Drug-resistant tuberculosis is poised to be a growing public health crisis, especially affecting low and middle-income countries.
by Dr Raph Hamers and Pearl Gan
The Problem
Tuberculosis (TB) causes more deaths worldwide than any other infectious agent, and is one of the top 10 causes of death worldwide, with a staggering estimated 10 million new cases and 1.6 million deaths in 2017.1 95 percent of those deaths occurred in low and middle-income countries (LMIC).
For a person to develop TB disease, two separate biological events need to occur: first, infection with M. tuberculosis (Mtb) is established by inhalation of infectious aerosol particles released from close contacts;2 this means they have been infected by Mtb but are not (yet) ill and hence cannot transmit the disease. Second, the latent TB infection progresses to TB disease, this often take years. TB usually affects the lungs, but can damage any tissue,2 and, if untreated, 7 of 10 persons affected may die.3
TB is an old disease that emerged about 70,000 years ago.4 Despite the discovery of the Bacillus-Calmette Guérin (BCG) vaccine (1908) and effective anti-tuberculosis drugs (since 1940s), TB remains a global epidemic today, with particularly large disease burdens in LMIC in sub-Saharan Africa and Asia.
Twelve Asian countries are included in the World Health Organisation (WHO)’s list of the 30 high TB burden countries: Bangladesh, Cambodia, China, DPR Korea, India, Indonesia, Myanmar, Pakistan, Papua New Guinea, Philippines, Thailand, and Vietnam.1 Collectively, India (27%), China (9%), Indonesia (8%) and the Philippines (6%) account for half of all global cases, and the Southeast Asia region alone accounts for 44 percent of all cases.1
Given the exceptional economic and technological regional progress of the past decades, why is TB still such a daunting problem across Asia? We outline the complex challenges of interrupting the chain of transmission, managing latent TB infections, optimising treatment outcomes, emerging highly drug-resistant forms of tuberculosis, and the drivers of the TB epidemic in Asia.
Transmission and Latency
About 50 million people are newly infected worldwide annually, amounting to a total of about one-third or two billion of the world’s population having latent TB. People with latent TB have a lifetime risk of developing active TB disease of 10 percent, but the risk is much higher in people with compromised immune systems, such as HIV patients, malnutrition or diabetes, or people who smoke tobacco. People with untreated TB disease could infect another 10 to 15 people each year.
There are two main health-care interventions that are currently adopted to prevent new infections of Mtb and their progression to TB disease. First, BCG in young children has high coverage throughout the region, although the vaccine has incomplete effectiveness.
Second, WHO strongly recommends preventive treatment of latent TB infection with antibiotics in two priority groups: people living with HIV, and children aged under five who are household contacts of someone who has bacteriologically confirmed pulmonary TB. In countries with a high incidence of TB, the latest WHO guidance in 2018 expanded the latter recommendation to all age groups. However, many Asian countries have not prioritised implementing preventive treatment of latent TB. For instance, the 2018 WHO report observed that in 2017 in Southeast Asia, only 12 percent of newly enrolled HIV-positive people had received preventive treatment for latent TB and 14 percent of children under five years with TB household contacts.1
Large gaps exist in our knowledge about how best to reduce transmission, apart from the obvious need to improve case finding, since many cases of tuberculosis are undiagnosed.
Diagnosis and Treatment
Accurately diagnosing TB is one of the greatest technical challenges to TB control and elimination in Asia. If we cannot find most of those infected, we also cannot treat them.
Successful diagnosis and treatment of people with TB has averted an estimated 54 million deaths over the period from 2000 to 2017, but there are still large and persistent gaps in case detection and global diagnostic capacity is low. Expansion of active, rather than passive, case finding is needed in high-risk groups to close the detection gap, including close contacts, people with HIV or diabetes, prisoners, people in high-prevalence settings, and people living in crowded conditions and slums. Access to more sensitive commercially available confirmatory tests based on nucleic acid amplification (NAATs) are being rapidly scaled up in the region, especially the WHO-endorsed GeneXpert MTB/RIF, which also provides rapid diagnosis of rifampicin-resistant tuberculosis.
The recommended first-line regimen for drug-sensitive tuberculosis (isoniazid and rifampicin for 6 months, together with pyrazinamide and ethambutol for the first 2 months) is highly effective. However, the regimen’s main drawback is the long duration, with considerable numbers of patients (reportedly 7 to 54% across programs) discontinuing therapy before completion.
The poor health outcomes of inadequately managed tuberculosis are partially due to underfunded local healthcare delivery services in LMIC. Ongoing clinical studies assess the possibility of shortening treatment by intensifying the regimen with increased dosage of rifampicin or the use of antibiotics known from other infectious disease for their re-purposed use against Mtb, e.g. the later-generation fluoroquinolones, linezolid and clofazimine.
To support countries to close gaps in TB detection and treatment, in 2018 WHO in collaboration with the Stop TB Partnership and the Global Fund to Fight AIDS, Tuberculosis and Malaria, launched an initiative called Find. Treat. All, with an ambitious target of detecting and treating 40 million people with TB from 2018 to 2022.5
Emerging Drug-Resistant TB Strains
Drug-resistant TB continue to present a growing public health crisis.6 In 2017, an estimated 558,000 people worldwide developed TB that was resistant to rifampicin, the most effective first-line drug, and of these, 82 percent had multidrug-resistant TB (MDR-TB), defined as resistance to the two major TB drugs, isoniazid and rifampicin.1
Extensively drug-resistant (XDR) TB, resistant to many second-line drugs, as well as strains resistant to all current drugs, are also emerging. Three countries accounted for almost half of the world’s resistant cases: India (24%), China (13%) and the Russian Federation (10%).1 Emergence of incurable or totally drug-resistant tuberculosis could eventually result in the transmission of untreatable strains in communities.
