Preventive treatment for latent tuberculosis from Indian perspective

Abstract

The persistent morbidity and mortality associated with tuberculosis (TB), despite our continued efforts, has been long recognized, and the rise in the incidence of drug-resistant TB adds to the preexisting concern. The bulk of the TB burden is confined to low-income countries, and rigorous efforts are made to detect, notify, and systematically treat TB. Efforts have been infused with renewed vigor and determination by the World Health Organization (WHO) to eliminate tuberculosis in the near future. Different health agencies worldwide are harvesting all possible strategies apart from consolidating ongoing practices, including prevention of the development of active disease by treating latent TB infection (LTBI). The guidelines for the same were already provided by the WHO and were then adapted in the Indian guidelines for the treatment of LTBI in 2021. While the long-term impact of TBI treatment is awaited, in this article, we aim to discuss the implications in the Indian context.

INTRODUCTION

Tuberculosis (TB) is a communicable disease caused by the resilient bacteria Mycobacterium tuberculosis (M. tb). It is a major cause of ill health and one of the leading causes of death worldwide. It mostly affects adults and is more common in men.[1] It is a curable and preventable disease and yet has persisted for centuries. Other than host and environmental determinants, the unique characteristic of tubercular bacilli to lie metabolically dormant in the host has been a key reason for their persistence in communities.[2] While relentlessly consolidating the management of active disease, the need to prevent the development of active disease from latent TB infection (LTBI) has long been recognized. The preventive host and environmental determinants include overcrowding, poverty, air pollution, hygiene, healthcare infrastructure, malnutrition, smoking status, diabetes mellitus, infection with human immunodeficiency virus, and immunocompromised status due to any other causes.[3,4,5] Another important step in this direction has been the administration of the BCG vaccine, which has nearly 80% efficacy in preventing the development of severe forms of TB.[6] Ever since its development, attempts have been made to develop novel anti-TB vaccines that are undergoing various stages of trial and awaiting approval.[7,8] Studies have reported that the preventive effects of isoniazid preventive therapy last for several years.[9,10,11,12] Consequently, as per the World Health Organization (WHO) recommendations, prophylactic treatment has been administered to high-risk populations.[13] Now that Tuberculosis Preventive Treatment (TPT) implementation is being extended to household contacts (HHCs) in India, one of the highest TB burden countries in the world, we aim to elaborate on the current status of latent TB in India and the possible pros and cons of preventive treatment in this article.

What is TB infection or latent TB?

Tuberculosis infection (TBI) is a state of persistent immunological response stimulated by M. tb antigens without any clinical manifestation of active tuberculosis.[14] Once phagocytized by the dendritic cells of the infection site, the bacilli multiply intracellularly. A cascade of cytokines, such as tumor necrosis factor alpha and interleukins 1 and 12, are released, triggering inflammation. Simultaneously, sensitization of T cells in regional lymph nodes occurs. However, by the time effective cell-mediated immunity develops (2–8 weeks), intracellular multiplication and spread continue to occur. It has genetic mechanisms that lead to blunting of bactericidal host responses, such as interference with antigen presentation by macrophages, phagolysosome formation inhibition that leads to persistence and multiplication of the bacilli, and modulation of cytokine response and triggering of macrophage apoptosis. When CD4+ T cells are activated, they migrate to the local site, release interferon gamma, and kill the infected macrophages. However, some bacilli resist this killing and persist in a dormant state. The exact mechanism contributing to latency is still not known. Epithelioid cells and fibroblasts are attracted by chemokines released from activated macrophage walls of this inflammation, which leads to granuloma formation.[2,15] [Figure 1]

Figure 1.

