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Management of latent tuberculosis infection in China: Exploring solutions suitable for high-burden countries

  • Author Footnotes
    1 Xiaojing Cui and Lei Gao contributed equally to this work.
    Xiaojing Cui
    Footnotes
    1 Xiaojing Cui and Lei Gao contributed equally to this work.
    Affiliations
    Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China–Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, No. 2, East Yinghua Road, Chaoyang District, Beijing 100029, China
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  • Author Footnotes
    1 Xiaojing Cui and Lei Gao contributed equally to this work.
    Lei Gao
    Footnotes
    1 Xiaojing Cui and Lei Gao contributed equally to this work.
    Affiliations
    NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, and Center for Tuberculosis Research, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
    Search for articles by this author
  • Bin Cao
    Correspondence
    Corresponding author.
    Affiliations
    Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China–Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, No. 2, East Yinghua Road, Chaoyang District, Beijing 100029, China
    Search for articles by this author
  • Author Footnotes
    1 Xiaojing Cui and Lei Gao contributed equally to this work.
Open AccessPublished:February 27, 2020DOI:https://doi.org/10.1016/j.ijid.2020.02.034

      Highlights

      • We review the burden, treatment, and management of latent tuberculosis infection (LTBI) in China.
      • Considering the LTBI burden, the availability of health resources, and other local determinants, we raise some suitable suggestions for the management of LTBI in China.

      Abstract

      China is one of the countries with a high burden of tuberculosis (TB) and latent tuberculosis infection (LTBI). It was recently estimated that China had the highest LTBI burden in the world, with approximately 350 million persons living with the infection. The prevalence of LTBI in China is overestimated by tuberculin skin test (TST) as compared to interferon-gamma release assay (IGRA). A population-based study found that IGRA positivity rates ranged between 13.5% and 19.8%. The annual TB infection rate in the rural population was 1.5% based on persistent positive IGRA results in converters. The development of active TB from LTBI in the general rural population was 0.87 per 100 person-years in the first 2 years among individuals who newly converted to IGRA-positive. TB control in students has been paid more attention by the government, which also improved LTBI management among students in close contact with active TB patients. A 3-month regimen of twice-weekly rifapentine plus isoniazid (3H2P2, both with a maximum dose of 600 mg) has been practiced for LTBI treatment in China for years. With respect to LTBI management in populations using immune inhibitors, an expert consensus on TB prevention and management in tumor necrosis factor antagonist application was published in 2013 in China. In order to achieve the global goals of the End TB Strategy, China needs innovative ideas and technologies to reduce the TB incidence by management of LTBI, such as the identification of populations for LTBI testing and treatment, selecting and developing reliable LTBI tests, exploring safe and effective preventive treatment tools, and establishing a set of optimized LTBI management systems.

      Keywords

      Introduction

      China is one of the countries with a high burden of tuberculosis (TB) and latent tuberculosis infection (LTBI). According to the Global Tuberculosis Report 2019 published by World Health Organization (WHO) (

      Geneva: World Health Organization. Global Tuberculosis Report 2019.

      ), the TB incidence rate in China was 61 per 100 000 population and TB incident cases in China accounted for 9% of the global total in 2018. In addition, it was recently estimated that China had the highest LTBI burden in the world, with approximately 350 million persons living with the infection (
      • Houben R.
      • Dodd P.
      The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling.
      ). It is now widely accepted that the management of active TB and LTBI are equally important for achieving the goals of the WHO End TB Strategy (
      • Uplekar M.
      • Weil D.
      • Lonnroth K.
      • Jaramillo E.
      • Lienhardt C.
      • Dias H.M.
      • et al.
      WHO’s new end TB strategy.
      ).
      In 2015, the WHO released the Guidelines on the Management of Latent Tuberculosis Infection to provide guidance for LTBI management in high-income and upper middle-income countries with an estimated TB incidence rate of less than 100 per 100 000 population, including China (
      • WHO
      Guidelines on the management of latent tuberculosis infection.
      ). Since then, LTBI management has been given a new historical mission, besides protecting at-risk individuals, in order to reduce TB incidence at the community level. However, targeting only the high-risk populations for LTBI management (such as people living with HIV and close household contacts), as recommended in the WHO guidelines, might not achieve a significant decline in TB incidence in China. Take HIV infections for example: in 2018, the contribution of incident cases from people living with HIV in China was only 2%, but it was 10% in America, 12% in Europe, and 25% in Africa (

      Geneva: World Health Organization. Global Tuberculosis Report 2019.

