Indian Journal of Medical Research

CENTENARY REVIEW ARTICLE
Year
: 2013  |  Volume : 137  |  Issue : 3  |  Page : 455--493

Tuberculosis: From an incurable scourge to a curable disease - journey over a millennium


Surendra K Sharma1, Alladi Mohan2,  
1 Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
2 Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, India

Correspondence Address:
Surendra K Sharma
Professor & Head, Department of Medicine, All India Institute of Medical Sciences, New Delhi 110 029
India

Abstract

Globally, tuberculosis (TB) still remains a major public health problem. India is a high TB burden country contributing to 26 per cent of global TB burden. During 1944-1980, TB became treatable and short-course chemotherapy emerged as the standard of care. When TB elimination seemed possible in the early 1980s, global human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS) pandemic resulted in a resurgence of TB. Widespread occurrence of multidrug-resistant and extensively drug-resistant TB (M/XDR-TB) is threatening to destabilize TB control globally. Atypical clinical presentation still poses a challenge. Disseminated, miliary and cryptic TB are being increasingly recognized. Availability of newer imaging modalities has allowed more efficient localization of lesions and use of image guided procedures has facilitated definitive diagnosis of extrapulmonary TB. Introduction of liquid culture, rapid drug-susceptibility testing (DST), molecular diagnostic methods has helped in rapid detection, speciation and DST profiling of Mycobacterium tuberculosis isolates. While treatment of TB and HIV-TB co-infection has become simpler, efforts are on to shorten the treatment duration. However, drug toxicities and drug-drug interactions still constitute a significant challenge. Recently, there has been better understanding of anti-TB drug-induced hepatotoxicity and its frequent confounding by viral hepatitis, especially, in resource-constrained settings; and immune reconstitution inflammatory syndrome (IRIS) in HIV-TB. Quest for newer biomarkers for predicting a durable cure, relapse, discovery/repurposing of newer anti-TB drugs, development of newer vaccines continues to achieve the goal of eliminating TB altogether by 2050.



How to cite this article:
Sharma SK, Mohan A. Tuberculosis: From an incurable scourge to a curable disease - journey over a millennium.Indian J Med Res 2013;137:455-493


How to cite this URL:
Sharma SK, Mohan A. Tuberculosis: From an incurable scourge to a curable disease - journey over a millennium. Indian J Med Res [serial online] 2013 [cited 2019 Sep 21 ];137:455-493
Available from: http://www.ijmr.org.in/text.asp?2013/137/3/455/110999


Full Text

 Introduction



The "captain of all these men of death", tuberculosis (TB) has been a scourge of the humankind from time immemorial. Till date, no other disease in history matches the sheer magnitude of the misery inflicted by TB on the human race in terms of morbidity and mortality. The social and economic consequences of TB have had a profound effect on human existence. Historically, even though several other diseases like smallpox and plague have killed millions of people, their reign has been relatively short-lived; TB has been ever present. The inexorable march of time has witnessed the changing face of TB: from an incurable disease to the hype and hope of being an eminently curable one. However, even today TB remains as a formidable foe threatening to annihilate the human race. This review attempts to provide an overview of our understanding of TB, availability of rapid diagnostic tests including imaging modalities and anti-TB drugs and to outline the challenges that lie ahead in TB control.

 Historical Background



Since ancient times, there have been references to TB or illnesses resembling TB from several parts of the world from many civilizations. The earliest references to TB can be found in the language Samskritam (Sanskrit). In the ancient Indian scriptures, The Vedas, TB was referred to as Yakshma (meaning wasting disease). Description of a TB-like disease has been documented in ancient Chinese and Arabic literature [1],[2],[3] . In English literature, the word "consumption" (derived from the Latin word consumer) has also been used to describe TB. The word "tuberculosis" appears to have been derived from the Latin word tubercula (meaning "a small lump") [4],[5] .

Fracastorius (1443-1553) believed that TB was contagious. Thomas Willis (1621-1675) had documented the clinical presentation of consumption in detail in his treatise Pthisiologica. Richard Morton (1637-1698) had described several pathological appearances of TB [2],[4],[6] . John Jacob Manget gave the description of classical miliary TB in 1700 [7] . In 1720, Benjamin Marten conjectured that TB could be caused by "certain species of animalcula or wonderfully minute living creatures". In 1865 Jean Antoine Villemin presented his results suggesting that TB was a contagious disease [1],[2] . However, it was Robert Koch who announced the discovery of the tubercle bacillus during the monthly evening meeting of the Berlin Physiological Society on 24 th March 1882 [8] . On this day, after thousands of years, Mycobacterium tuberculosis, the organism causing TB finally revealed itself to humans. Commemorating the centenary of this event, since 1982, 24 th March is being celebrated as "World TB Day" world over. Wilhelm Conrad Roentgen's discovery of X-rays, facilitated radiographic visualization of changes caused by TB in a living person. Thus, it was in the early years of 20 th century that basic concepts related to aetiological agent of TB, consequent pathological changes in humans and detection of the organism became established.