Schematic diagram depicting the events in the pathogenesis of primary TB infection. M.tb: Mycobacterium tuberculosis, CR3: complement 3 receptor, MHC: major histocompatibility complex, IFN: interferon

After initial TB infection, 5–10% will develop active TB disease over the course of their lives, usually within the first 5 years after initial infection.[16,17] The risk is higher in children under the age of 5 years and people with compromised immunity.[14] Additionally, the risk is increased to >25 times among contacts of bacteriologically confirmed TB patients compared to the general population, 16–21 times in cases of HIV coinfection and 3–4 times in other immune-compromised statuses, such as diabetes. The risk of disease following infection in the first 2 years is age dependent; it decreases with increasing age due to greater innate and acquired immunity.[18]

Magnitude of the problem

As per the Global Tuberculosis Report 2022, the TB incidence was 10.6 million in 2021. India accounts for 28%, the highest burden, of the global incidence of TB. The estimated incidence of all forms of TB in India for 2021 was 2.95 million (~210 per 100,000).[1] The total number of incident TB patients (new and relapsed) reported during 2021 was 19,33,381, which was 19% higher than that in 2020.[19] In the face of the COVID-19 pandemic, in view of reduced access to TB diagnosis and treatment, TB deaths have increased.[20,21] TB was the leading cause of death from a single infectious agent until the COVID-19 pandemic. Global TB deaths among the HIV-negative population in 2021 were 1.4 million; 1,87,000 deaths among the HIV-positive, with an overall mortality of 1.6 million. India accounted for 35% (4.94 lakhs) of global TB deaths among HIV-negative people, 31% of combined TB deaths in HIV-negative and HIV-positive people and a case fatality ratio of 17%.[22]

The problem has long been recognized, and TB elimination has been incorporated into the Sustainable Development Goals (SDGs) with the aim to reduce TB incidence.

In 2018, the United Nations high-level meeting was held and declared the Global Plan to end TB with an estimated target to detect and treat nearly 40 million patients with TB between 2018 and 2022. India proposed the END TB strategy with the goal of reducing TB incidence and mortality.[22,23]

As far as the latent TB burden is considered, globally, nearly one-fourth of the world’s population is estimated to have latent TB.[24] In India, the National TB Prevalence Survey 2019-21 documented the prevalence of TBI as 21.7% in the age group ≥15 years using a robust standard errors model.[25] Mohan et al. noted a similar prevalence among the general population in a recent regional study.[26] A much higher prevalence has been documented among the HHCs of active pulmonary TB patients roughly ranging from 50–70% in regional studies.[27]

Diagnosis of latent tuberculosis

There is no gold standard test to diagnose TBI or predict progression to TB disease or to distinguish newly acquired infection from remote infection among those infected with M. tuberculosis. The available testing options are the tuberculin skin test (TST) and interferon-gamma release assay (IGRA). These are tests of the immune response to TB antigens, measuring immune sensitization (Type 4 hypersensitivity) to mycobacterial protein antigens. The decision to select a test between TST or IGRA should be based on setting, cost and availability, as there is no clear-cut advantage for predicting future risk of active TB.[28] The time taken to obtain a positive result varies from 2 to 8 weeks after exposure. Interpreting TST is based on the pretest probability, patient profile and setting where the test has occurred. The effect of BCG vaccination on TST positivity varies with the time of vaccination. There are several studies that report that those vaccinated at infancy may have low-level reactivity (<10 mm), while those who were vaccinated after infancy had a false positivity rate of >20% after 10 years of vaccination.[29,30] TST is useful for serial testing in healthcare workers and close contacts of pulmonary TB cases in low-burden countries. Those with baseline positivity (within 2.5 weeks of exposure) are considered to have prior TBI. If negative, a second test is performed at 8 weeks after the end of the exposure. TST positivity is then considered a recent TST conversion. As per CDC, TST positivity can be interpreted for different patient groups in the ≥5 mm group, ≥10 mm group, and ≥15 mm group.[31] A higher cutoff increases the specificity but decreases the sensitivity of the test. Thus, interpreting high cutoffs is reserved in low prevalence settings and high non-tubercular mycobacterium (NTM) exposure.

