6 months for MDR-TB
HD: high dose; RIF: rifampicin; INH: isoniazid; RFP: rifapentine; ETM: ethambutol; PZA: pyrazinamide; MFX: moxifloxacin; LFX: levofloxacin; LZD: linezolid; ETH: ethionamide; BDQ: bedaquiline; DLM: delamanid; Pa: pretomanid; CFZ: clofazamine; Kan: kanamycin; Pro: prothionamide; Pl: Placebo. # : ClinicalTrials.gov identifier. Information from [ 1 , 104 ].
While many of these trials demonstrate promise for an improved approach to TB treatment, it is essential that we see long-term data on their efficacy and relapse rates prior to implementing them on a global scale. The fear is that these patients may have excellent short-term results, but disease recurs soon after with the added potential for drug resistance to develop.
In addition to shorter regimens, with new or re-purposed drugs, there is research into methods of modifying the host immune response to improve treatment outcomes and prevent permanent morbidity from TB disease. As previously discussed, upon infection with Mtb the host can either suppress bacillary replication into a latent state, or the host is overwhelmed and active disease develops [ 72 ]. Both deficient and hyperinflammatory states have been associated with TB disease morbidity and mortality, suggesting that tailoring a balanced immune response is of paramount importance to survival [ 73 ]. With evolving knowledge of the pathways and subcellular responses involved, new therapeutic targets are being developed to assist with bacillary quiescence in the so called “host directed therapy” approach [ 74 ]. Numerous drug targets have been suggested, largely centred on modulating macrophage activity [ 75 ]. Proposed adjunctive therapies include vitamin D, everolimus, auranofin and CC-11050, a novel anti-inflammatory compound. Preliminary results from trial data suggest none of these compounds improve rates of sputum conversion; however, patients in receipt of CC-11050 or everolimus had increased recovery of FEV 1 (forced expiratory volume in 1 s) post-treatment, perhaps solidifying the role of a balanced immune response to infection [ 76 ].
Going forward, with a combination of new drugs, altered durations and more effective testing of response to treatment, it is likely that each patient will have a tailored approach to TB treatment [ 49 ]. With studies like PredictTB, aiming to determine biomarkers and radiographic appearances that predict response and likelihood of relapse, we will be able to devise a drug combination and duration with greater specificity for each patient [ 77 ]. Similar technology may even assist with developing even more efficacious drugs in early-stage clinical trials [ 78 ]. Additionally, it is essential that any new drug or technology developed is affordable and available to all institutions, most importantly hospitals in low-resource environments, where the majority of the global TB burden persists.
Despite ongoing research, treatment for DS-TB has remained unchanged for decades. This highly effective regimen is often poorly tolerated by patients, and “drug holidays” are frequent during treatment. This, of course, increases the likelihood of relapse and evolution of drug resistance. Moreover, patients with resistant TB have to endure longer regimens with their own associated side-effects. While awaiting the development and approval of less toxic regimens, there are a number of measures we can take to ameliorate adverse effects of treatment and promote patient adherence. It has been shown that comprehensive patient-centred approaches, involving nutritional, financial and psychological support, have higher rates of completion. In addition, patients with increased contact with healthcare workers tended to have lower drop-out rates during treatment [ 79 ]. The evidence base for this is provided by systematic reviews of mostly observational case studies and case cohorts, and as such randomised research in this area is required to determine a formal link.
Directly observed therapy (DOT) has been a standard of care in TB treatment for several years. The premise is that patients are more likely to comply if medication ingestion is witnessed multiple times per week. Current recommendations are that it should be implemented in MDR- or XDR-TB cases, or for patients with complex or vulnerable care needs, such as homelessness, comorbid psychiatric illness or addiction [ 80 ]. There have been conflicting results from systematic reviews on the efficacy of DOT [ 81 , 82 ]. What is known, is that community-based DOT appears to be the most effective strategy, as it is less disruptive for patients and thus their adherence is more likely to be maintained [ 83 ]. In recent years, attention has switched towards the use of smartphone technology. Video observed therapy (VOT) has been suggested as an even less disruptive form of monitoring adherence [ 84 ]. Patients can either upload videos of medication ingestion to a secure platform to be watched at a later date, or it can be taken while on a live feed with their healthcare team. VOT has been shown to have a higher uptake rate and patient preference rating [ 85 ]. While plausible that this will improve adherence, and thus relapse should be less likely, this study was not sufficiently powered to assess this, nor did it follow up on relapse rates at an appropriate interval. A real-world efficacy and cost-effectiveness study is ongoing in a tertiary hospital in Ireland at present [ 86 ].
