Review Article - (2025) Volume 33, Issue 1
Received: 26-Sep-2023, Manuscript No. IPQPC-23-17838; Editor assigned: 29-Sep-2023, Pre QC No. IPQPC-23-17838 (PQ); Reviewed: 13-Oct-2023, QC No. IPQPC-23-17838; Revised: 02-Jan-2025, Manuscript No. IPQPC-23-17838 (R); Published: 08-Jan-2025, DOI: 10.36648/1479-1064.33.1.48
According to the World Health Organization, diagnosing and treating Latent Tuberculosis Infection (LTBI) is a crucial strategy for accelerating the worldwide TB epidemic's decline and achieving TB eradication. Several obstacles have impeded the implementation or expansion of LTBI treatment programs, even in low-TB burden nations that have attained high rates of identification and successful treatment for active TB. The existing diagnostic tests have a low predictive value and only a small percentage of TB infection cases progress to active disease. Due to the lengthy duration of therapy and uncomfortable side effects, isoniazid (INH) treatment for LTBI has a low completion rate. Patients and medical professionals frequently believe that the danger of toxicity is greater than the chance of TB reactivation. As a result, outside of nations with abundant resources and low illness burden, the role of LTBI treatment has been minimal or nonexistent. With the development of new technologies, it is now possible to diagnose LTBI more precisely, particularly in those who have received the Bacillus Calmette-Guerin (BCG) vaccine. Rifamycin-based treatments that are shorter and better tolerated are proving to be secure and efficient substitutes for INH. Although yet insufficient, modeling studies in the United States show that TB prevention utilizing this novel diagnostic and treatment methods is cost-effective and has the potential to advance TB preventive efforts. To create improved tools, more study is required to comprehend the host-organism interactions that occur across the spectrum of LTBI. Latent TB research is a top priority in India towards TB eradication.
Latent tuberculosis; Tuberculin skin test; C-TB; PPD; IGRA; Treatment
According to the WHO, Latent Tuberculosis Infection (LTBI) is a condition in which the immune system continues to respond when stimulated by antigens of M. tuberculosis even without any evidence of clinically apparent active Tuberculosis (TB).
According to latest estimates, about one-fourth of the global population is infected with LTBI. LTBI can endure in healthy people for their entire lives, and the latency period is varies. Reactivation happens in a very limited percentage of cases (5%–15%), frequently within the first 2–5 years after infection [1-3]. When subclinical LTBI infection converted into an active TB disease, it is known as reactivation. So, LTBI patients serve as a significant source of newly discovered active TB cases. With about 40% of the affected population, India is the largest TB burden country in the world [4-6]. Additionally, those with poor immunological or nutritional conditions like frequently overlapping socioeconomic and clinically sensitive populations (People living with HIV (PLHIV), Children living with HIV (CLHIV), diabetic patients, geriatric, malnourished people, homeless people, silica industry workers) have a remarkable greater chance of developing or reactivating the TB disease. Without a profound diagnosis and treatment strategies to break the chain of disease transmission, reaching the global TB elimination program seems unlikely [6-9].
The WHO’s "END TB STATERGY" now place a higher priority on LTBI detection and treatment. The WHO released guidelines in 2015 for diagnosing, managing, and treating of LTBI among contacts of infected people who have the highest possibilities of developing an active TB disease. All These recommendations is for a focused public health strategy that involves screening and diagnosis of particular population that are most susceptible to LTBI reactivation as well as prophylactic treatment for those who will most benefit from it [1]. The following populations are targeted: Those who are HIV-positive, adult and pediatric contacts of sputum positive pulmonary TB cases, those starting anti-TNF (tumor necrosis factor) therapy, dialysis patients, organ transplant candidates, and silicosis patients. Other vulnerable populations having a greater risk of TB disease include people those are living in correctional facilities, those with drug and alcohol addictions, homeless people, and persons living in long-term assisted facilities, primitive communities, and foreign-born immigrants from countries with high TB burden [11].