IGRAs are in vitro tests that quantify the response of lymphocytes when exposed to M. tuberculosis antigens. They are of two types: the QuantiFERON TB gold in-tube test (QFT-GIT) and T-SPOT. QFT-GIT uses ELISA, whereas T-SPOT uses enzyme-linked immunospots. The antigens used in IGRAs (ESAT-6, CFP-10, and TB7.7) are present in M. tuberculosis and wild-type Mycobacterium bovis but absent in BCG strains of M. bovis and NTM species, except Mycobacterium kansasii, Mycobacterium szulgai, Mycobacterium leprae, and Mycobacterium marinum. This confers higher specificity than TST, especially in BCG-vaccinated persons and in low-burden countries with high background NTM infections. IGRA tests are interpreted as positive, negative, or indeterminate/borderline. Immunosuppressed patients and HIV-positive patients are more likely to have indeterminate results. Here, repeat testing with IGRA/TST may be of use.[32] The preferred tests according to different guidelines are summarized in Table 1.

Table 1.

Summary of guidelines for choosing between Tuberculin skin test (TST) and Interferon gamma release assay (IGRA)

Preferred test	IGRA	TST	EITHER
Recommendation
Indian[35]			HHCs >5 years of pulmonary TB patients after ruling out active disease; on immunosuppressants, anti-TNF alpha drugs, dialysis, silicosis patients, preparing for transplant
WHO[13]		Low- to middle-income countries with limited resources and a high TB burden, such as India, testing is recommended only in HIV and children <5 years of age. TST is preferred in view of the comparable performance and lower cost of TST	High- to upper-middle-income countries with a TB incidence of<100 per 100,000: HIV, contacts of active cases, patients on dialysis, antitumor necrosis factor (TNF) therapy, and immunosuppressed, patients with silicosis those living in close conditions include prisons and nursing homes
ATS, CDC, IDSA[36]	Low to intermediate risk of progression to active disease patients who are unlikely to return for TST read and a history of BCG vaccination		High risk of progression to active disease; A dual testing strategy can be performed, i.e., If one test comes negative, perform the other; any one of the positive tests is considered positive
NTCA[37]	Non-United States-born patients who had received BCG vaccination	For other individuals, depending on availability and cost, either a TST or IGRA may be used	Dual testing can be considered for patients who are at risk of severe forms of TB disease, and TB infection is strongly suspected and has a poor immune response

HHCs: household contacts; WHO: World Health Organization; HIV: human immunodeficiency virus; anti-TNF: anti-tumor necrosis alpha; ATS: American Thoracic Society; CDC: Center for Disease Control; IDSA: Infectious Diseases Society of America; BCG: Bacille-Calmette-Guérin; NTCA: National Tuberculosis Controllers Association

In April 2022, the WHO recommended the use of three new skin tests for the diagnosis of LTBI: C-TB (Statens Serum Institut, Copenhagen, Denmark), C-TST, and Diaskintest; all include the same M. tb-specific antigens present in the commercially available IGRAs (ESAT-6 and CFP-10). The sensitivity of C-TB, an ESAT-6/CFP-10-based skin test for active or latent tuberculosis in children and HIV-infected persons, is similar to that of the TST and Quantiferon-TB-Gold-In-Tube (QFT).[33] EC-Test (Zhifei Longcom Biologic Pharmacy Co., Anhui, China) is a new test for the diagnosis of LTBI.

Indications for TBI testing

The goal of testing is to identify individuals with an increased risk for the development of active TB disease who would benefit from treatment of LTBI. They can be categorized into two groups[22,34]:

1. Increased risk of new TB infection

2. Increased risk of reactivation as compared to healthy individuals

   1. High risk: Risk of reactivation is at least six times higher

   2. Moderate risk: Risk of reactivation that is three to six times higher

   3. Slightly increased risk: Risk of reactivation that is 1.5 to 3 times higher

Persons with a very low likelihood of TBI should not be tested, as the yield of the test is low and there are chances of false-positive tests. As per the TBI guidelines, WHO (2018), a new recommendation states that children >5 years, adolescents, and adults who are HHCs of microbiologically proven TB may be screened for TBI after screening for active infection.[13] Additionally, the National Tuberculosis Controllers Association (NTCA)[35] in 2020 states that subsequent LTBI testing is deferred until 4 weeks after administration of the last COVID-19 vaccine dose.