Discovery of streptomycin, para-amino salicylic acid (PAS) and the availability of isoniazid ushered in modern era of effective treatment of TB in the mid-1940s. With the emergence of 'short-course' treatment cure for TB has become a reality. In the late 1970s, though TB continued to ravage developing countries like India, there was an optimism in the developed world that TB may cease to be a public health problem [1] .

The emergence of the human immunodeficiency virus (HIV) infection and the acquired immuno-deficiency syndrome (AIDS) ended this optimism and fuelled the resurgence of TB worldwide. Recognizing the importance of the impact of TB globally, the World Health Organization (WHO) took an unprecedented step and declared TB to be a "global emergency" in April 1993 [8] . The late 1990s also witnessed the resurgence of drug-resistant TB (DR-TB) with multidrug-resistant TB (MDR-TB) emerging as a major threat [9],[10],[11] . The first decade of the 21 st century has been ravaged by extensively drug-resistant TB (XDR-TB) [12] . Recently, concern has been expressed regarding the occurrence of extremely drug-resistant TB (XXDR-TB) [13],[14] , super XDR-TB [15] , totally drug-resistant TB (TDR-TB) [15],[16] from some parts of the world. The report on the occurrence of TDR-TB from India [17] has raised concern and consternation [18] . Over the millennia, TB never respected anyone and had treated the rich and poor alike with equal disdain.

 Definitions



Certain key definitions concerning clinically important forms of TB, drug-resistant TB are listed in [Table 1]A [19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37] and IB [9],[10],[11],[12],[13],[14],[15],[16],[31],[32],[33],[34],[35],[36],[37] respectively. {Table 1}

 Epidemiology



Global burden of TB

The global burden of TB as described in the 16 th global report on TB published by WHO in 2012 [37] is shown in [Table 2]A; most of the cases occurred in Asia (59%) and Africa (26%). {Table 2}

Indian scenario

The current estimated TB burden in India is listed in [Table 2]B [30],[37],[38],[39] . India has featured among the 22 high TB burden countries; and has accounted for an estimated one quarter (26%) of all TB cases worldwide [30]

 M/XDR-TB



The results of surveillance data on MDR-TB should be interpreted carefully keeping in mind the fact that globally, less than 4 per cent of new bacteriologically-positive cases and 6 per cent of previously treated cases were tested for MDR-TB in 2011 in accredited laboratories, with particularly low levels of testing in the South-East Asia (where India is located) and Western Pacific regions [37] . The recent global epidemiological data on M/XDR-TB are shown in [Table 3]A, [Figure 1]A and 1B. XDR-TB has been documented from many parts of the world [Figure 1]C [40],[41] . {Figure 1}{Table 3}

 Indian scenario



Observations from reliable accredited mycobacteriology laboratories from India suggest that the prevalence of MDR-TB is quite low in new TB cases (<3%) compared with previously treated patients (15-30%) [42],[43],[44],[45] [Table 3]B. The prevalence of XDR-TB in studies published from India where drug-susceptibility testing (DST) was carried out in quality-assured, accredited laboratories is shown in [Table 3]C [46],[47],[48],[49],[50],[51],[52][,[53] .

 Risk factors



Conventionally several genetic, social, environmental and biological determinants of health have been intuitively recognized by clinicians as risk factors for TB [Table 4] [54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73] . Some of these risk factors are discussed below.{Table 4}

Genetic factors

Certain key issues should be considered while evaluating genetic susceptibility to TB disease. Susceptibility to TB does not follow a Mendelian pattern and is polygenic and multifactorial. Presence of two different genomes, (of the TB bacillus and the host) and their interaction can have influence on the disease [58] . Several reports have implicated a long list of genes with risk of developing TB [Table 4] [58],[59],[60],[61] .

HIV infection

HIV infection and AIDS stand out as the most significant among all the risk-factors for TB and has consistently and significantly altered the incidence rate of TB over the last three decades [62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73] . The impact of HIV/AIDS has been most profound in HIV prevalence sub-Saharan Africa where a dramatic increase in TB notification rates have been documented concurrent with increasing HIV prevalence. Among persons living with HIV (PLWH) TB can develop at any stage of HIV infection and there is a strong evidence suggesting that a declining CD4+ T-lymphocyte count and high viral load are risk factors for disease, while treatment with highly active antiretroviral therapy (HAART) reduces risk [62],[63],[64].

HIV infection and MDR-TB: Even though several institutional outbreaks of MDR-TB among HIV-infected patients drew attention to the problem two decades ago [74],[75],[76],[77],[78] as per currently available evidence [79],[80],[81] , HIV infection per se does not appear to be a risk-factor for MDR-TB.

Diabetes mellitus

The lethal interaction between diabetes mellitus (DM) and TB is being increasingly recognized world over [82],[83],[84] . Epidemiological modelling data suggest that in India, 14.8 per cent of all pulmonary TB cases and 20 per cent of sputum smear-positive cases have DM [84] suggesting that DM substantially contributes to the burden of TB, especially sputum smear-positive pulmonary TB in India.