      ). Therefore, selecting at-risk populations for LTBI testing and treatment should be adapted to the national epidemiology of TB, the availability of health resources, and other local determinants. However, such guidelines and strategies suitable for China and other high-burden countries have not yet been systematically developed.

      LTBI burden in China

      LTBI is a state of persistent immune response to stimulation by Mycobacterium tuberculosis (Mtb) antigens with no evidence of clinically manifest active TB. Currently, there is no gold standard for the diagnosis of LTBI. The interferon-gamma release assay (IGRA) and tuberculin skin test (TST), which are based on cellular immune responses, are two available LTBI testing methods.
      In the fourth national survey performed in 2000, it was estimated that 44.5% of the population were infected with Mtb by TST (
      • Technical Steering Group of National Tuberculosis Epidemiological Sampling Survey
      Report on fourth national epidemiological sampling survey of tuberculosis national technic steering group of the epidemiological sampling survey for tuberculosis.
      ). In 2013, Gao et al. started a population-based multicenter prospective study to assess the LTBI burden in rural China. They found that the prevalence of LTBI in China may be overestimated by TST as compared to IGRA. The baseline data of this study, involving four selected study sites, showed that age- and sex-standardized TST positivity rates (TST ≥10 mm) ranged from 15.5% to 41.7%, but IGRA positivity rates ranged between 13.5% and 19.8% (
      • Gao L.
      • Lu W.
      • Bai L.
      • Wang X.H.
      • Xu J.S.
      • Catanzaro Antonino
      • et al.
      Latent tuberculosis infection in rural China: baseline results of a population-based, multicentre, prospective cohort study.
      ). It is well known that the TST overestimates LTBI numbers, because its performance is significantly affected by bacillus Calmette–Guérin (BCG) vaccination and some non-tuberculous mycobacteria (NTM) infections. In contrast, IGRAs are unaffected by previous BCG vaccination or exposure to most NTM, because they use antigens coded by Mtb complex-specific regions of difference that are absent from most NTM and from all strains of BCG. Therefore, epidemiological studies addressing LTBI prevalence in the general population show good consistency when using IGRAs (
      • Gao L.
      • Lu W.
      • Bai L.
      • Wang X.H.
      • Xu J.S.
      • Catanzaro Antonino
      • et al.
      Latent tuberculosis infection in rural China: baseline results of a population-based, multicentre, prospective cohort study.
      ).
      With the increased availability of IGRAs in China, the prevalence of LTBI has been re-estimated recently in several specific populations. LTBI prevalence among household contacts was found to be relatively high (32–48%) (
      • Zhang H.C.
      • Ruan Q.L.
      • Wu J.
      • Zhang S.
      • Yu S.L.
      • Wang S.
      • et al.
      Serial T-SPOT.TBin household contacts of tuberculosis patients: a 6-year observational study in China.
      ,
      • Hu Yi
      • Zhao Q.
      • Graviss E.A.
      • Jiang W.
      • Yuan Z.
      • Xu B.
      Use of the T-SPOT.TB assay to screen latent tuberculosis infection among the TB contacts in Shanghai, China.
      ). The TB infection rate in healthcare workers (HCWs) was found to range from 15% to 70% depending on the level and the location of the hospital (
      • Guo L.P.
      • Jiang Y.
      • Liu Y.M.
      • Cao B.
      First assessment of interferon gamma release assay results among healthcare workers at a general hospital in China.
      ,
      • Di M.J.
      • Song Y.D.
      • Xiong Y.C.
      • Zhao F.
      • Hu D.M.
      • Li M.
      • et al.
      Comparison and analysis of TST and IGRAs for testing tuberculosis infection of health care workers.
      ). IGRA positivity was observed to be lower than 10% in schoolchildren and adolescents (
      • Hu Y.
      • Zhao Q.
      • Wu L.
      • Wang W.
      • Yuan Z.
      • Xu B.
      • et al.
      Prevalence of latent tuberculosis infection and its risk factors in schoolchildren and adolescents in Shanghai, China.
      ,
      • Li H.
      • Xin H.
      • Qian S.
      • Li X.
      • Zhang H.
      • Li M.
      • et al.