The recommended MDR-TB regimens are toxic, poorly tolerated, prolonged (12 to 24 months), and not based on data from controlled trials. Treatment success rates in many countries are only around 50 percent.6 Urgent action is required to improve the care for people with drug-resistant TB. After decades of stagnation, a range of new anti-tuberculosis drugs are in clinical development, two of which, bedaquiline and delamanid, have been registered for use in drug-resistant tuberculosis in recent years.7
Drivers of the Asian Epidemic
The modest progress achieved to date is under threat by a range of important drivers of the TB epidemic. Experts have attempted to estimate the proportions of global TB cases that could be attributed to each of these risk factors as follows: HIV (11%), smoking (15.8%), diabetes (7.5%), alcohol abuse (9.8%), undernutrition (26.9%), and indoor air pollution (22.2%) – although they may vary greatly between countries.8 Several countries of particular concern, including Indonesia, Philippines and Pakistan, are facing rapidly expanding HIV epidemics, which are increasingly driving their national TB co-epidemics.
Additionally, type 2 diabetes mellitus is a global epidemic out of control, affecting an estimated 425 million individuals in 2017, with numbers predicted to increase to 629 million in 2045.9 More than 80 percent of people with diabetes live in LMIC, with the Asian region most heavily affected.
The converging epidemics of tuberculosis and type 2 diabetes mellitus pose an increasingly urgent public health challenge, especially in urban settings where these conditions coexist with greater frequency.9 Major efforts are needed to improve integrated screening and co-management of HIV and DM among newly diagnosed TB cases in TB clinics.9,10
Long view for a Particularly Tough Problem
Asia has great room for improvement in the social, technical, health system and governance response to this tough problem. More active, aggressive approaches and more effective tools and interventions are needed to reach the target set out in The End TB Strategy: a 90 percent reduction in the absolute number of TB deaths and an 80 percent reduction in TB incidence by 2030, compared with levels in 2015.11
We need greater public awareness, better diagnostics, case finding, treatment, and a more effective vaccine – interventions that must also be cost-effective, affordable and scalable. Modelling studies have suggested that tuberculosis elimination is probably only achievable if therapeutic and diagnostic interventions (early case detection and high cure rates) are combined with preventive strategies (more effective vaccines and treatment of the enormous latent tuberculosis reservoir).
Technological breakthroughs are urgently needed, prioritising a widely available low-cost screening test to improve detection rates, a vaccine or new drug treatment to prevent TB disease in latent infections, and simpler, shorter drug regimens for treating TB disease, including the emerging drug-resistant forms. Moreover, to further reduce TB incidence, Asian nations must step up efforts to alleviate extreme poverty, overcrowding and to provide universal health access. [APBN]
References
- World Health Organisation. Global tuberculosis report 2018. 2018 https://apps.who.int/iris/bitstream/handle/10665/274453/9789241565646-eng.pdf?ua=1.
- Bloom BR, Atun R, Cohen T, et al. Tuberculosis. In: Holmes KK, Bertozzi S, Bloom BR, Jha P, eds. . Washington (DC), 2017. DOI:10.1596/978-1-4648-0524-0/ch11.
- Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJD. Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review. PLoS One 2011; 6: e17601.
- Comas I, Coscolla M, Luo T, et al. Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nat Genet 2013; 45: 1176–82.
- World Health Organisation, the Stop TB Partnership, and The Global Fund to Fight AIDS, Tuberculosis and Malaria Joint Initiative ‘Find. Treat. All. #ENDTB’. 2018.
- Dheda K, Gumbo T, Gandhi NR, et al. Global control of tuberculosis: from extensively drug-resistant to untreatable tuberculosis. Lancet Respir Med 2014; 2: 321–38.
- Dheda K, Barry CE 3rd, Maartens G. Tuberculosis. Lancet (London, England) 2016; 387: 1211–26.
- Lonnroth K, Castro KG, Chakaya JM, et al. Tuberculosis control and elimination 2010-50: cure, care, and social development. Lancet (London, England) 2010; 375: 1814–29.
- van Crevel R, Koesoemadinata R, Hill PC, Harries AD. Clinical management of combined tuberculosis and diabetes. Int J Tuberc Lung Dis 2018; 22: 1404–10.
- International Union Against Tuberculosis and Lung Disease. Management of Diabetes Mellitus-Tuberculosis. A Guide to the Essential Practice. 2018 https://www.theunion.org/what-we-do/publications/technical/english/TheUnion_DMTB_Guide_October2018_Text_AW_02.pdf.
- World Health Organisation. The End TB Strategy. 2014.
About the Authors
Dr. Raph Hamers is a senior clinician scientist based at the Eijkman-Oxford Clinical Research Unit (EOCRU) and the Faculty of Medicine of the University of Indonesia, Jakarta, Indonesia.
Pearl Gan is a photographer in residence at the Oxford University Clinical Research Unit in Vietnam.