TUBERCULOSIS

Tuberculosis remains the leading cause of death from infectious diseases among adults worldwide.
Advances in diagnosis could change this situation. Data on increased efficacy with new and repur-
posed drugs have led WHO to recommend all-oral therapy for drug-resistant tuberculosis for the
first time ever in 2018. Advances must be made in providing high-quality, people-centered care for
tuberculosis. Renewed political will, coupled with improved access to quality care, could relegate
the morbidity, mortality, and stigma long associated with tuberculosis, to the past.

INTRODUCTION

Tuberculosis has been considered a global public health emergency for the past 25 years. Drug-re-
sistant forms of tuberculosis are currently on course to be the world’s deadliest pathogens. Great
ambition and radical action are needed to tackle this completely curable pathogen, which remains
one of the greatest health problems in the world. Numerous advances have been made in the under-
standing of the epidemiology, risk factors, and pathophysiology of tuberculosis, and new diagnos-
tics and treatment for all forms of tuberculosis infection and disease are appearing on the horizon.

EPIDEMIOLOGY, PATHOGENESIS, AND RISK FACTORS

Tuberculosis is a disease of poverty.

Global tuberculosis incidence is estimated to be slowly declining (~1.6%), far from the estimation
to be required to reach WHO’s End TB Strategy targets (4-5%). By contrast, mortality is declining
more rapidly.

Mycobacterium tuberculosis and humans have coexisted for thousands of years. Many people glob-
ally are estimated to be infected, only some of these people develop active tuberculosis.

Immunity to tuberculosis also appears to fluctuate over time. The incubation of M tuberculosis is
probably around 24 months.

Addressing socioeconomic factors could be just as important as addressing host and pathogen fac-
tors in easing the global burden of tuberculosis.

DIAGNOSIS

Although multiple advances have been made in the diagnosis of tuberculosis, no reliable, simple,
point-of-care test exists to definitively diagnose the disease. WHO currently endorses a range of di-
agnostic and drug susceptibility tests.

Digital chest x-rays with computer-aided detection of tuberculosis have been increasingly used in
various settings. It becomes a triage test and is recommended by WHO for screening and diagnosis
in some populations.

Tuberculosis bacteria shed lipoarabinomannan (LAM), which forms the basis of the urinary LAM
test, the use of which has been associated with a mortality reduction for tuberculosis. It is associated
with a higher rate of case detection, a lower rate of mortality and is cost-effective. The test is cur-
rently recommended for patients who have HIV and a CD4 count of fewer than 100 cells per micro-
liter, are seriously ill, and are hospitalized.
To date, no predictive biomarker signatures are close to commercialization and no clinically useful
biomarker tests are available on the market.

The Xpert MTB/RIF test (Cepheid, CA, USA) remains the genotypic diagnostic test of choice. A
more sensitive version called Xpert MTB/RIF Ultra has been endorsed by WHO, and is being used
in South Africa; however, it has a lower specificity, and so interpretation of so-called trace-positive
results remains a challenge. An expanded version called Xpert XDR, which allows for the detection
of resistance to isoniazid, injectable agents, and fluoroquinolones was also shown to be effective.
Whole-genome sequencing is becoming an increasingly appealing option for the detection of drug
resistance in M tuberculosis and can also be used to improve the understanding of tuberculosis
transmission.

For the diagnosis of latent tuberculosis infection, Included in WHO guidelines: the tuberculin skin
test (TST) and the interferon-release assay (IGRA). Neither test can accurately differentiate. Both
tests have low sensitivity in a variety of immunocompromised populations, and low predictive value
for progression from infection to active tuberculosis.

TREATMENT

The treatment landscape for tuberculosis has changed dramatically, more tuberculosis treatment
studies are happening than ever. To date, no major changes in the treatment of drug-susceptible tu-
berculosis. For pan-susceptible tuberculosis, treatment with fixed-dose combinations consists of
four drugs given for a total of 2 months followed by two drugs given for an additional 4 months.

Therapeutic advances in the treatment of drug-susceptible tuberculosis have focused on two areas:
high-dose rifampicin and the addition or substitution of fluoroquinolones in the regimen.

Isoniazid-resistant forms of tuberculosis are the most common forms. WHO has recommended all-
oral therapy of 9–12 months (compared with the standard 18–24 months) resulting in greatly im-
prove treatment.

Bedaquiline was recommended by WHO in 2013, and again in 2017 as a core drug in the treatment.
In South Africa, there was a high treatment success rate and reduced mortality. Although QTc pro-
longation was seen, few required discontinuation. Consequently, the South African Government
committed to providing bedaquiline for all people with rifampicin-resistant tuberculosis in the coun-
try.

The second novel drug to be both conditionally approved by regulatory authorities and recom-
mended by WHO in 2014 is delamanid. Delamanid has been shown to be safe and effective in
short-term pharmacokinetic studies. The drug can be safely given in combination with bedaquiline.