Use of immunomodulator biologicals

Use of immunomodulator drugs (biologicals) has been associated with the development of fatal TB in rheumatoid arthritis [85],[86] .

Tobacco smoking

Data from recent systematic reviews on tobacco smoking and TB suggest that tobacco smokers have about three-fold higher risk of TB than non-smokers; even after adjustment for other factors [87],[88],[89],[90],[91] .

 Changing clinical presentation of TB



Natural history of TB

The natural history of TB [Figure 2] [23],[27],[62],[92],[93],[94],[95],[96] is influenced by several factors, the course being determined by the balance between the host immunity and the virulence of the TB bacillus. This understanding also facilitates identification of areas where interventional strategies can be identified for control of TB.{Figure 2}

Atypical clinical presentations

Cryptic miliary TB: Miliary TB that was earlier seen primarily as a disease of children, is being increasingly encountered in adults since the 1970s [23],[27],[28],[97] . Apyrexial presentation with progressive wasting strongly mimicking a metastatic carcinoma (cryptic miliary TB) that has been described especially among older people [23],[27],[28],[98],[99] often used to be diagnosed only at autopsy. This entity is being increasingly diagnosed during life in young immunosuppressed persons presently. This has been possible by the advances in imaging studies and increasing use of interventional procedures to procure tissue for confirming the diagnosis.

Acute lung injury and acute respiratory distress syndrome: TB as a primary cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is also being reported in the recent years especially in areas where TB is highly endemic [100],[102],[103] . Increased awareness regarding this entity among intensivists, invasivists and internists, has resulted in a focused search for TB as the treatable cause in patients presenting with ARDS of obscure aetiology.

TB in patients receiving immunomodulator biologicals: Data regarding the clinical presentation of TB in patients receiving immunomodulator biological, such as, anti-tumour necrosis factor (anti-TNF) antibodies infliximab, adalimumab, golimumab and certolizumab pegol; and the soluble TNF receptor etanercept are emerging. The rate of TB was three to four-fold higher in patients receiving infliximab and adalimumab than in those receiving etanercept [86.

Presentation as 'pyrexia of unknown origin': In areas where the disease is endemic, TB tops the list of aetiological causes of pyrexia of unknown origin (PUO) [104],[105] . Till about two decades ago, clinicians either empirically administered anti-TB treatment or had to resort to invasive surgical procedures such as scalene node biopsy, laparotomy to ascertain the diagnosis. Often, the TB was diagnosed only on post-mortem examination. In patients presenting with PUO, miliary TB [27],[28] , intrathoracic (e.g., paratracheal, mediastinal, hilar) and intraabdominal (e.g., retroperitoneal, porta hepatis) lymph node TB [94],[106] , intestinal, omental and mesenteric, hepatic, splenic TB [107] , vertebral TB (often with paraspinal cold abscess) [108] , pelvic ascites [109],[110] are important occult locations that are identified as the focus of fever by imaging methods facilitating ante-mortem diagnosis. Many times, bone marrow aspirate and biopsy smear, mycobacterial culture and molecular test evidence could be the only discernible cause of TB in these patients [62],[94] .

Sudden cardiac death: Sudden cardiac death due to TB myocarditis, especially in young persons is increasingly being recognized. This condition is often diagnosed at autopsy and extensive TB infiltration of the myocardium with minimal systemic involvement has been described; occult miliary TB has been implicated as the possible cause of myocarditis [111],[112] . Ante-mortem diagnosis of this condition is now possible with echocardiography, and cardiac magnetic resonance imaging (MRI) [113],[114] .

 TB among healthcare workers



Health-care workers (HCWs), who are often in close proximity to patients with TB are at an increased risk of developing TB. It has been estimated that in areas of high TB incidence (>100/100,000 population), the stratified pooled estimates for LTBI and TB incidence rate ratios were 8.4 (95% CI 2.7-14.0%) and 3.7 per cent (95% CI 2.9-4.5), respectively; median estimated population-attributable fraction for TB was as high as 0.4% (115). These figures serve as warning bells, especially with regard to HCWs caring for patients with X/MDR-TB [116] and highlight the need for institution of preventive measures. Further, it has been shown that institution of basic administrative and engineering controls and personal protection measures can be effective in reducing the annual tuberculin skin test (TST) conversion rates in HCWs [117] .

 Diagnosis



Latent TB infection

Diagnosis of LTBI has been considered important as a tool for assessing the burden of TB for epidemiological purposes. Because LTBI contributes significantly to the pool of active TB cases later on, its recognition is assuming importance in high-risk groups where there is a potential for instituting treatment for this condition [92] . The tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) have been used as diagnostic tests for the detection of LTBI [Table 5]A [118],[119],[120],[121] . {Table 5}

In high burden TB countries, neither IGRAs nor TST have been found to be adequate in accurately identifying persons who will benefit from treatment of LTBI with false positivity rates greater than 50 per cent being reported for both [122],[123],[124],[125] . In this connection, a recent policy statement issued by the WHO [125] and the European Centre for Disease Prevention and Control guidelines [124] discourage the use of IGRAs in preference to TST, in areas where TB is highly endemic.