      Testing of tuberculosis infection among Chinese adolescents born after terminating the Bacillus Calmette-Guérin booster vaccination: subgroup analysis of a population-based cross-sectional study.
      ). Among people living with HIV infection, the prevalence of LTBI was found to be 9% in a population of men who have sex with men (MSM) (
      • Xin H.N.
      • Li X.W.
      • Zhang L.
      • Li Z.
      • Zhang H.R.
      • Yang Y.
      • et al.
      Tuberculosis infection testing in HIV-positive men who have sex with men from Xi’an China.
      ). This low prevalence might be explained, at least in part, by immunological deficiency, which decreases the sensitivity of the IGRA and thus increases the number of false-negatives.
      As in other countries, very few prospective studies have been conducted in the general population to estimate the annual risk of TB infection in China. In the study by Gao et al., among 12 749 eligible participants identified as IGRA-negative in the baseline survey, 390 (3.1%) were IGRA converters within the first year of follow-up. However, during the second year of follow-up, only half of the converters were found to be consistently positive and the others showed reversion. Hence, they estimated that the annual TB infection rate in the rural population was 1.5% based on persistent positive IGRA results in converters (
      • Gao L.
      • Bai L.
      • Liu J.
      • Lu W.
      • Wang X.
      • Li X.
      • et al.
      Annual risk of tuberculosis infection in rural China: a population-based prospective study.
      ). Increasing age, male sex, and close contact with active TB patients were found to be independent risk factors for TB infection. The findings of this study provided population-based evidence that the rural elderly of China carry a double burden of both a high prevalence of LTBI and higher risk of new infection. Ageing and chronic diseases related to attenuation of immunity might explain the higher susceptibility of the elderly population to infection and reinfection. Thus, infection control should be strengthened in the elderly in rural China to prevent the transmission of TB infection in this vulnerable population.
      The development of active TB from LTBI in the general rural population was also investigated by Gao and colleagues (
      • Gao L.
      • Li X.
      • Liu J.
      • Wang X.
      • Lu W.
      • Bai L.
      • et al.
      Incidence of active tuberculosis in individuals with latent tuberculosis infection in rural China: follow-up results of a population-based, multicenter, prospective cohort study.
      ,
      • Xin H.
      • Zhang H.
      • Yang S.
      • Liu J.
      • Lu W.
      • Bai L.
      • et al.
      5-year follow-up of active tuberculosis development from latent infection in rural China.
      ). They observed that the incidence rate of active TB was 0.87 per 100 person-years in the first 2 years (2014–2015) after the baseline survey (performed in 2013) and 0.26 per 100 person-years in the following 3 years (2016–2018), among individuals who were IGRA-positive. Their prospective results persistently suggested that about 30% of TB incidence in rural China may be attributed to a history of prior TB. Based on the findings of this prospective study, they suggested that in order to achieve the target of decreasing incidence at the community level in China, individuals with a history of prior TB should be considered for LTBI testing and treatment, in addition to those with a likely recent infection, such as close contacts of patients with active TB.

      Current situation of LTBI management in China

      In China, LTBI management is not currently an important part of the national TB control strategies. People living with HIV, children <5 years old who have had contact with a pulmonary TB patient, and those with clinical indications such as silicosis, anti-tumor necrosis factor (TNF) treatment, dialysis, and transplantation have been recommended as target populations for LTBI treatment. However, this has not been conducted systematically due to the lack of national guidelines.
      Nevertheless, in China, it was estimated in 2018 that there were 13 900 children under 5 years old who were household contacts of a bacteriologically confirmed pulmonary TB case but who were not systematically covered by preventive treatment (

      Geneva: World Health Organization. Global Tuberculosis Report 2019.