Since MTB isolation only possible in an active phase, the diagnosis of LTBI is mostly depends upon the indirect assessment of immune response to antigenic challenge. Bacteria of the MTC can survive in a dormant state for several years or possibly the whole life of the host by escaping both innate and adaptive immunity. Approximately 10% of all infected people will develop active replication from an LTBI and develop TB illness. Currently, the predominant source of TB transmission and maintenance among humans is active pulmonary TB [12,13]. In this article, we examine the state-of the-art understanding of the immunology and natural history of LTBI, talk about clinical diagnosis prophylaxis treatment, and finally cover the major strategies for the future.
Disease
While only 10% of LTBI positive respondent experience active TB disease; the majority of these cases advanced during the first 2-3 years of exposure. A primary infection that is actively spreading and the reactivation of LTBI are the two potential pathways for the emergence of an active illness. Reactivation, which typically results from a host immune response going wrong, can happen years after infection in older people. Depicts the insight view of latent tuberculosis infection [2,5,6].
MTC Factors
In order to survive inside the human host, MTB has a number of techniques at its disposal. At first, a distinctive structure of cell wall with a high lipids disposal that shields the bacterium from the phagosome's extreme acidic ph. It can also stop the fusion of phagosomes and lysosomes. Third, it interferes with antigen presentation and the correct functioning of CD8+ T cells, the complement assault complex and the natural killer cells. Fourth, M. tuberculosis has a high level of resistance to host-originated anti-microbials, such as susceptible oxygen and nitrogen species intermediates [6,8,9].
Risk Factors
As stated earlier, both the natural combat mechanism (representation of macrophage and arrival natural killer cells to the infected site, complement activation system, ciliary clearance mechanism, and major airways secretion) and the acquired defense mechanism, which consists of both T cell and B cell (cellular and humoral immunity), involved in human immune response to the MTC. The primary element of the cell mediated action that protects against TB bacilli and encourages memory cell response and granuloma organization is composed of T cells. Although formerly B cells and antibody mediated immunity weren't seen as offering any defense, few researches have proven they help in regulate the immune system [14,15].
The key advantage of an acquired immune response is the occurrence of immunological memory, which allows each antigen to be copied and stored in memory T cells for use in future encounters with that antigen with a quicker and more potent immune response. This is the underlying mechanism of the Tuberculin Skin Test (TST), a DTH reaction (delayed-Type Hypersensitivity) generated when formerly sensitized T cells are disclose to antigens of PPD and produce cytokines. Even though hypersensitivity reaction and immune protection are related, immunity alone cannot provide full protection. Despite the fact numerous previous works have demonstrated that TST-positive responder are less likely to reactivate than non-respondent, reactivation cannot be stopped without specialized therapy [16-18].
The human host gets ready for two different sorts of reactions between 2 and 4 weeks following the initial interaction between MTC bacterium and macrophages. The earliest one is DTH (delayed-type tubercle bacilli hypersensitivity), which leads to tissue-damage, with encourages the eradication mycobacterium carrying dormant macrophages. Another of same kind is a cell-mediated reaction that causes macrophages to get activated and start eating germs. These two reactions are in a dynamic balance and can either cause TB to progress or MTC to be contained [1,20].
Since it is impossible to collect MTC from the host unless there is active TB, it is impossible to directly diagnose LTBI. Instead, an exposure evaluation by immunological technique is performed which determine the lymphocytes' responsiveness of the host to antigen of MTB, by in vivo with the TST or by in vitro using INF-release assays (IGRAs).
A detail into mode of Infection: Upon inhalation, M. tuberculosis encounters the initial cell-mediated immunity barrier of the natural immune system and enters in to the major airway and alveoli. Alveolar macrophage invades the membrane, phagocytose the pathogen and isolate it. M. tuberculosis can also infect type 1 and type 2 alveolar epithelial cells, endothelial cells, and M cells in the alveolar space of the lungs. In the early stages of infection, M. tuberculosis replicates intra cellular after being internalized by dendritic cells and macrophages, and other immune cell loaded bacterially may breach the alveolar barrier to produce systemic spread.