Undoubtedly, a burden of TB infection will persist for years to come. However, we have a chance to prevent many of these patients from progressing to active disease. Screening for TB infection in groups at high risk of progressing to TB disease remains a cost-effective and essential component to the global initiative. Screening via either of the endorsed interferon-γ release assays (QuantiFERON-TB Gold In-Tube and T-SPOT.TB) or traditional tuberculin skin testing is recommended in certain populations. The WHO has advised that clinical judgement is paramount in interpreting these tests, and cautions that a higher rate of false negatives occurs in the most vulnerable populations [ 87 ]. Another essential component of the sustainable development goals is robust public health policy to assist in contact tracing of index cases and early treatment of contacts. In addition, prior to any prophylactic treatment being commenced, it is essential that due caution is taken to rule out the presence of active TB disease.
Currently the WHO advocates for treatment with 4 months of RIF or 6–9 months of INH in cases where the index case is known to be drug sensitive [ 87 ]. A 3-month combination of RIF and INH is also approved, although rarely used due to potential toxicity. Additionally, weekly INH and RFP for 3 months has been shown to demonstrate equal efficacy and toxicity in comparison to 6 months of INH therapy, while higher levels of adherence were noted in the INH/RFP arm [ 88 ]. Moreover, a 1-month regimen of RFP/INH therapy was non-inferior to 9 months INH monotherapy in preventing TB in HIV-infected patients [ 89 ]. However, this regimen has yet to be endorsed by major international consortia.
The recommendations for TB contacts of DS-TB cases who demonstrate evidence of TB infection are as per those above. For contacts of MDR-TB cases, the current recommendation is for 6–12 months treatment with a FLQ with or without a second drug. If a FLQ cannot be used due to resistance in the index case, treatment with ETM and PZA is to be considered [ 87 ]. Regardless of the regimen in use, it is vital that strict adherence is maintained to ensure efficacy and prevent resistance.
At present, the decision to treat is based on the potential for progression to active disease based on similar case profiles. Going forward, we could vastly improve the cost efficacy of this intervention by being able to determine exactly which patients were going to progress to active TB disease or not. It had been hoped the answer would lie in serum transcriptional biomarkers and host response-based gene signatures [ 90 , 91 ]. Recently, a four-protein biomarker panel has shown 67.3% sensitivity and 96.3% specificity at determining active from latent TB [ 92 ]. This subclinical phase of TB disease can be difficult to interpret due to its lower inflammatory profile and person specific confounding factors that influence our immune response. Recent results from transcriptomic studies have been disappointing overall, but may potentially suggest a role for these panels in symptomatic patients with known TB infection and their risk of progression to TB disease in an imminent 6-month period [ 93 ].
Given the current prevalence of TB infection, with the associated lifetime risk of progressing to active disease, it is paramount that we protect future generations from this burden by halting transmission entirely. With greater understanding of the cellular processes involved in Mtb susceptibility and pathogenesis, scientists have been able to identify various potential targets with a role in vaccination. Central to this is the cellular immune response, with a need to upregulate T-helper cell (Th)1, and downregulate Th2 and regulatory T-cell responses [ 94 ]. It appears that Mtb has also recognised the need to adapt to this hypo-inflammatory phenotype with more modern strains displaying shorter latency and higher virulence than previously seen [ 95 ].
The only worldwide approved vaccine against TB remains bacillus Calmette–Guérin (BCG), effectively reducing the risk of severe childhood disease from TB, with an 85% reduction in TB meningitis and miliary TB in those <10 years of age [ 96 ]. It has also been noted that infants innoculated with BCG have increased survival and lower rates of other childhood infections. This observation is likely secondary to BCG's ability to prime innate immunity through epigenetic modification of innate immune cells [ 97 ].
Vaccination can be categorised into preventive pre-exposure, preventive post-exposure or therapeutic [ 98 ]. Vaccines can alternatively be classified according to their biochemical forms: live attenuated, inactivated, protein subunit or recombinant [ 99 ]. With each of these forms, the aim is to target various cells or subcellular components of TB pathogenesis.
MTBVAC, a pre-exposure live attenuated vaccine, has shown promising results from preclinical trials with a higher protection against TB than BCG [ 100 ]. This live vaccine is based on a genetically modified mutant Mtb strain containing deletions in transcription factors important for Mtb growth in macrophages and subsequent virulence.