      ). By December 2018, there were 1 250 000 people living with HIV in mainland China. These two populations with a high likelihood of developing active TB after infection should be widely protected by LTBI treatment.
      Fortunately, TB control in students has been paid more attention by the government, which also improved LTBI management among students in close contact with active TB patients. The Code of Practice for Prevention and Control of Tuberculosis in School (
      • General Office of National Health and Family Planning Commission
      • General Office of the Ministry of Education
      Code of practice for prevention and control of tuberculosis in schools.
      ) clearly requests that children in kindergarten, primary school, and middle school who are <15 years old should be tested by TST on admission, and that anyone with a strong TST-positive results (>15 mm or with blister) should undergo a chest X-ray for active TB screening. In addition, high school and college students who are ≥15 years of age should undergo a chest X-ray for active TB screening directly on admission. Annual routine examinations for teachers should also include TB screening. Once an active TB case is confirmed, all close contacts including roommates, classmates, and teachers should be investigated and screened for active TB and LTBI. Individuals with a strong TST-positive result and normal chest radiograph are recommended for preventive treatment. Although this technical pathway needs improvement, as the TST might introduce many false-positives for LTBI management, this action has played an important role in controlling the TB epidemic in schools.
      In schools, a 3-month regimen of twice-weekly rifapentine plus isoniazid (3H2P2, both with a maximum dose of 600 mg) has been practiced for LTBI treatment in China for years. A non-randomized controlled trial (RCT) was conducted involving TST-positive college students using 3H2P2 (1948 treated and 1765 untreated); the occurrence of liver dysfunction (alanine aminotransferase (ALT)/aspartate aminotransferase (AST) higher than the normal levels) was reported to be 2% and the protective rate was observed to be 75% during 4 years of follow-up (
      • Liu Y.Q.
      • Tu D.H.
      • An Y.S.
      Control in university students in Beijing: preventive therapy for tuberculosis-infected persons.
      ). Application of the 3H2P2 regimen rather than the WHO-recommended 3HP regimen (3-month regimen of once-weekly rifapentine plus isoniazid, both with a maximum dose of 900 mg) was determined based mainly on the following two points: (1) it has been reported that the individual’s genetic background, such as drug-metabolizing enzyme gene polymorphisms, might contribute to various risks of anti-TB drug-induced liver injury (
      • Cai Y.
      • Yi J.Y.
      • Zhou C.H.
      • Shen X.Z.
      Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis.
      ); and (2) Asians have been reported to carry a higher frequency of rapid acetylator genotypes of N-acetyltransferase 2 (approximately 50%) than Caucasians (approximately 5%). Rapid acetylators are prone to treatment failure, probably due to insufficient exposure to isoniazid (
      • Motta Ilaria
      • Calcagno Andrea
      • Bonora Stefano
      Pharmacokinetics and pharmacogenetics of anti-tubercular drugs: a tool for treatment optimization?.
      ). Therefore, the reduced single dosage and increased frequency were adopted in the 3H2P2 regimen.
      With respect to LTBI management in populations using immune inhibitors, an expert consensus on TB prevention and management in TNF antagonist application was published in 2013 in China (
      • Xue Qin
      • Wang Nian-song
      Interpretation of expert position paper on tuberculosis prevention and management in tumor necrosis factor antagonist application.
      ). This suggested that all patients about to start TNF antagonist therapy should be investigated for LTBI or prior TB. The screening includes taking a detailed medical history to evaluate the risks of TB, a chest X-ray or chest computed tomography if necessary, and TST and/or IGRA. Preventive treatment should be given to individuals with LTBI, using either a 6HR regimen (6 months, once-daily isoniazid with a dose of 300 mg plus rifampicin with a dose of 450 mg) or 6H2P2 regimen (6 months, twice-weekly isoniazid plus rifapentine, both with a maximum dose of 600 mg).
      The population of China is huge and the size of the LTBI population is astonishing, even when estimated by IGRAs. Furthermore, the risk of re-exposure is still high, reducing the feasibility of scaling up LTBI testing and treatment in China. It is clear that China should not systematically implement the guidelines of low-burden countries. To develop suitable strategies for LTBI management in China, we are facing several gaps: (1) Improved leadership is needed to acknowledge that LTBI treatment should be scaled up to help eliminate the pool of TB infection and achieve the End TB Strategy targets (