Diagnosis of active TB disease

The current diagnostic and genotyping methods for TB are listed in [Table 5]B [125],[126], [127],[128],[129],[130],[131],[132],[133],[134],[135],[136],[137],[138],[139],[140],[141] . Innovations such as use of fluorescent staining, light-emitting diode (LED) based microscopes have helped optimizing the yield of sputum smear examination [126] . Sputum mycobacterial culture is considered to be the 'gold standard' for the diagnosis of TB and it also facilitates DST. However, reliable, periodically accredited facilities for mycobacterial culture and DST are not widely available in TB high burden countries limiting their usefulness. Conventional sputum mycobacterial culture takes 6-8 weeks time and valuable time is lost in establishing the definitive diagnosis. In the 1980s, new semi-automated and automated culture systems based on liquid culture medium became available, such as the BACTEC-TB460 radiometric system (Becton Dickinson, Sparks, MD, USA) and facilitated rapid culture and detection of M. tuberculosis with a turn-around time of about 10 days [127],[129] . For nearly a two decades, this was used for rapid culture and DST. The non-radiometric rapid liquid culture methods like Mycobacteria Growth Indicator Tube (MGIT) and BacT/ALERT (BioMe´rieux) then emerged. In 2007 the WHO endorsed the use of liquid culture assays, DST [129] and rapid speciation (strip speciation) tests that detect a TB-specific antigen from positive liquid or solid cultures to confirm the presence of TB bacillus [Capilia TB; Tauns Laboratories Inc., Shizuoka, Japan] [130] for faster diagnosis of TB and MDR-TB [37] .

The nucleic acid amplification based TB diagnostic tests (NAAT) are based on the amplification of short specific sequences of DNA or RNA of M. tuberculosis complex by PCR and the amplified products are then detected by agarose/acrylamide gel electrophoresis, or by various hybridization methods [142] . Several in-house PCR assays and commercial kits have been used for rapid diagnosis of TB.

Integrated automated NAAT, the GeneXpert (Cepheid Inc., Sunnyvale, CA, USA) platform combines automated sample preparation, real-time PCR amplification, identification of M. tuberculosis and detection of rifampicin resistance in less than 120 minutes [142] . GeneXpert has the advantage of being simple to use even in field conditions and appears promising technology for rapid diagnosis of TB. However, this test requires uninterrupted electric power supply and is expensive. This test is being evaluated by Revised National Tuberculosis Control Programme (RNTCP) in field conditions.

Promising results from studies carried out in low-resource countries suggest that loop mediated isothermal amplification (LAMP) has the potential to be a candidate as a molecular test for the rapid diagnosis of TB in clinical samples [143],[144] . M. tuberculosis produces volatile organic compound (VOC) metabolites in-vitro, and their presence in the breath has been considered to be apparent biomarkers of infection [145],[146] .

 Serodiagnostic Tests



A broad range of serodiagnostic tests with a varying degree of reliability, repeatability and concordance have been used for the diagnosis of TB. Since no commercial serological assay could consistently result in an improved outcome, the WHO recently recommended that commercial serological tests should not be used for the diagnosis of pulmonary and extrapulmonary TB [147] . This view has been endorsed by the RNTCP of Government of India also [148] .

Diagnosis of extrapulmonary TB (EPTB)

The yield of conventional AFB smear and mycobacterial culture and some commonly used non-conventional tests in the diagnosis of EPTB is shown in [Table 6] [149],[150],[151],[152],[153],[154],[155],[156],[157],[158],[159],[160],[161],[162],[163] . A focused diagnostic approach, procurement of appropriate body fluid and tissue specimens and subjecting these to a battery of diagnostic tests including culture (and DST where feasible) will enhance the diagnostic yield in EPTB. There is a need to systematically evaluate and establish the utility of recently available newer tests such as GeneXpert to facilitate an early diagnosis and increase the diagnostic yield. {Table 6}

Development of accreditation system, quality assured laboratory network expansion

The eventual goal of controlling and probably eliminating TB hinges on rapidly and correctly identifying all TB cases and ensure that all diagnosed patients receive individualized treatment with anti-TB drugs tailored to the DST profile of the isolates obtained [164] . The ongoing struggle to meet the global target for case detection of diagnosing at least 70 per cent of new smear-positive cases, reflects the yawning gap between the need and the availability of quality assured laboratory infrastructure, especially in developing countries like India. Strengthening the capacity of public-sector laboratory networks, ensuring their accreditation initially and periodically thereafter so that a network of reliable quality assured accredited laboratories is eventually available to take TB control forwards are initial steps in this direction. The Expanding Access to New Diagnostics for TB (EXPAND-TB) project [165] , a collaboration among WHO, the Global Laboratory Initiative (GLI), Foundation for Innovative New Diagnostics (FIND) and the Global Drug Facility (GDF), and funded by UNITAID and other partners aims to improve capacity to diagnose MDR-TB in upgraded laboratory services in 27 countries.