VPM1002, another live recombinant BCG vaccine, is undergoing phase III studies at present to evaluate its efficacy at not only preventing infection, but in preventing active disease in those already affected [ 101 ]. This vaccine can modify T-cell immune response and enhance Th1 immunity, important in TB disease pathogenesis.
Another promising post-exposure candidate is M72/AS01E, a subunit vaccine, that prevents pulmonary TB in adults already infected with Mtb in 54% of patients, and thus could be a potentially life-saving intervention for one quarter of the world's population [ 102 ]. Also known as Mtb72F this vaccine comprises two immunogenic proteins that promote T-cell proliferation and interferon-γ release [ 103 ].
Further randomised control trials are warranted in a timely manner if the END TB strategy is to be achieved.
The future is bright for TB treatment. Never before has there been such a global effort to develop new technologies and treatment for TB patients. Combining these advancements, it is possible that we will base each patient's treatment on their own protein biosignatures in conjunction with the genomic expression of mutations in the Mtb strain they have been affected with. If we are to achieve our goal of global eradication of TB, it is essential that we continue to collaborate and share our expertise on an international scale to ensure each patient gets the appropriate treatment and support to overcome their TB diagnosis without significant morbidity.
Conflict of interest: C.M. Gill has nothing to disclose.
Conflict of interest: L. Dolan has nothing to disclose.
Conflict of interest: L.M. Piggott has nothing to disclose.
Conflict of interest: A.M. McLaughlin has nothing to disclose.
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Tuberculosis (TB), which is caused by bacteria of the Mycobacterium tuberculosis complex, is one of the oldest diseases known to affect humans and a major cause of death worldwide. Tuberculosis continues to be a huge peril disease against the human population and according to WHO, tuberculosis is a major killer of the human population after HIV/AIDS. Tuberculosis is highly prevalent among the low socioeconomic section of the population and marginalized sections of the community. In India, National strategic plan (2017-2025) has a national goal of elimination of tuberculosis by 2025. It requires increased awareness and understanding of Tuberculosis. In this review article history, taxonomy, epidemiology, histology, immunology, pathogenesis and clinical features of both pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis (EPTB) has been discussed. A great length of detailed information regarding diagnostic modalities has been explained along with diagnostic algorithm for PTB and EPTB. Treatment regimen for sensitive, drug resistant and extensive drug resistant tuberculosis has been summarized along with newer drugs recommended for multi drug resistant tuberculosis. This review article has been written after extensive literature study in view of better understanding and to increase awareness regarding tuberculosis, as a sincere effort that will help eliminate tuberculosis off the face of the earth in near future.
Keywords: Immunology; Tuberculosis diagnosis; Tuberculosis pathogenesis; Tuberculosis treatment.
Copyright © 2020 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.
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Which papers have provided the most interesting recent advances in tuberculosis research? Which new discoveries in pathogenesis, epidemiology, drug discovery or vaccine development have been the most important or are likely to have the highest impact to the field?
Rather than relying on citations, we posed these questions directly to the tuberculosis community and asked TB researchers to identify what they perceived as the most important papers over the past 3 years. We received feedback from around 50 experts. Their responses were astonishingly diverse, no doubt reflecting the diverse expertise of the scientists we polled. The hot list—papers suggested by at least three experts—along with some illuminating comments, is presented below. The numbers in blue show the percentage of respondents who picked that paper.
Topping the list is the identification of a new drug for tuberculosis that works by inhibiting a completely new target. Such new drugs are sorely needed, and nothing highlights this more strongly than the paper that appears at number two in the hot list. The Lancet report by Gerald Friedland and colleagues describes the extremely high mortality rates seen in HIV-infected patients infected with extensively drug-resistant TB (XDR-TB)—a strain resistant to almost all currently available drugs.
Perusing the other papers, five themes emerged as having seen important advances: secretion of virulence factors, new tools in genomics, new drugs, bacterial survival and metabolism. The papers from the top twenty that advanced these areas (shaded in yellow) are placed in context by experts in the field in the News and Views articles on pages 279–287 . The remaining papers from the list (shaded in blue) are discussed in brief on pages 288–289 . And to find out how much resemblance this top twenty bears to a list of high-impact papers generated by more traditional means (citations), turn to page 278 .
Andries, K. et al . A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis . Science 307 , 223–227 (2005).
“One of the most promising new anti-TB drugs currently in development.” Christopher Walsh , Harvard
Ghandi, N.R. et al . Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 368 , 1575–1580 (2006).