When specialized pathogen recognition receptors identify pathogen-associated molecular patterns, the host's coordinated innate immune response is triggered, which allows M. tuberculosis to enter alveolar space with phagocytic immune cells. Host receptors such as TLRs (Toll-Like Receptors), NOD (Nucleotide-binding Oligomerization Domain), NLRs (NOD Like Receptors), and C-type lectins are able to recognize the M. tuberculosis components. (MR) Mannose Receptor, DC-SIGN (Dendritic Cell-Specific Intercellular Adhesion Molecule Grabbing Non-integrin), Mincle (macrophage inducible C-type lectin), and dectin-1 (dendritic cell-associated C-type lectin-1) are examples of C type lectins. TLR signaling is the primary component of innate immunity, and MTB that has been internalised through other receptors may also have diverse outcomes. A pro inflammatory response (beneficial to the host) is triggered when M. tuberculosis ligands interact with TLRs, but the bacterium has also developed new combat mechanism that can reduce the effectiveness of innate immune response (beneficial to the pathogen). By activating a Myeloid differentiation primary response protein 88 (MyD88) dependent or MyD88-independent pathway, the pro inflammatory process activate the nuclear transcription factor (NF)-κB and production of pro-inflammatory cytokines, chemokines, and nitric oxide. Alveolar Macrophages (AM) release inflammatory cytokines and chemokines as soon as M. tuberculosis enters the body, signaling the start of an infection. Monocytes, neutrophils, and lymphocytes move to the infection's focal region, but they are unable to effectively eradicate the bacteria there. During this time, the bacilli inhibit the fusion of the phagosome and lysosome, grow inside the phagosome space, and escaping from the phagosome resulting in necrosis of macrophage. The ESAT-6 (Early Secreted Antigenic Target protein) and ESX-1 protein secretion system encoded by RD-1 Region of Difference) specifically present in M. tuberculosis and M. bovis strains but missing in the M. bovis vaccine strain help the M. tuberculosis escape from phagolysosome. In association with dimyristoylphosphatidylcholine and cholesterol-containing liposomes, ESAT-6 destabilizes and lyses the liposome. By inserting and rupturing the lipid bilayer of phagosome, it helps in escaping of tubercle bacilli. During the acidification of phagosome ESAT-6 released from ESAT-6:CFP-10 (culture filtered protein-10) protein complex which is secreted by M. tuberculosis through the ESX-1 secretion system. Additionally, the ESAT-6 promotes the spread of M. tuberculosis by causing macrophage death through the caspase-dependent route and cytolysis of type 1 and type 2 alveolar epithelial cells. Depict the ESAT-6 macrophage differentiation and secretion of different cytokines.
Early granuloma formation appears to be advantageous to MTB because ESAT-6 encourages the aggregation of macrophages at infection site, where the bacilli replicate unchecked as a result the affected macrophages may spread the bacilli to different parts of the human body. As a result of an efficient immune response, solid granulomas eventually form, which isolate bacilli from the remaining of lung tissue, prevent bacterial dissemination, and create an environment in which macrophages, different immune cells, and chemokines and cytokines can interact. It is clear that people with MTB infection exhibit variations in response of innate immunity that result in the development of physiologically unique granulomatous lesions. While few of these lesions completely eradicate all bacteria, others allow viable MTB to survive in the microenvironment. From this point on, the battle for survival of the bacterium and the containment of the infection by the macrophages will be fought for dominance. MHC-II (Major Histocompatibility Complex MHC class II) molecules are used by affected macrophages and dendritic cells to exhibit M. tuberculosis antigens during phagosome formation. As they move through the lymphatic system and into nearby mediastinal lymph nodes, these expert antigen-presenting cells that exhibit MTC markers stimulate CD4+ helper T-cells (Th4). By forming and maintain a granuloma through a pro inflammatory signal cascade (Interferon gamma (IFN-γ), Interleukin-2 (IL-2), and Tumour Necrosis Factor alpha (TNF α)), it attracts mononuclear cells and T lymphocytes to the infection site along with activation of CD8+ cytotoxic T cells, B lymphocytes. All these cells are responsible for the secretion of