In India, The RNTCP has also adopted a rigorous procedure for granting accreditation to culture and DST laboratories both in public and private sectors and medical colleges to provide accurate and reliable services for MDR-TB diagnosis and treatment follow-up. By 2015, it is expected that universal access to MDR-TB diagnosis and treatment will be made available for all smear positive TB cases under the RNTCP [30] .

 Imaging Studies



Imaging modalities such as conventional radiography, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography CT (PET-CT) have been used to localize the disease, assess the extent of organ involvement and evaluate response to treatment. The chest radiograph is the mainstay of imaging pulmonary TB [Figure 3]A-E. However, the chest radiograph can be normal in HIV-infected patients with late HIV disease with active TB disease and in some patients with miliary TB [166],[167] . Ultrasonography helps in detecting pleural effusion and ascites (which may sometimes be loculated), focal lesions in the liver and spleen, cold abscesses, intra-abdominal lymphadenopathy, involvement of other abdominal organs. High resolution CT (HRCT), thin-section multidetector row CT (MDCT) have been helpful in identifying pulmonary and miliary lesions, even in those in whom the chest radiograph is normal and has facilitated more frequent antemortem diagnosis of 'cryptic miliary TB' that was earlier diagnosed only at autopsy. CT of the thorax also allows detection of intrathoracic lymphadenopathy, calcification, pleural, pericardial and vascular lesions [Figure 3]F-I, [Figure 4]. CT and MRI of the brain and CT of the abdomen have also been extensively used to study CNS TB and abdominal TB, respectively [Figure 5]. Magnetic resonance spectroscopy (MRS) has been found to be useful in patients with intracranial tuberculomas where a characteristic large lipid peak with reduced n-acetyl aspartate peak can be seen. PET-CT using 18 F labelled 2-deoxy-D-glucose (FDG) is helpful in locating, defining the extent of activity of TB at various organ sites (that may sometimes not be clinically discernible) [Figure 6] especially in patients with disseminated TB and assessing the activity of lesions that might persist following anti-TB treatment on follow-up. [11] C-choline PET scans can help differentiate between lung cancer and tuberculoma. The standard uptake value of tuberculoma is low in [11] C-choline PET scans [168] .

In patients presenting with PUO with no focal localizing clue, nuclear medicine techniques using gallium-67 citrate, technetium-99m methylene diphosphonte [Figure 7], radiolabelled white blood cells, and human immune globulin imaging have been used to identify occult foci of infection especially in the bones. However, these techniques have been relatively non-specific and have not been able to distinguish bacterial mediated infection from non-bacterial inflammation due to other causes [169] . Recently, the radiopharmaceutical technetium-99m labelled ciprofloxacin ( 99m Tc-CPF) has been developed and shown to localize in high concentrations in bacterial abscesses, and not in areas of sterile inflammation [170],[171] . Though not specific for TB, this technique has been used to localize foci of TB osteomyelitis as well [172] and also assess the adequacy of short-course treatment of TB osteomyelitis [173] .{Figure 3}{Figure 4}{Figure 5}{Figure 6}{Figure 7}

Procurement of body fluids/tissues for diagnostic testing

Radiographic image guided interventional procedures, biopsy of peripherally accessible lesions ( e.g., lymph nodes), endoscopic procedures like laparoscopy, colonoscopy, thoracoscopy, can be used in appropriate settings to procure material for diagnostic testing for TB. Endoscopic interventions, such as, endobronchial ultrasound bronchoscopy (EBUS) and endoscopic oesophageal ultrasound, FNACs, biopsies are useful in situations where patients are sputum smear-negative, are unable to produce sputum, present with intrathoracic ( e.g., mediastinal, sub-carinal, hilar) lymphadenopathy to procure tissue. Material thus obtained should be subjected to cytopathological, histopathological, microbiological (including DST) and molecular methods for confirmation of TB diagnosis.