Treatment of latent tuberculosis

Before we dive into the guidelines regarding the treatment of TBI, let us first examine the biology of tubercular infection, which will provide insight into the basis of treating TBI. M. tb is an aerobic organism. Under unfavorable conditions, it grows only intermittently or remains dormant for prolonged periods. In an infected patient, several subpopulations of bacilli, each with a distinctive metabolic state, could exist[36]:

1. Rapid growers: found in the wall of cavitary lesion where oxygen tension is high. These are highly susceptible to isoniazid (H) and to a lesser extent to rifampicin (R), ethambutol (E), and streptomycin (S).

2. Slow growers: located intracellularly, inside macrophages and at inflamed sites. These are targeted by pyrazinamide (Z).

3. Spurters: found within caseous material with low oxygen tension. Here, the bacilli grow intermittently with occasional spurts of active metabolism. Rifampicin is the most active in this subpopulation.

4. Dormant: these bacilli remain totally inactive for prolonged periods. Notably, no antitubercular drugs are significantly active against them. TPT is directed at the prevention of conversion of dormant form to any of the aforementioned states.

The Indian guideline recommends that TPT be provided to target populations, including people living with HIV (PLHIV), HHC and extended populations with certain immunocompromised conditions[37] [Table 2]. It is important to note that while TBI testing is recommended in certain settings, it is not a mandatory criterion for the initiation of preventive therapy. Indeed, lack of standardized tuberculin reagents across the country makes the sensitivity questionable and, therefore, should not be a compulsory requisition.[38,39] These recommendations are grossly the same as those of the WHO except for the current lack of extension of TPT to a child born to a woman with active TB in whom congenital TB has been ruled out.[13]

Table 2.

Target population for TB preventive treatment

PLHIV	HHC	Extended population
Adults and children >1 year of age	All HHCs <5 years of age after ruling out active tuberculosis	On immunosuppressants, anti-TNF alpha drugs, dialysis, silicosis patients, preparing for transplant and LTBI test positivity
Infants (<1 year) in contact of active TB case	All HHCs >5 years of age after ruling out active tuberculosis and LTBI test positivity

PLHIV: People living with human immunodeficiency virus; HHC: household contacts

The treatment options available for treating TBI are isoniazid monotherapy for 6 months, rifampicin and isoniazid combination daily for 3 months (in children <15 years), and rifapentine and isoniazid weekly for 3 months. In countries with a high TB incidence, isoniazid is given at a dose of 5 mg/kg in adults and 10 mg/kg in children up to a maximum of 300 mg. Rifampicin, when used, is given at a dose of 10 mg/kg in adults and 15 mg/kg in children up to a maximum of 600 mg.[13] Indian guidelines currently recommend the use of isoniazid therapy for 6 months under the program. The rifamycin-based regimens may be used when availability can be ensured.[3] The efficacy of shorter rifamycin-based regimens is comparable to the 9-month IPT in both HIV and non-HIV individuals with better treatment completion rates. The use of an isoniazid-based regimen also warrants administration of a pyridoxine supplement; its unavailability should not refrain from the administration of IPT.[40,41]

Feasibility in India

The WHO originally provided preventive treatment for low-burden TB countries. In a high-burden country (defined as TB incidence >100 per 100000) such as India, there are multiple factors that must be taken into account while implementing such an important policy on a large scale [Figure 2].

Figure 2.