cytokines via endocrine and paracrine signaling. A granuloma is "the hallmark tissue reaction of TB" and is composed of these cell types, B lymphocytes, and dendritic cells. Different kinds of Th cells will emerge depending on the cytokine environment. contrarily, IL-10 and IL-4 limit the formation of Th1 cells, which are responsible for clone expansion, differentiation into memory cells, and Th1 cell production. IFN-secreting Th1 cells control cell-mediated immunity and trigger the activation of natural killer cells. For the development of Th2 cells, production of memory cells and clonal growth high concentrations of Interleukin-4 (IL-4), Interleukin-5 (IL-5), and Interleukin-10 (IL-10) are required and this development is suppressed by IFN-γ. Th2 cells are in charge of regulating humoral immunity and plasma cell activation in B cells. After MTC exposure and infection, adaptive immunity can take up to 42 days to develop. During this time, epithelioid cells, lymphocytes, and giant cells are also comes to the infection site, where a substantial number of active macrophages are engaged to form granuloma. Lowering the pH causes internal necrosis, which prevents bacterial replication but promotes dormancy by depriving the granuloma's center of oxygen. The fact that isoniazid is only bactericidal against M. tuberculosis replication suggests that some replication still takes place in order for it to work against LTBI. During the formation of granulomas, the nearby macrophages and the dendritic cells also carry bacilli to the neighborhood lymph nodes, allowing infection to spread, especially to very well-oxygenated regions such as apical zone of lungs, adrenal glands, cortex of the brain, bone, and bone joints.
Macrophages infected with MTB are not able to present antigens of M. tuberculosis to CD4+ T cells as a result of the suppression of macrophage reaction to M. tuberculosis. Due to insufficient effector T cell activation, M. tuberculosis is able to evade immune monitoring and establish itself in new habitats. M. tuberculosis enters a dormant state as a result of hypoxia, food shortage, low pH and nitric oxide's inhibition of respiration in the granuloma's microenvironment. These circumstances cause surviving bacilli to enter a dormant stage with barely any metabolic as well as replicative property. Additionally, M. tuberculosis is shielded against ubiquitin derived peptide-induced death by decreased outer membrane permeability. As a result, certain resistant (non replicating) bacilli evade the immune system's destruction and survive. The DTH (Delayed-Type Hypersensitivity) reaction to PPD (pure protein derivative) made from filtrates of cultured M. tuberculosis: TST (Tuberculin Skin Test) is indicative of LTBI in a person lacking indications of progression of the disease. Latent bacilli can reside in the granuloma for the duration of the host's life, but they can start growing again if the immune system is weakened known as reactivation of TB. M. tuberculosis must emerge from dormancy in order for the latent infection to be reactivated. The endopeptidase (RipA) and lytic transglycosylases otherwise known as RPF (Resuscitation Promoting Factors) have been identified in M. tuberculosis act as crucial elements for emergence from latency.
Diagnostic Tools for the Diagnosis of Latent Tuberculosis Infection
Even though the identification and subsequent treatment of people who are latently infected with MTB (LTBI) is the major focus of WHO and NTEP (National Tuberculosis Elimination Program) in many developed and developing countries like India, but till now there is no "gold standard". The existing diagnostic procedures like T-SPOT TB assay, Tuberculin skin test, protein derivative based C-TB skin test and T-cell based IGRA test. All these tests are solely intended to assess the host adaptive immunological response to MTB, which normally occurs six to eight weeks following exposure to the bacilli.
T-SPOT
Another commercially available assay is called T-SPOT. TB employs the antigens ESAT-6 and CFP-10 from M. tuberculosis. The ELISPOT technique, on which this assay is based, counts the quantity T cells producing IFN-γ (spot-forming cells). Its clinical applicability is constrained in developing nations due to the need for pricey readers and software as well as specialized trained people. Despite their strong correlation, the T-SPOT. TB and QuantiFERON assays are less frequently employed. There has been a lot of documented difference between TST and T-SPOT-TB testing in LTBI patients.