 Treatment



Evolution of modern multiple drug treatment

The humankind had to wait for more than 60 years following Robert Koch's momentous announcement of the discovery Mycobacterium tuberculosis for drug(s) that could cure TB to become available [Figure 8] [174],[175],[176],[177],[178],[179],[180],[181],[182],[183],[184],[185],[186],[187],[188],[189],[190],[191],[192],[193],[194] . The first controlled clinical trial in the history of medicine conducted by the British Medical Research Council (BMRC) [179] demonstrated the activity of streptomycin. The BMRC assessed the addition of PAS to streptomycin in a controlled clinical trial [181] which showed a lower rate of clinical deterioration, higher rate of culture conversion, and a lower rate of streptomycin resistance in patients receiving streptomycin plus PAS, suggesting that combination treatment with PAS was helpful in preventing the emergence of drug resistance to streptomycin. The first clinical trial with isoniazid was initiated in 1951 [182] . Subsequent studies by BMRC [183],[184] further assessed the utility of using two of the three drugs, namely, streptomycin, isoniazid and PAS in various combinations to treat TB. A later clinical trial by BMRC [185] established the duration of anti-TB treatment that would effectively prevent relapse, to be 18-24 months. {Figure 8}

Ethambutol, discovered in 1961 got added to the armamentarium of anti-TB drugs [186] and soon replaced PAS in the standard regimens. In the 1960s seminal research conducted by Wallace Fox and co-workers at the National Institute for Research in Tuberculosis (NIRT), Chennai [then called as Tuberculosis Chemotherapy Centre, Madras; later renamed as Tuberculosis Research Centre (TRC), Madras in 1978] showed that home or ambulatory treatment was almost as effective as sanatorium treatment "provided the regular use of anti-TB medication was well organized and supervised", a fact that is often neglected even today [187] . The classic NIRT studies [187],[188] also established the efficacy of intermittent administration of anti-TB medications. These fundamental principles have since then remained the pillars on which modern treatment of TB is based.

Subsequently, with the introduction of rifampicin [189] based on the data from studies conducted in the 1970s [190] the standard treatment duration of anti-TB treatment could be shortened to 9 months. By then the 9-month rifampicin containing regimens replaced the then prevailing standard treatment of 18-months. In 1972, the therapeutic role of pyrazinamide used in a reduced dosage was rediscovered in the studies conducted by East Africa Medical Council and BMRC [193] . Combining pyrazinamide to rifampicin containing regimens then ensued. The 6-month regimens containing rifampicin and pyrazinamide were as effective as either rifampicin or pyrazinamide containing regimens in the clinical trials by the British Thoracic Society [194] heralding the modern 6-month short-course chemotherapy endorsed by the WHO that has become the standard of care worldover. Since then, most countries have been using the WHO endorsed standardized daily or thrice-weekly intermittent treatment regimens in National TB Control Programmes.

National Tuberculosis Programme (NTP)

In 1962, the NTP was started in India, the first time ever a 'national programme' was conceived to tackle the menace of TB in the world. Short-course chemotherapy was introduced in the NTP by 1985. However, uninterrupted drug supply and treatment adherence continued to plague the NTP and the programme did not make a significant epidemiological impact on the prevalence of TB in the country [195] . This led to introspection and a comprehensive joint review of the TB programme in India by members of several organizations including the Government of India, WHO and Swedish International Development Agency (SIDA) in 1992 identified many issues that were affecting the programme performance [196] .

Revised National Tuberculosis Control Programme

To revamp TB control in India, in 1993, the RNTCP, based on the WHO-recommended DOTS strategy, began operations in five pilot sites. Following pilot testing, large scale expansion of RNTCP in India began in 1997 in a phased manner and by March 24, 2006, the whole country was covered by the RNTCP. The Programme aims at achieving and maintaining a cure rate of at least 85 per cent among new sputum positive (NSP) patients, and to achieve and maintain case detection of at least 70 per cent of the estimated NSP cases in the community [196],[197] .

Treatment of active TB disease: issues concerning dosing frequency and duration of treatment

The current treatment regimens listed in the recent WHO guidelines for national programmes [29] and the RNTCP of Government of India [30] are shown in [Table 7]A, B and C. The WHO guidelines [29] suggest that HIV patients co-infected with TB should be treated with daily regimens. This recommendation has been based on evidence from meta-analyses [198],[199] that showed that HIV co-infected patients with pulmonary TB were at a higher risk of acquired rifampicin resistance, when failing a three times weekly short-course intermittent regimen. In the meta-analysis [199] of treatment of active TB in HIV co-infected patients, data from six randomized trials and 21 cohort studies showed that compared with daily therapy in the initial phase (n=3352 patients from 35 study arms), thrice-weekly therapy (n=211 patients from 5 study arms) was associated with higher rates of treatment failure (adjusted risk ratio, 4.0; 95% CI 1.5-10.4) and relapse (adjusted risk ratio 4.8; 95% CI 1.8-12.8) and a trend toward higher relapse rates if rifamycins were used for only 6 months, compared with 8 months or more, or if antiretroviral therapy was not used. In a study from India [200] the outcome of fully intermittent thrice-weekly antituberculosis treatment regimens of 6-month isoniazid, rifampicin, pyrazinamide and ethambutol, followed by 4 months of isoniazid and rifampicin; and a 9-month regimen where the intensive phase was same but continuation phase was 7 months, were assessed in HIV-TB co-infected patients. In the 'intent-to-treat analysis', among patients who had a favourable outcome at the end of treatment, bacteriologically confirmed recurrence rate was significantly higher with the 6-month regimen compared with the 9-month regimen. {Table 7}