Factors to be considered to assess the feasibility of mass TB preventive treatment in India

1. Population size

   India is the most populous country in the world, with 1.38 billion people.[36] Nearly 31% of the population is infected with M. tb, which is approximately 430 million.[25] Nearly 9% of the population (approximately 124 million) is diabetic, and 160 million consume alcohol, thereby contributing to an enormous vulnerable population.[42,43] The average household size in India is 4.8.[44] Approximately, 19.33 lakh cases were reported in 2021; applying the aforementioned 4.8 cutoff for HHC yields a huge target population of 13.6 million. Additionally, the definition of HHC includes one who has shared the living space with the TB patient for ≥1 night in the last 3 months prior to diagnosis.[37] Taking into consideration the living conditions and the social life in India, it is practically impossible to trace all the HHCs, and if at all done, this number will be gigantic. In such a scenario, the feasibility of administering preventive therapy to roughly half a billion people with multiple risk factors requires adequate planning and preparation.

2. Risk factors other than direct transmission

   The most common attributable risk factors for tuberculosis include poor nutrition, alcohol consumption, smoking, and diabetes mellitus, followed by HIV infection. Apart from these, there are issues of overcrowding, indoor air pollution, poverty, and poor healthcare infrastructure that remain to be addressed.[3,4,5] Active disease in this country is not solely due to activation of latent TB but multifactorial. Additionally, there are epidemiological differences. The prevalence of TB is higher in rural areas, while the rate of infection is higher in urban settings. While directing a considerable number of resources and finances to preventive treatment, addressing the vast conundrum of aforementioned risk factors that have contributed to the spread is desirable. Scheme such as Nikshay Poshan Yojana is a commendable step in such direction aiming to address malnutrition in TB patients.[45]

3. Lack of evidence from the Indian subcontinent

   There are numerous studies worldwide that report the preventive effect of preventive treatment to last for several years post-discontinuation; however, there are no data from the Indian subcontinent. A few pilot studies in different regional settings would have assisted in predicting the probable outcome of the widespread policy. The isoniazid preventive treatment that has been implemented on children under five years of age who are HHCs and in PLHIV should form the ground to frame further management guidelines.

4. Cost

   The cost of mere preventive treatment may not amount much, although the rifapentine-based regimen will be costlier than the isoniazid-only treatment; the issue lies with the funds required for resources and infrastructure needed to rule out active tuberculosis before initiation of preventive treatment, such as chest radiographs, sputum microscopy, and rapid tests such as GeneXpert.[46] Likewise, there is a need for manpower to follow up with the target population, ensuring adherence, timely identification of active disease development, if it occurs at all, and facilities for diagnosis and management of adverse effects if any.

5. Programmatic management

   As far as case detection and treatment is considered under the NTEP, there has been great progress in ensuring drug availability and treatment adherence.[45] However, we are far from the TB elimination goal, and it is important to keep up the momentum. It is imperative to provide adequate training and sensitize the workforce and provide resources to consolidate the existing program and systematically upscale it to HHCs.

6. Regulation of the private sector

   A large subgroup of TB cases still receive treatment from a private setup with no record of treatment adequacy. Vigorous attempts have been made by the Government of India to ensure notification and correct treatment by offering incentives as well as making failure of notification a punishable offence. Nevertheless, there is a long way to go to attain the target notification goals.[47] Often, treatment is initiated on an empirical basis with no microbiological evidence or confirmation of drug resistance status. At times, second-line drugs are also initiated without definite indication, so the possibility of misuse and mismanagement of preventive therapy should also be considered.[47,48]

7. Lack of clear protocol

   There is no standard test for the confirmation of latent tuberculosis. Thus, the guideline states that TPT should not be withheld in the event of a lack of TBI testing.[37] There is a need for clarification even if an HHC tests negative for LTBI, then TPT should also be provided to all HHCs. However, that raises the question of the significance of the testing. If the aim is to extend TPT to all households, it would not be rational to channelize the already scarce resources for further boosting active case finding rather than TBI detection. Also, there is a lack of continuous availability of standardized strength of purified protein derivatives across the country, which needs to be addressed if it is utilized as a diagnostic test for TBI.[39]