Tuberculin Skin Test
Tuberculin is injected intra-dermally as part of the Tuberculin Skin Test (TST). Although many methods have been employed, one of the most popular worldwide is the Mantoux skin test technique, which is applied to the volar side of the forearm. PPD or RT-23 is both viable tuberculin sources. The recommended doses are equivalent to 0.1 mL or 5 PPD units or 2 RT-23 units. These two forms of tuberculins derivative contain a diverse array of purified antigens, involving Mycobacterium bovis-BCG strains, different Non-Tuberculous Mycobacteria (NTM), and MTB antigens. Through T cells, tuberculin derivatives will trigger a DTH reaction. An induration at the injection site can be used to identify a positive TST 48–72 hours following the test. As a result, the induration's transverse diameter is determined, which is typically measured in millimetres. Immunosuppression and the prevalence of TB in the area should both be taken into account while analyzing the outcomes; cutoff point of 15 mm will be used for patients living healthily in areas of high prevalence, and a 5 mm cutoff will be considered negative. In a few circumstances, an unvaried 10 mm cutoff point is used. Comparing TST features across research in various groups and nations is challenging because to these disparate and subjective considerations. TST's main drawback is its limited specificity, which is brought on by prior BCG vaccinations and NTM infections. There are further issues with this ostensibly straightforward test. TST may be less sensitive in participants with long-term incapacitating diseases or immunosuppression than in healthy individuals. It must be administered and read by qualified experts in order to prevent outcomes that are inconsistent. Additionally, two clinical appointments are necessary, and confidentiality difficulties may arise if the test results are favorable.
C-TB
The creation of an advance diagnostics toll for LTBI has been sluggish, but few recent developments like a skin test called C TB that uses MTB-specific antigens derivative alike those are utilized in IGRA, eradicating cross-reaction of the BCG vaccine while ensuring the sensitivity mark of the current TST test.
A very specific skin test called C-TB (developed by Statens Serum Institute, Copenhagen, Denmark) was developed to overcome the limitations of TST and IGRAs in the diagnosis of LTBI. C-TB is administered and measures the cutoff in the same manner as TST, but it is relay on the IGRA antigens CFP-10 and ESAT-6. No matter whether BCG, HIV, or both are present-thanks to its great specificity-C-TB adopts a global cut-point induration of 5 mm. The C-Tb test-positivity rates in a latest contact tracing trial that involved groups with varying levels of exposure to active PTB (Pulmonary Tuberculosis) cases were consistent with increasing TB exposure and were extremely sensitive consistent with QFT (QuantiFERON Test).
Interferon Gamma Release Assay (IGRA)
By using patient's blood sample to assess the amount of IFN-γ that T cells produce in vitro after being stimulated with particular MTC antigens. The QuantiFERON-TB Gold In-Tube (QFT) and the T-SPOT.TB are two IGRAs that have been created. ESAT-6 and CFP10 are used in both experiments, and they are both coded by genes found in Mycobacterium tuberculosis complex RD-1 segment. The third antigen in QFT tube is TB7.7 (RD-11). It uses an ELISA-based assay (whole blood). IFN-levels in a cell suspension's supernatant are measured. Software can quickly process the result, which is shown by International Units per millilitre (IU/mL). The amount of T cells producing IFN-γ is the outcome. As the three derivatives ESAT-6, CFP10, and TB7.7 are present in the MTC genome RD-1 segment but not in M. bovis-BCG or the other majority of NTMs, the major benefit of IGRAs is their specificity mark. Additionally, IGRAs can distinguish between a negative result and anergy using a positive control that boosts IFN- production using phyto-hemagglutinin. Tuberculin skin test and Interferon gamma assay cannot identify TB infection in its early stages. A period of approximately 8 weeks following infection is necessary for a valid outcome since they assess the acquired immune activity to MTC.
Both varieties of immunologic tests share three significant drawbacks. Their low PPV (positive predictive value) for developing active TB disease is the first one. Numerous investigations have attempted to link the threat of advancement quantitatively by both in vivo testing (TST response) and in vitro tests (i.e., the concentration of IFN-γ producing T cells in QFT tubes), but till now there is no clear cut findings. According to a latest meta-analysis report, IGRAs have a lightly higher Positive Predictive Value (PPV) than TST (TST-2.4% and IGRA-6.8% among high-risk population), indicating that seven person will get TB in a cohort of 100 IGRA-positive subjects evaluated for LTBI who would not give preventive therapy. Due to several limitations of TST and IGRA to differentiate between LTBI and active disease, the WHO has advised against using IGRAs to diagnose active TB because a negative result does not always imply that the patient has the illness. The tests' inability to differentiate between current and future infection is the third problem. The profiles of responses for previous and current infections are similar type. Individual result needs to be carefully analyzed and customized because the host's characteristics may change the sensitivity and specificity mark of both the tests. Depict the diagnosis tools and outcomes of tests at different stages of tuberculosis infection.