Another medication in the nitroimidazole class is pretomanid. Concerns were raised about the safety
of pretomanid in combination with moxifloxacin and pyrazinamide resulted in fulminant hepatitis.
Pretomanid has not been used outside of clinical trials.

Various other novel chemical entities are in development for tuberculosis. The process for drug de-
velopment is hampered by several factors, and a seeming difficulty for countries to roll out new
drugs even when their efficacies have been established.

Besides new medications for the treatment of tuberculosis, interest in repurposed drugs is increas-
ing. Chief among these drugs is linezolid, an oxazolidinone antibiotic. Safety is a concern as the
drug has been associated with bone marrow suppression, optic neuritis, and peripheral neuropathy;
however, studies are ongoing to find strategies to reduce these toxic effects.

Another repurposed agent, clofazimine, has been shown to be effective against rifampicin-resistant
tuberculosis in a randomized, non-placebo controlled trial done in China.

Commonly used agents were found to be associated with worse treatment outcomes, even when
used in people with susceptibility to these medications, suggesting that the toxicity of these agents
might be worse than previously thought. Regimens containing bedaquiline, linezolid, or third-gener-
ation fluoroquinolones were associated with improved treatment outcomes and lower mortality. In
addition, the drugs clofazimine and cycloserine were found to be associated with improved treat-
ment outcomes.

All-oral regimens are now recommended for the majority of people living with rifampicin-resistant
tuberculosis.

A 9–12 month regimen, often known as the Bangladesh regimen (since its effectiveness was first
shown in the country) has overall outcomes that were non-inferior to a longer 18–24 month regi-
men. WHO recommended this regimen in 2016, and has maintained the recommendation in their
2018 guidance, although the organization now notes that the shorter regimen should not be given to
people with resistance to any drug in the regimen (except isoniazid) and that outcomes might be
worse than with administration of bedaquiline, linezolid, or both. The continued use of the in-
jectable agents in the shorter regimen is problematic given the high amounts of hearing loss re-
ported with this class of drugs.

Treatment choice should take into account considerations for special populations, the use of adjunc-
tive therapies, and long-term effects.

SUPPORT FOR SUCCESSFUL OUTCOMES

Adherence support has historically relied on the use of directly observed therapy (DOT). DOT can
be a way to ensure daily contact with vulnerable individuals and close monitoring for the develop-
ment of adverse events. However, DOT can add a substantial burden to the lives of people living
with tuberculosis which could increase the loss to follow-up. Self-administered treatment results in
similar outcomes but can be enhanced by digital tools that could improve adherence nowadays.

The first pillar of WHO’s End TB Strategy is patient-centered care. Ideally, this term should mean
that services and support for individuals affected by tuberculosis should be focused on them and
their needs as opposed to the needs of the health system.

All services provided to people with tuberculosis, from the time of presentation with initial symp-
toms to the time of discharge with non-relapsing cure, must be of the highest quality possible. This
will require system-wide action to develop high-quality health systems.

PREVENTION

Prevention has focused on vaccination and the treatment of latent tuberculosis or tuberculosis infec-
tion. Some studies show that intrapulmonary administration might be more immunogenic and de-
velopment of an inhaled BCG vaccine could be an important strategy to pursue.

In the past few years, major advances in the treatment of tuberculosis infection have occurred. Sub-
stantially shorter tuberculosis prevention regimens have been developed, and have been shown to be
as effective as 9 months of daily isoniazid. However, concerns about the development of drug resis-
tance when using a single drug in patients with undiagnosed active tuberculosis disease remain.

WHO recommends that one of four regimens be used for the treatment of tuberculosis infection:
daily isoniazid for 6 to 9 months, daily rifampicin for 4 months, daily isoniazid and rifampicin for 3
months, or weekly isoniazid and rifapentine for 12 weeks.

People who have been exposed to rifampicin-resistant tuberculosis previously had few options to
treat their infection. Individualized regimens with multiple drugs based largely on fluoroquinolone
were only available in selected settings. It is cost-effective as well as reduces 90% the risk of the
development of tuberculosis.

HOW TO MODERNIZE TUBERCULOSIS

For some improvements to be made, such as the development of a better vaccine or a shorter drug
therapy, new investments are urgently needed. High-quality systems for data management need to
be established and maintained for national and international monitoring, resource allocation, and ac-
curate problem-solving.

POLITICAL WILL TO END TUBERCULOSIS

On Sept 26, 2018, a UN meeting focused on tuberculosis was held in New York, NY, USA. New
global accountability systems are badly needed to ensure that “ending tuberculosis” does not be-
come yet another slogan tied to limited action of little benefit for those most affected by tuberculo-
sis.

CONCLUSION

Although tuberculosis continues to be one of the most important public health problems of the 21st
century, clinical and scientific advances exist that stand to revolutionize the diagnosis, treatment,
and prevention of all forms of this disease.