8. Mechanism and duration of TPT

   Isoniazid and rifamycin (rifampicin, rifabutin, and rifapentine) are used as single agents or in combinations in the preventive treatment of drug-sensitive TB, while levofloxacin is used for drug-resistant TB. All these drugs are bactericidal. Isoniazid acts via inhibition of mycolic acid biosynthesis, while rifamycin inhibits DNA-dependent RNA polymerase and inhibits protein synthesis.[49] In summary, these drugs act when the bacteria are multiplying and are most effective against spurters. Therefore, theoretically, the rationale for prescribing bactericidal drugs for dormant populations of bacilli is based on the expectation that the bacilli will multiply during ongoing prophylactic treatment. Regarding the half-lives of the drugs used for preventive treatment, that of rifabutin is the longest (45 ± 17 hours).[50] The currently recommended regimens either use a daily regimen or a weekly regimen with evidence gained from multiple studies.[51,52,53] However, combining two drugs of variable half-lives in a once-weekly regimen is again questionable.

9. Ruling out active disease

   The chest radiograph is abnormal in roughly 50% of the TB cases, and microbiological confirmation is subject to the quality of the sputum if the contact is produced.[54] Thus, even after our best efforts to screen active cases among contacts, there is a need for a high index of suspicion and prompt response to symptom development.

10. Risk of fluoroquinolone resistance

    DR-TB is already on the rise with India contributing to one-fourth of global cases. The treatment of MDR-TB still remains a challenge with cure rates of less than 60%. The treatment requires constitution of a regimen with at least 4–5 sensitive drugs while reserving drugs for potential replacement in case of adverse effects or development of additional resistance or break in drug supply. The preventive treatment for MDR contacts is levofloxacin for 9 months. There are systematic reviews questioning the efficacy of preventive treatment for MDR-TB contacts.[55,56] The prevalence of fluoroquinolone resistance in India is already high at ~30%.[57] Although the risk of development of drug resistance with preventive treatment has been considered theoretical so far, there has been evidence reporting resistance development in M. tb with the use of FQ for as short as 13 days.[58]

11. Adverse effects of TPT

    The administration of drugs like isoniazid or rifamycin for prolonged durations is not without adverse effects.[59,60] The population group subjected to the preventive treatment needs to be educated about the risk benefit aspect of the therapy and the potential side effects along with their presenting symptoms. A screening baseline liver function test may be obtained while ruling out active tuberculosis and the healthcare infrastructure needs to be upscaled accordingly. The guideline for further management in the event of side effect development needs to be clarified to the providers.

12. Psychological aspect

    Tuberculosis has long been associated with a social stigma and the need for prolonged multi-drug treatment puts additional stress on the patient and the family.[61] In such a situation, subjecting other members of the family to a long preventive treatment may be perceived in different lights. On one hand, they may be relieved to receive such measurements to prevent development of active TB, while some may feel additional burden and apprehension.

13. Adherence

    Inadequate treatment has been a driving force behind the development of drug-resistance TB. Defaulting once there is symptomatic relief has been a common trend in patients with TB.[48,62] Ensuring adherence for a prolonged duration in a person not suffering from active disease is certainly a challenge. If such subjects discontinue the preventive treatment and later develop active disease in future, there is a theoretic possibility of the development of resistant TB.

14. Positive outcomes in HIV and pediatric age groups

    TPT has provided high protective efficacy among HIV individuals as has been documented in several studies.[63,64,65] Although the population of HIV patients is relatively less in India, the successful results can certainly be replicated in other groups with effective programmatic implementation. The regional studies conducted in India show highly variable coverage of TPT among children (roughly ranging from <25% to 70%) so far and call for further strengthening of the program.[66,67,68,69]

CONCLUSION

Prevention is a crucial step in reducing TB incidence while targeting its elimination. Implementing TPT that was originally meant for low TB burden countries in the country with the highest TB burden calls for careful consideration for the development of a sustainable policy. The unclear mechanisms of action of drugs on the persister bacilli population, the limitations of LTBI testing and active cases, cost and programmatic regulations, and adverse effects for treatment population wide are important issues. And yet, the favorable response in the pediatric age group and HIV patients provides hope for successful execution of the policy with robust planning and management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.