Sensitivity Due to absence of "gold standard" for the diagnosis of LTBI, the sensitivity and specificity mark of the existing diagnostic tests cannot be determined. Only active TB patients from whom MTC germs can be isolated are known to have a confirmed TB infection. A latest meta-analysis report of diagnostic tests used in active TB patients revealed results with sensitivity mark of 0.70 for TST, 0.81 for QFT, and 0.88 for T-SPOT.TB.
Since TB is a common contributor of anergy, the immunological response to LTBI infected and active TB patients are probably not comparable. Consequently, sensitivity is possibly greater in people with good health. TST or IGRA negative in this cohort excludes active TB infection and has a nearly NPV (Negative Predictive Value) of 100% for developing into active TB disease. However, in other clinical circumstances, such as when there is a clinical presumption of active TB disease or when participants are immunosuppressed, a negative result might not be trustworthy. The effectiveness of IGRAs under these particular conditions has been examined in several studies; IGRAs appear to be less influenced by immunosuppression than the TST.
Specificity TST and IGRAs differ mostly in terms of specificity. Since the MTC, M. bovis-BCG, and NTMs all include antigens that are shared by tuberculin, a positive TST result does not always indicate that a person has TB infection. This is especially true for BCG-vaccinated individuals, who tend to have a greater rate of false-positive results. Instead, because they employ antigens encoded in certain MTC genome regions, IGRAs exhibit exceptional specificity. In those who have received the BCG vaccine and those who have not, pooled specificity data suggest that the range for IGRAs is 0.86 to 0.99 versus 0.97 and 0.59 for TST, respectively. As false positive results will be disregarded, improved specificity limits the overuse of medication to stop development. Approximately 50% of 1,000 healthy contacts of PTB cases who underwent TST testing could be positive for it and require treatment. Instead, if an IGRA test was employed, only 30% would receive treatment, leading to huge financial saving by avoiding needless therapy.
The recent fourth generation QuantiFERON-TB Gold Plus tube (QFT-Plus; Qiagen, Hilden, Germany) test measures IFN-γ in the two populations of CD4+ and CD8+ T cells. Its objective was to increase the detectability of immunological responses to MTB in patients who had recently contracted TB, were HIV positive, or were youngsters. It has so far shown characteristics in adults that are comparable to QFT-GIT. With an additional antigen tube (TB2), QFT-Plus is an advanced version of QTF-Gold in Tube (QFT-GIT). To stimulate cell mediated immunological responses from CD4+ T-helper cells, the TB1 tube contains peptides derived from ESAT-6 and CFP-10 (TB-7.7, present in QFT-GIT, has been eliminated) and it is intended to trigger a particular CD4 T cells response. Both CD4+ and CD8+ T-cells can produce IFN thanks to novel peptides found in TB2.
According to available data, CD8+ T-cells play a significant role in the defense mechanism of host against MTB through releasing cytokine and cytotoxic action. In peripheral blood ex vivo, a direct link between certain CD8+ T-cells and elevated MTB burden has been discovered. In a recent study it was mentioned that compared to smear-negative and LTBI individuals, people with smear-positive TB exhibited detectable CD8+ T-cell response. According to this paradigm, patients with smear-positive TB have a higher prevalence of MTB-specific CD8+ T-cells than patients with smear-negative TB, and PTB is more common than EPTB (Extra Pulmonary TB). TB 7.7 derivative which is present in the QFT-GIT, is absent from the QFT-Plus. Despite the fact that the control and active TB groups were unaffected by the difference in antigen, It's probable that different IFN-γ responses in the LTBI groups were caused by the absence of TB7.7 in QFT-Plus antigen tubes. IFN- levels in patients with active TB were greater by QFT-GIT than by QFT-Plus.