      Geneva: World Health Organization. Global Tuberculosis Report 2019.

      ). (2) National guidelines should be developed as the highest priority, which is the primary guarantee to improve implementation. (3) According to the risk classification, coverage of preventive treatment should be greatly improved as soon as possible for the high-risk groups such as those with HIV infections and children younger than 5 years of age who have been in close contact with people with TB (
      • Surie D.
      • Interrante J.D.
      • Pathmanathan I.
      • Patel M.R.
      • Anyalechi G.
      • Cavanaugh J.S.
      • et al.
      Policies, practices and barriers to implementing tuberculosis preventive treatment-35 countries, 2017.
      ,
      • Hamada Y.
      • Glaziou P.
      • Sismanidis C.
      • Getahun H.
      Prevention of tuberculosis in household members: estimates of children eligible for treatment.
      ). (4) Considering that the epidemic situation and economic level in different regions of China are very different, it might be beneficial to systematically practice LTBI management first in economically developed and less epidemic regions. The scale-up of LTBI treatment is a step-by-step process, and many efforts and inputs are needed.

      Developing LTBI management strategies suitable for China

      Indeed, there currently remain many challenges to effectively manage TB and LTBI in high-burden countries with limited resources. However, in the absence of an effective vaccine, it is very important to start such a virtuous circle combining prevention with treatment. It is well known that population-based LTBI testing and treatment is not feasible, but for infected individuals at high risk of progression to active disease, the benefits are greater than the harm. Therefore, LTBI management should be centered on at-risk populations, whether in high-burden countries or in low-burden countries. Furthermore, treatment should be delivered effectively to guarantee that the majority of those starting a treatment regimen will complete it, with no or minimal risk of adverse events. Nevertheless, the current situation is that LTBI tests are imperfect, there are risks of serious side-effects for preventive chemotherapy, and the cost of management is relatively high based on currently available tools. In China, we need innovative ideas and technologies to control active TB disease by management of LTBI.

      The identification of populations for testing and treatment of LTBI

      These populations should share a common feature, i.e., being at high risk of infection and disease development (such as close contacts of active TB patients, those with HIV infections, immune inhibitor users, and HCWs). However, in order to achieve the goals of reducing incidence in high-burden countries, such populations could, at least in part, influence TB incidence at the community level as well. Therefore, epidemiological studies are needed to identify such targets from the perspective of public health. Artificial intelligence technology, for example electronic chest radiograph reading systems, would improve the feasibility of population-based screening for at-risk subgroups, such as those with an abnormal chest X-ray.

      Selecting and developing reliable LTBI tests

      Considering that BCG vaccination has been included in the national immunization program in China for almost 40 years, TST results should be interpreted with caution, especially for children and students. A two-step approach has been suggested for regions with BCG vaccination but limited resources: to test LTBI by IGRA in TST-positive subjects. This has also been found to be suitable for use in Chinese adolescents (
      • Li H.
      • Xin H.
      • Qian S.
      • Li X.
      • Zhang H.
      • Li M.
      • et al.
      Testing of tuberculosis infection among Chinese adolescents born after terminating the Bacillus Calmette-Guérin booster vaccination: subgroup analysis of a population-based cross-sectional study.
      ). In addition, the development of a novel specific skin test based on ESAT-6 and CFP10 antigens will provide more choice for LTBI testing (
      • Ruhwald M.
      • Aggerbeck H.
      • Gallardo R.V.
      • Hoff S.T.
      • Villate J.I.
      • Borregaard B.
      • et al.
      Safety and efficacy of the C-Tb skin test to diagnose, Mycobacterium tuberculosis, infection, compared with an interferon γ release assay and the tuberculin skin test: a phase 3, double-blind, randomised, controlled trial.
      ).