Daily vs thrice-weekly treatment: Under the RNTCP, in India, 15,852,745 patients have been treated with thrice-weekly intermittent treatment and 2,853,494 lives have been saved [201] reflecting the huge success achieved by the RNTCP programme over the last 15 years. While thrice-weekly intermittent treatment seems adequate in HIV-seronegative patients, use of daily therapy is an important issue to contend with in HIV-seropositive persons. The prospect of considering the implementation of a daily treatment regimen and the logistics of direct observation of treatment are being actively considered and a clear-cut government policy on the same is expected to be available soon. However, head-on comparisons of adequately powered, fully daily, partial daily (daily intensive phase and thrice-weekly intermittent continuation phase) and fully thrice-weekly intermittent regimens are not available in the literature and studies of this nature will help in arriving at optimal dosing frequency issue so that policy can be modified.

There is also a lack of consensus regarding the optimal duration of therapy in patients with EPTB, especially bone and joint TB, neurological TB; disseminated and miliary TB. While 6-months of treatment may be adequate in HIV-seronegative new patients with pulmonary TB and focal extrapulmonary TB, individual patients may require 9 to 12 months of treatment when TB meningitis is present given the serious risk of disability and mortality; and 9 months of treatment when bone and joint TB is also present. The efficacy and safety of erstwhile Category III (intermittent thrice-weekly rifampicin, isoniazid and pyrazinamide for 2 months, followed by rifampicin and isoniazid for 4 months) DOTS has been documented in the patients with uncomplicated small (<1500 ml) unilateral pleural effusion [202] , and peripheral lymph node TB [203] .

Treatment of HIV-TB co-infection and X/MDR-TB

Treatment of active TB in patients co-infected with HIV requires careful consideration of drug-drug interactions between anti-TB and anti-retroviral drugs [Figure 9] [204],[205] . Treatment of X/MDR-TB is expensive and time-consuming, and requires special facilities with adequate infrastructure, reliable, access to periodically accredited mycobacterial culture and sensitivity laboratories, medical, nursing and para-medical personnel trained in the management of X/MDR-TB [206] . In India, the RNTCP started treatment of X/MDR-TB through the DOTS-Plus services in 2007 in a phased manner and at present all Indian states have been covered [30] .{Figure 9}

 Key issues in TB treatment monitoring



Drug-drug interactions

Clinically significant interactions during anti-TB treatment should be carefully monitored as these may sometimes result in therapeutic failure or drug toxicity [207],[208] . This is particularly important in HIV-co-infected persons, the elderly and those with significant co-morbidities receiving treatment for the same (Box 1[SUPPORTING:1]) [207],[208],[209],[210],[211],[212],[213],[214],[215],[216],[217],[218],[219],[220],[221],[222],[223],[224],[225],[226],[227],[228].

Drug induced hepatotoxicity (DIH)

Principles underlying evaluation of patients with DIH are listed in Box I [207], ],[208],[209],[210],[211],[212],[213],[214],[215],[216],[217],[218],[219],[220],[221],[222],[223],[224],[225],[226],[227],[228] .

Immune reconstitution inflammatory syndrome (IRIS)

Paradoxical deterioration of lesions of TB in patients receiving anti-TB treatment has been known for a long time (218). Key developments in the understanding of IRIS are listed in Box I [219],[220],[221],[222],[223],[224],[225],[226],[227],[228] . Minor manifestations of IRIS can be managed with non-steroidal anti-inflammatory drugs (NSAIDS). Moderate-to-high dose corticosteroid treatment, sometimes for prolonged periods may be required for the treatment of paradoxical TB-IRIS and may be beneficial in TB-IRIS with CNS manifestations, tracheal compression due to lymphadenopathy, acute kidney injury and acute respiratory distress syndrome (ARDS) [218],[219] .

Treatment of LTBI

The WHO has stressed on the importance of interventions like ART provision and the three Is for HIV-TB coinfection, namely intensified TB case finding, infection control, and isoniazid preventive therapy (IPT), as part of prevention, care and treatment services [229] . The diagnosis and treatment of LTBI have been extensively reviewed recently [92] . It is necessary to rule out active TB disease before initiating treatment for LTBI. Important issues concerning LTBI and its treatment [92],[230],[231],[232],[233],[234] are listed in [Box 2[SUPPORTING:2]].

 Control of TB



Global measures: India conceived the NTP and set an example to the world in the programmatic approach to TB control in 1962 [197] . Since then several efforts have been undertaken globally to achieve control of TB and are summarized in [Box 3[SUPPORTING:3]] [235],[236],[237],[238] . These developments reflect the efforts towards achieving universal access to preventive, diagnostic and treatment services for all forms of TB.