Treatments
In order to effectively control TB in low/high burden countries, it has been found that tracing contacts of sputum smear positive pulmonary TB cases for exposure to TB bacilli resulting in LTBI and treating latently infected people at high risk of converting to active TB disease has proven to be incredibly effective in controlling TB. The likelihood of developing in to active TB disease is significantly reduced with the prophylaxis treatment of LTBI persons. Guideline for the treatment and management of LTBI were released by American Thoracic Society (ATS) and the Centres for Disease and Prevention (CDC) in 2000. This recommendation was updated in 2005 which include guideline for pediatric TB treatment.
The use of only isoniazid, only rifampin, isoniazid combined with rifampin, and isoniazid combined with rifapentine are the four primary antibiotic regimens currently available for the treatment of LTBI. Monotherapy for 6–12 months has been used for decades and has a 90% success rate in halting the development of TB illness. However, because of its lengthy duration and potential for hepatotoxicity, it has proven less effective overall due to low rates of adherence and completion. Shorter rifamycin-based regimens are more frequently utilized and have comparable efficacy. When compared to isoniazid monotherapy, these regimens have higher completion rates and a lower risk of hepatotoxicity. Importantly, research has not demonstrated an elevated incidence of isoniazid or rifamycin-resistant TB illness following the administration of LTBI therapy regimens containing these medications.
A daily dose of isoniazid for six to twelve months: Mycolic acids are necessary building blocks of the mycobacterial cell wall, and isoniazid prevents their formation. For many years, isoniazid mono-therapy was thought as the gold standard for treating LTBI. The efficacy of this medicine in preventing TB has been shown in numerous investigations. The usual adult dosage of isoniazid is 300 mg per day, or 5 mg/kg/day. Hepatitis (exhaustion, loss of appetite, abdominal pain, nausea, and jaundice) and peripheral neuropathy are possible side effects of isoniazid. Three to four months of rifampin every day, by interacting with the RNA polymerase from mycobacteria, rifampin prevents RNA production. Comparing isoniazid and rifampin for LTBI, rifampin has been shown to be as effective and to cause less liver damage. Rifampin is given over the course of three to four months at a dose of 10 mg/kg/day (the standard dose for adult is 600 mg daily). Rifampin may result in gastrointestinal symptoms (such as nausea and abdominal pain), haematological side effects, hypersensitivity responses, and hepatotoxicity, orange colouring of urine and other bodily fluids. Rifampin act as strong CYP3A activator and may interfere with the metabolic action of a number of medications, including cyclosporine, methadone, anti-retrovirals drugs, anticonvulsants, warfarin, azole antifungals drugs. As a result, it is recommended to look for any possible drug-drug interactions before using rifampin for LTBI.
Every day for three to four months, isoniazid and rifampin: In both HIV-positive and HIV-negative individuals, randomised trials compared 6-12 months isoniazid monotherapy for daily vs. 3-4 months isoniazid+rifampin daily. Comparing the isoniazid+rifampin combination regimen to traditional isoniazid monotherapy, identical rates of TB prevention and safety profiles have been established. INH and RPT, two antibiotics that are effective against TB, are combined in the short-course TPT regimen known as 3HP. For a total of 12 weeks (12 dosages in 3 months), 3HP is taken once per week. It has been shown to be efficient and secure for PLHIV and their household contacts older than two years. INH and RIF, two antibiotics that are effective against TB, are combined in the short-course TPT regimen known as 3RH. For a period of 12 weeks (90 doses in three months), 3RH is taken once daily. The 3RH regimen is referred to as an alternative to the 6H regimen in the WHO LTBI guidance document that was published in the early months of 2018 for the treatment of LTBI in children and adolescents under the age of 15 in nations with a high TB incidence.