      Exploring safe and effective preventive treatment tools

      The efficacy of currently available preventive treatment regimens ranges from 60% to 90%. However, none of the WHO-recommended regimens have been evaluated in Chinese populations by RCT. Gao et al. conducted an RCT to study the performance of the 3HP regimen among individuals with LTBI (aged 50–69 years) in the general population (
      • Gao L.
      • Zhang H.
      • Xin H.
      • Liu J.
      • Pan S.
      • Li X.
      • et al.
      Short-course regimens of rifapentine plus isoniazid to treat latent tuberculosis infection in older Chinese patients: a randomized controlled study.
      ); however, due to the increasingly rapid growth and unexpected high frequency of adverse effects, the treatment was terminated early. In contrast, a 6-week twice-weekly rifapentine plus isoniazid regimen (both with a maximum dose of 600 mg) showed a protective efficacy of >60% in this study (
      • Gao L.
      • Zhang H.
      • Xin H.
      • Liu J.
      • Pan S.
      • Li X.
      • et al.
      Short-course regimens of rifapentine plus isoniazid to treat latent tuberculosis infection in older Chinese patients: a randomized controlled study.
      ). In addition, a 1-month regimen of rifapentine plus isoniazid was found to be non-inferior to 9 months of isoniazid alone for preventing TB in HIV-infected patients (
      • Swindells S.
      • Ramchandani R.
      • Gupta A.
      • Benson C.A.
      • Leon-Cruz J.
      • Mwelase N.
      • et al.
      One month of rifapentine plus isoniazid to prevent HIV-related tuberculosis.
      ). Such innovative regimens with ultrashort courses and optimized use of drugs are a significant advance in vulnerable populations and in resource-limited areas. Very recently, it was reported that vaccination with M72/AS01E provided protection against disease progression from LTBI for at least 3 years (
      • Tait D.R.
      • Hatherill M.
      • Van Der Meeren O.
      • Ginsberg A.M.
      • Van Brakel E.
      • Salaun B.
      • et al.
      Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis.
      ). The development of such novel tools will provide great support for LTBI management in high-burden countries.

      Establishing a set of optimized LTBI management systems

      Currently, the TB management system mainly consists of two parts: one is the designated hospitals providing the clinical treatment for active TB and the other is the Centers for Disease Control and Prevention (CDC) responding to patient management, including the implementation of directly observed therapy (DOT). To manage LTBI, it will be necessary to provide a combination of resources from hospitals and the CDC. Considering that the LTBI population size is much larger than that of TB patients, this will require much greater public health resources, and community doctors might be one of the major forces to implement LTBI management. Timely evaluation and optimization is very important, as well as guaranteeing the flexibility and efficacy of strategies and technical pathways.

      Summary

      In summary, LTBI testing and treatment in individuals at-risk of developing active TB has been proved to be an effective strategy for TB control in low-burden countries. In order to achieve the global goals of the End TB Strategy, China should act on LTBI management and protect high-risk individuals in order to reduce the community incidence. Nevertheless, innovative work is needed to develop guidelines on LTBI management suitable for China and other regions in a similar situation with a high burden of both TB and LTBI.

      Funding

      This study was supported by the non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2019TX320004), CAMS Innovation Fund for Medical Sciences (2018-12M-1-003), and the National Science and Technology Major Project of China (2017ZX10201302-002).

      Ethical approval

      Ethical approval was not required.

      Conflict of interest

      All the authors have no competing interests to declare.

      Acknowledgements

      This article is part of a supplement entitled Commemorating World Tuberculosis Day March 24th, 2020: “IT'S TIME TO FIND, TREAT ALL and END TUBERCULOSIS!” published with support from an unrestricted educational grant from QIAGEN Sciences Inc.

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