“A jolt to reality. The XDR-TB patients all died and almost all died within 16 days of the sputum samples being collected. It gave a crisis perspective to a problem we all knew existed but were adopting an ostrich approach to.” Salim Abdool Karim , KwaZulu-Natal
Grode, L. et al . Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guerin mutants that secrete listeriolysin. J. Clin. Invest. 115 , 2472–2479 (2005).
“Previously the only type of TB vaccine more potent than BCG was BCG overexpressing a major TB antigen. This paper represents another type of altered BCG vaccine. Although it has not yet been reported to show superior efficacy in the more stringent guinea pig model, it is a promising new approach.” Marcus Horwitz , UCLA
Champion, P.A., Stanley, S.A., Champion, M.M., Brown, E.J. & Cox, J.S. C-terminal signal sequence promotes virulence factor secretion in Mycobacterium tuberculosis . Science 313 , 1632–1636 (2006).
Munoz-Elias, E.J. & McKinney, J.D. Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat. Med. 11 , 638–644 (2005).
“The first indication of the signal that promotes virulence factor secretion.” Paul Van Helden , Stellenbosch
McShane, H. et al . Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat. Med. 10 , 1240–1244 (2004).
“The first clinical trial showing that a novel subunit TB vaccine could boost IFN- g responses in BCG-vaccinated humans, paving the way for further clinical trials.” Philip Marsh , Health Protection Agency, UK
Cosma, C.L., Humbert, O. & Ramakrishnan, L. Superinfecting mycobacteria home to established tuberculous granulomas. Nat. Immunol. 5 , 828–835 (2004).
Matsumoto, M. et al . OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med. 3 , e466 (2006).
Reed, M.B et al . A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431 , 84–87 (2004).
“An important addition to the TB drug pipeline. We need several candidates such as this one to develop a totally new regimen that shortens the current treatment duration to 2–3 months.” Koen Andries , Johnson & Johnson
Boshoff, H.I. et al . The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J. Biol. Chem. 279 , 40174–40184 (2004).
Burman, W.J. et al . Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am. J. Respir. Crit. Care Med. 174 , 331–338 (2006).
“Moxifloxacin is the furthest along new drug for TB. Among other things this paper highlights the need for greatly increased clinical trials capacity for TB.” Neil Schluger , Columbia
Flores-Villanueva, P.O. et al A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with increased susceptibility to pulmonary tuberculosis. J. Exp. Med. 202 , 1649–1658 (2005).
“The first study to identify in ethnically diverse human populations a common genetic variation that predisposes those infected with Mycobacterium tuberculosis to develop clinically evident disease.” Carl Nathan , Cornell
Gutierrez, M.C. et al . Ancient origin and gene mosaicism of the progenitor of Mycobacterium tuberculosis . PLoS Pathog. 1 , e5 (2005).
Makinoshima, H. & Glickman, M.S. Regulation of Mycobacterium tuberculosis cell envelope composition and virulence by intramembrane proteolysis. Nature 436 , 406–409 (2005).
Manjunatha et al . Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis . Proc. Natl. Acad. Sci. USA. 103 , 431–436 (2006).
Rengarajan, J., Bloom, B.R. & Rubin, E.J. Genome-wide requirements for Mycobacterium tuberculosis adaptation and survival in macrophages. Proc. Natl. Acad. Sci. USA 102 , 8327–8332 (2005).
Sassetti, C.M., Boyd, D.H. & Rubin, E.J. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol. 48 , 77–84 (2007).
Stanley, S.A., Raghavan, S., Hwang, W.W. & Cox, J.S. Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system. Proc. Natl. Acad. Sci. USA 100 , 13001–13006 (2003).
Voskuil, M.I. et al . Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. J. Exp. Med. 198 , 705–713 (2003).
“Another promising clinical candidate. The authors investigate mutants that are resistant to PA-824, teasing apart both the molecular basis of resistance and the mechanism of its intracellular activation, both of which will provide clues to help guide structure–activity relationships in this drug class.” Michael Fischbach , Harvard
“The greatest challenge in treating tuberculosis is that organisms persist for extended periods of time despite antibiotic therapy. This paper describes some of the physiologic responses that underlie one of the possible mechanisms of persistence—adaptation to low-oxygen environment.” Eric Rubin , Harvard
Walburger, A. et al . Protein kinase G from pathogenic mycobacteria promotes survival within macrophages. Science 304 , 1800–1804 (2004).
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