It is significant to note that the cytochrome P450 oxidase system is strongly induced by RIF and RPT. The pharmacokinetics of other medications, especially certain Anti-Retrovirals (ARVs), may be impacted by their administration. Both 3HP and 3RH are safe to administer with efavirenz-based ART to HIV/AIDS patients without adjusting the dose. Without changing the dosage, 3HP is safe to provide with ART that is based on dolutegravir to adults. Both 3HP and 3RH lower nevirapine and lopinavir-ritonavir levels. Dosing changes are therefore required. The result is that neither can be used with lopinavir-ritonavir or nevirapine. Therefore, the best TPT regimen for HIV-infected kids receiving lopinavir/ritonavir, nevirapine, or dolutegravir is 6H (preferably with the dispersible formulation), which does not require dosage adjustment. According to studies, 3HP is just as efficient as IPT at halting the development of latent TB into active TB. The 3HP regimen is also less complicated, shorter, and demands fewer doses from patients. There is evidence that participants undergoing 3HP are more likely to finish their course of treatment than those following the more time consuming IPT regimen. The load on TB and HIV programs is reduced when a shorter, weekly dose is given as opposed to IPT. The 3HP regimen may be cost-effective, lowering the financial burden of TB control efforts, according to modeling studies.
The greater global health issue of TB has an occult face, which is represented by LTBI. Because LTBI patients may eventually advance to the active form of TB, a precise diagnosis and effective treatment of these patients are crucial to the control of TB. Due to its ease of use and the in vivo proof of an anti mycobacterial cellular immune response it offers, the TST has become the most widely utilized approach for the diagnosis of LTBI. However, it has the drawback of being present in those who have had the BCG vaccine. The addition of C-TB and IGRAs has increased specificity and the new version of QTF gold plus appears to be effective at telling the difference between active TB and LTBI.
LTBI regimens that are shorter and more tolerable are currently being developed. The 3HP 3 month isoniazid (INH) rifapentine (RPT) combine drugs presents a significant advancement in shortening the length of LTBI treatment and improving adherence, enabling widespread use. Currently, there are efforts to produce enduring medication appropriate for treating LTBI attempting to overcome difficulties brought on by a low incidence of treatment completion and poor treatment adherence present in LTBI regimens.
Treatment with antibiotics can stop this; typically recommended regimens last 6-9 months mono therapy medication or at least 3 months with two medications. The likelihood of subsequent adverse events rises as the treatment regimens dosage is increased. The crucial question is therefore, who should be targeted for therapy, given that only a tiny percentage of LTBI-positive people go on to acquire active TB, that LTBI treatment is ineffective, and that there are adverse effects associated with it. This issue arises because none of the tests that are currently available can reliably forecast future development. It is well known that young children, immunosuppressed individuals, and the period immediately following infection carry the highest risk of advancement. Therefore, these people should be the focus of LTBI screening and treatment pragmatically. With the exception of close contacts of TB patients those who are multi drug-resistant, in these circumstances, testing may be used to guide "watchful waiting". This would typically lead to an "intention to test is an intention to treat" strategy. Short course regimens may lower barriers to LTBI therapy, but the drug must be affordable and readily available globally. India must therefore expedite and give latent TB research a top priority.
Global TB prevention initiatives would undoubtedly benefit from improved point-of-care diagnostic tests that can discriminate between active and latent TB in conjunction with a risk analysis, radiographic detection of fibrotic lesions and LTBI treatment that is less time-consuming. Although it will have the biggest immediate impact, focusing resources on people who are most at TB infection and reactivation risk may not be enough to completely eradicate the disease. Therefore, the development of crucial evidence policy for the management of LTBI in India and global health care settings is to be addressed via a research agenda and global discussion.
All authors have reviewed the final version of the review article and consented to publish.
The authors declare that they do not have any conflict of interests.
The authors have not received any funding for this study.
Braja Sundar Barik is a Ph.D. student and was involved in literature search and writing the draft review. Shally Pandit and Sudatta Chandan were involved in writing and reviewing the entire manuscript. Dr. Tahziba Hussain reviewed and edited the review throughout all the stages. Dr. Sashmita Nayak of KIIT University and Dr. Sanghamitra Pati has provided guidance for this review.
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Citation: Barik BS, Pandit S, Chandan S, Hussain T, Nayak S, et al. (2025) New Approaches in the Diagnosis and Treatment of Latent Tuberculosis in Public Healthcare Facilities of India: An Insight Review. Qual Prim Care. 33:48.
Copyright: © 2025 Barik BS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