As a result of the implementation of RNTCP, prevalence of all forms of TB has been brought down (from 338/100,000 population in 1990 to 249/100,000 population in 2009); TB mortality has also reduced (from >42/100,000 population in 1990 to 23/100,000 population in 2009) in India. The Phase II (2006-2012) of the RNTCP has achieved the set goals, the country is coursing towards achieving "universal access" for control of TB [197] and appears to be on track to achieve the TB related United Nations Millenium development Goals (UNMDG). Jointly with National AIDS Control Programme (NACP), RNTCP has developed "National framework of joint TB/HIV collaborative activities" that are being implemented in the country [197] .

Involvement of Medical Colleges in TB control

For the first time in the global history of TB control, Indian Medical Colleges were involved in the RNTCP. This unique experiment in the history of TB control has resulted in medical colleges providing diagnostic services (Designated Microscopy Centres), treatment (DOT Centres), referral for treatment, recording and reporting data, carrying out advocacy for RNTCP and conducting operational research on the RNTCP [238] .

 Prevention



Even though the declining trends observed in the global burden of TB currently [37],[239],[240],[241],[242] , this trend seems insufficient to achieve the global target of elimination of TB in 2050 [164] . Therefore, the need for other measures including infection control measures, newer or repurposed anti-TB drugs, newer and better vaccines for TB is pressing.

Airborne infection control measures

Recognizing the importance of airborne infection control and in view of the association of TB with HIV and the emergence of X/MDR-TB, guidelines have been issued for implementing the same by the WHO [239] and the RNTCP [240] as well. However, there is a wide gap between the needs and the actual implementation of these guidelines presently especially in the overcrowded government hospitals in India and other developing countries.

 TB Vaccine



Till date the bacille Calmette-Guerin (BCG) vaccine is the only vaccine available for TB [241],[242],[243],[244] . Though BCG confers consistent protection against severe forms of TB, such as TB meningitis, disseminated and miliary TB in children in areas where TB is endemic its ability to protect against pulmonary TB has been found to be variable [245],[246] . New candidate vaccines for TB are in various stages of development and are listed in [Table 8] [241],[242],[247] . {Table 8}

The summary of important changes in TB during the last 130 years since the time of Robert Koch in 1882 are listed in [Table 9].{Table 9}

 The Future



The search for newer and more efficient biomarkers for predicating a durable (non-relapsing) cure, indication of reactivation risk, prediction of eradication of LTBI; and prediction of vaccine efficacy [248],[249] , discovery of newer anti-TB drugs [250],[251],[252],[253] and development of newer additional candidate vaccines [254],[255],[256],[257] is required to achieve the WHO and UNMDG goal of halting the incidence, prevalence and death rates associated with TB by 2015 and eliminating the disease altogether by 2050 [197] . Translation of newer innovative diagnostics for TB, such as, use of a 'hand-held' nuclear magnetic resonance (NMR) apparatus capable of offering a 30-minute diagnosis of TB [258] , applications of nanotechnology [259],[260] to point-of-care diagnostic tests needs to be pursued.

 Newer, repurposed drugs in pipeline



Presently, several newer or repurposed drugs are in pipeline in various stages of development as anti-TB drugs [252],[261] . Among the newer drugs, delamanid (OPC67683), bedaquiline (TMC207) and the nitroimidazole-oxazine PA-824 have been found to be active against both drug-sensitive and drug-resistant strains. Bedaquiline (TMC207) has been approved for use by the United States-Food and Drug Administration (US-FDA). Their efficacy and safety have been demonstrated in MDR-TB patients in double-blind, placebo controlled phase II clinical trials [262],[263],[264] . The Government of India is planning to regulate the introduction of these newer drugs in a systematic fashion by streamlining the conduct of clinical trials in India. Evidence is available that isoniazid-resistant clinical isolates of M. tuberculosis remain fully susceptible to the drug pyridomycin, a compound produced by Dactylosporangium fulvum with specific bactericidal activity against mycobacteria [265] . Pyridomycin merits further evaluation as an anti-TB drug.

Initiatives like the Critical Path to New TB Regimens (CPTR) involving several pharmaceutical companies and non-governmental organizations have been attempting to develop the newer drugs concomitantly in combination trials so that the best regimen and the shortest duration of time can be evolved [266] . Additional vaccine candidates are likely to enter clinical trials in future [254],[255],[256],[257] .

The last 70 years have witnessed an initial euphoria of emergence of drug treatment of TB that raised hopes and even signalled a likely 'elimination' of TB. Inspite of political commitment, global and national programmatic strategy to contain and control TB, eventual elimination of TB in near future appears to be a mirage as of now. The widespread occurrence of X/MDR-TB threatens to take us back to the era of untreatable TB. TB has come a long way, from despair and the status of an incurable malady, through a brief interlude of a curable disease to a scourge that is menacingly threatening the return to dark ages. The fall in the absolute number of TB cases globally observed since 2006 is heartening. With newer and repurposed anti-TB drugs emerging and becoming available for use, the march of the humankind towards the goal of TB elimination, i.e., reducing the annual incidence to less than 1 case/1,000,000 population by 2050 [267] appears to be on course in the right direction.

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