resistant to rifampin, he said. In many high-burden countries, the test has replaced acid-fast bacilli smear microscopy, the standard method for initial detection.

Researchers developed a rapid point-of-care test for drug-resistant TB that uses the same GeneXpert software and reported in The New England Journal of Medicine last year that the investigational assay can speed up the detection of drug-resistant TB, helping clinicians determine the right treatment for patients.

Vaccine candidates

One goal outlined in the declaration signed at the U.N. is to develop effective vaccines against TB. The bacille Calmette-Guérin (BCG) vaccine is used in many countries and has demonstrated protection against disseminated TB in children but does not prevent primary infection or reactivation of latent pulmonary TB, according to WHO. BCG is not widely recommended in the U.S.

There have been differing results in recent trials of investigational vaccines, with results from each being published in The New England Journal of Medicine. One study showed that an investigational vaccine, H4+IC31 (AERAS, Sanofi Pasteur), and BCG were both ineffective against initial infection in a phase 2 trial. But a phase 2b trial showed that another vaccine candidate, M72/AS01E (GlaxoSmithKline), provided 54% protection against active TB in infected adults, offering some hope.

In a related editorial, Barry R. Bloom, PhD, the Joan L. and Julius H. Jacobson Research Professor of Public Health at the Harvard T.H. Chan School of Public Health, said there has been controversy over the value of the BCG vaccine and skepticism among scientists that an effective TB vaccine is even feasible, and among industry members that it can be economically viable.

Bloom said the M72/AS01E study “represents an important step forward toward developing an effective immunization against tuberculosis.”

“The results reinforce the importance of international collaborations, set the stage for testing additional candidates, and offer renewed hope that effective new vaccines can be developed for tuberculosis,” he wrote.

What’s next?

The first milestone of WHO’s End TB Strategy initiative is to decrease cases per year by 4% to 5% and lessen the proportion of people with TB who die from the disease to 10% by 2020. However, WHO said the TB incidence rate is falling by about 2% annually, making this milestone unlikely.

But the disease is at least getting more attention. September’s high-level meeting at the U.N. marked only the fifth time in history that a global health topic was discussed at the General Assembly.

“TB is preventable, treatable and curable and yet it claimed 1.6 million human lives, including 300,000 people who live with HIV,” Maria Fernanda Espinosa Garcés, president of the General Assembly, said. “Further and unfortunately, multidrug-resistant TB remains a serious health crisis around the world, and this, my friends, is unacceptable.”

A second U.N. meeting is being scheduled for 2023 to make sure accountability is maintained and progress is being made.

“We must ensure we hold our leaders accountable for the actions they promise to take, and we must hold ourselves accountable for keeping the pressure on,” said Ambassador Eric Goosby, MD, U.N. special envoy on tuberculosis. “Accountability is key to unlocking the strong hold that TB has had on global health since the time of the Egyptians. We must not allow ourselves to start strong in our efforts to build a TB free world, only to stop when the obstacles become too overwhelming. I would say that all of us, as a global health community, have done that for too long. No one is immune to TB. TB is preventable. TB is treatable. TB is curable. We must all be held accountable.” – by Caitlyn Stulpin

• References:
• Abubakar I, et al. Lancet Infect Dis. 2018; doi.org/10,1016/S1473-3099(18)30355-4.
• Nemes E, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1714021
• Van Der Meeren O, et al. N Engl J Med. 2018:doi:10.1056/NEJMoa1803484.
• WHO. Global tuberculosis report 2018. http://www.who.int/tb/publications/global_report/en/. Accessed September 18, 2018.
• WHO. Rapid communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB). http://www.who.int/tb/publications/2018/rapid_communications_MDR/en/. Accessed August 21, 2018.
• Xie YL, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1614915.
• Zhoa Y, et al. Clin Infect Dis. 2018;doi/10.1093/cid/ciy727/

• For more information:
• David Cohn, MD, can be reached at: David.Cohn@dhha.org.
• Rebecca Martin, PhD, can be reached at: Globalnews@cdc.gov.
• Sean Wasserman, MBChB, MMed, can be reached at sean.wasserman@gmail.com.
• Karin Weyer, PhD, can be reached at: gtbprogramme@who.int.

Disclosures: Bloom reports serving as an editor for the Proceedings of the National Academy of Sciences of the United States of America for a manuscript that reported the effectiveness of the investigational GlaxoSmithKline vaccine in nonhuman primates and serving as an external reviewer of the South African TB Vaccine Initiative in 2015, which did not include a discussion of the vaccine. Cohn, Garces, Goosby, Kasaeva, Martin, Swaminathan, Tedros, Wasserman and Weyer report no relevant financial disclosures.