Tuberculosis (TB), an incessant granulomatous infection caused by Mycobacterium tuberculosis (MTB), is one of the oldest known diseases to scourge mankind. It can be deemed immortal since its deleterious spread continues unlike other scourges like plague and smallpox that have almost vanished. Global Tuberculosis Report published by World Health Organisation (WHO) in 2017 reports TB as ninth leading cause of death, bypassing HIV-AIDS. TB has affected one third of the global population with 10.4 million individuals infected in 2016. In most cases, curing TB is possible; however, large gaps between timely and accurate diagnosis and treatment are main constraints in its management. The cure rates, even for drug susceptible TB are significantly lower than anticipated, making TB a formidable foe.
Despite exceptional endeavours led by WHO, the global TB burden continues to escalate, with a new person being infected with TB every second. Association with HIV infection also fuels the intensity of TB pandemic. A frightening statistic is the resurgence of TB even in the urbanized nations. END TB strategy implemented by World Health Organization (WHO) with the vision ‘A WORLD FREE OF TB- zero deaths, disease and suffering due to TB’ aims to reduce TB deaths by 95 per cent and new TB cases by 90 per cent between 2015 and 2035. A milestone of END TB strategy set for 2020 targets 35 per cent reduction in TB deaths and 20 per cent reduction in its incidence, as compared to 2015. In keeping with this strategy, the Government of India has doubled the budget for TB control compared to 2016, to achieve the goal of ending TB by 2025.
Challenges in TB
One major hindrance in management and treatment of TB is delayed case detection. Most of the therapeutic strategies are directed to tackle active form of TB where the organism is virulent and multiplying rapidly rather than the latent form. Latent TB infection (LTBI) is manifested by carriers of MTB who do not exhibit overt symptoms of TB. More recently, LTBI has gained importance for design of newer therapeutics. This however is not the purview of this article. Upsurge of drug resistant strains represents a major setback in TB management beginning with Multi drug resistance (MDR TB)- resistance to two first line drugs, progressing to Extensive drug resistance (XDR TB)- resistance to first line drugs plus injectables or worst of all Total drug resistance (TDR TB).
This deteriorating situation demands a paradigm shift in TB therapy with simultaneous focus on approaches for efficient prevention, diagnosis and treatment of TB. Prevention of TB primarily necessitates efforts in sanitation and hygiene. Diagnosis and treatment could be advanced through technological development.
A. TB therapeutics
Efforts in designing therapeutic regimens to control TB using known drugs have been intensive. Initiated through the development of combination therapeutics when signs of resistance first emerged, WHO has recommended directly observed therapy, short course (DOTS) comprising of multi drug combinations to tackle resistance and to improve patient compliance by bringing down total duration of therapy. Based on these recommendations, several multi drug combinations have emerged in market. Few such combinations (marketed by Lupin Labs) are listed in Table 1:
Nevertheless, development of drug resistance remains unabated and the challenges are severe. This demands for development of newer drugs.
As of 2017, 10 molecules including 8 new molecules and 2 molecules with fast track approval have entered different phases of clinical trials as stated in WHO Global TB report (Table 2). To overcome long duration between discovery of new drug and its approval, regulatory bodies have come up with accelerated clearance strategies to enable rapid therapeutic applications. Bedaquiline (Brand name- Sirturo) and Delamanid (Brand name- Deltyba) are two such drugs with Bedaquiline being recently cleared for MDR TB. Repurposing of pre-existing drugs also offers a promising alternative to conventional regimens. 7 such repurposed molecules are under various phases of clinical trials (Table 2).
Nano strategies for TB
While on one hand newer drugs are being discovered, exploiting nanocarriers for targeted delivery of anti TB drugs is rapidly gaining importance with a number of research groups focussing in this area. Despite highly promising success stories in the preclinical evaluation, overcoming the limitations of scalability of nanocarriers and their toxicity implications continue as impediments.
B. TB diagnostics
Early detection of TB could revolutionize the control and treatment of TB. Delayed detection and misdiagnosis resulting in advanced progression of the disease prior to initiation of therapy reiterates the need for prolonged therapy with associated patient non-compliance issues, thereby enhancing the possibilities of resistance development. Conventional approaches like chest X-Ray, sputum smear microscopy or Tuberculin skin test (TST)/ Mantoux test are relied on for diagnosis to date. Microbial culturing techniques are still used for monitoring drug resistance and identification of appropriate therapeutic regimens.
Efforts for development of efficient and rapid point of care diagnostics are ongoing. Over the years, various serological tests like Interferon ? release assays (IGRAs) have proven to be advantageous in patients who are unable to produce sufficient sputum or those with suspected extrapulmonary TB. IGRAs measure INF ? release by the cytokines in response to antigens in event of infection and provide greater specificity and sensitivity compared to TST.
Molecular diagnostic assays based on amplification of target DNA using polymerase chain reaction (PCR) sequences have been developed for detection of resistant strains. Xpert MTB/RIF is one such assay based on Gene Xpert Omni endorsed by WHO possessesing ability to simultaneously test for infection and Rifampicin resistance. This assay has been adopted by 28 high burden nations for preliminary screening of suspected cases. Next generation Xpert MTB/RIF Ultra cartridge has demonstrated improved sensitivity in detecting samples with low bacilli count. However, this is accompanied by a decreased specificity. Other resistance detection assays in pipeline include rapid first-line LPAs (line probe assays) for testing rifampicin and isoniazid resistance and rapid second-line LPAs for testing resistance to fluoroquinolones and injectable TB drugs. Few nanocarrier based diagnostic platforms based on nanoparticles (metallic/ silica/magnetic), quantum dots and various electrochemical devices are in nascent research stages for diagnosis of TB.
C. TB vaccines
Bacille Calmette-Gu?erin (BCG) vaccine developed almost 100 years ago was relied on for prevention of TB in children for many years. Nevertheless, today it prevents only against some forms of TB and lacks ability to protect adults against pulmonary TB. This has necessitated a concerted effort for development of newer and effective vaccine candidates. 12 new vaccine candidates are reported in different phases of clinical trials according to WHO Global TB Report 2017. These candidates are mycobacterial live cultures/ whole cell or extracts, viral vectors or protein/adjuvant vaccines. In addition to intradermal and intramuscular routes, aerosol route is being evaluated for some vaccines. While most vaccines are being developed as preventives, few vaccines are also being explored for therapeutic application. Vaccine candidates in different phases of clinical trials are listed below
Phase I: Ad5 Ag85A, ChAdOx185A-MVA85A, MTBVAC
Phase IIa: RUTI, H4:IC31, H56:IC31, ID93 + GLA-SE, TB/FLU-04L
Phase IIb: DAR-901 booster, VPM1002, M72/AS01E
Phase III: Vaccae™
Conclusion
Intensive global eradication efforts to eradicate TB
certainly present great
promise. The horizon although not clearly visible today, atleast appears reachable tomorrow.
(Prof. Padma V. Devarajan is Professor in Pharmacy & coordinator of World Bank Programme TEQIP and Priyanka Jahagirdar is Senior Research Fellow at Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai)