4.1. Expanding the High-Risk Groups for TB Preventive Therapy
Currently, it is recommended that PLHIV newly enrolled in care and treatment receive TB preventive therapy [33
]. The number of PLHIV newly enrolled in care is considered as the denominator against which WHO reports the percentage receiving TB preventive therapy on an annual basis [4
]. However, giving TB preventive therapy to all PLHIV, regardless of how long they have been on ART, is likely to be beneficial and should be considered. Laboratory studies have shown that long-term recovery of TB specific immune function is incomplete on ART [49
], and clinical studies have shown that length of time on therapy and ART-induced immune recovery still do not fully protect against TB in high exposure environments [50
Household contacts of patients with bacteriologically confirmed TB are high priority for TB preventive therapy. There are several research questions that need to be answered around the index patient and the household contacts if practice is to be refined and improved (Table 5
). The accepted definition of a household contact is “a person who shared the same enclosed living space for one or more nights or for frequent or extended periods during the day with the index case during the 3 months before commencement of the current treatment episode” [51
]. This is an arbitrary definition and in the local context it needs to be tested out through operational research and adapted as necessary. For example, the amount of exposure to MTB
will vary from sharing the same bed to living somewhere else within the same household complex and the actual duration of infectiousness may be longer or shorter than 3 months.
Currently, only patients with end-stage renal disease are recommended for systematic testing and treatment of LTBI [33
]. However, a well-conducted cohort study in Taiwan showed that there is an increased risk of TB in early stage chronic kidney disease (CKD) [52
], and it has been suggested that TB prevention efforts be targeted to all people with this condition. This recommendation needs further study because over the last 25 years, the global all-age prevalence of CKD has increased by 29% with nearly 700 million patients of all-stage CKD recorded in 2017 [53
In high TB burden countries, prisoners, people who inject drugs and health care workers are all at high risk of TB [35
]. Operational research should be conducted to assess whether in the local context and based on available resources it is cost-effective to systematically enrol such groups into TB preventive therapy services. Finding ways to ensure adherence in prisoners and people who inject drugs will need operational research.
Currently, WHO does not recommend that persons with diabetes mellitus (DM) be systematically screened and treated for LTBI [33
]. This needs to be revisited especially in the Asia Pacific Region. Persons with DM have an overall three-times higher risk of TB compared with the general population [54
]. A systematic review and meta-analysis estimated that the pooled prevalence of DM amongst TB patients between 1986 and 2017 was 15%, with the Asia Pacific in particular having a higher prevalence than other regions at 19% [56
]. In Indonesia, TB incidence was found to be significantly higher in persons with DM with established LTBI (1.7 per 100 person-years) compared with those without LTBI (0.5 per 100 person-years) [57
]. In Singapore, TB incidence was higher in persons with DM compared with the normal population and increased significantly in persons with DM as their body mass index dropped, being highest in those who were underweight [58
]. Further research is needed to determine whether persons with DM should be targeted for systematic LTBI testing and TB preventive therapy. In this regard, a prospective randomised controlled study is approved and about to start in Tanzania and Uganda using 3HP (European Union–EDTCP2 programme and grant number RIA2018CO-2514-PROTID). If TB preventive therapy is found to be cost-effective and taken up by WHO, this would considerably expand the pool of people potentially eligible for LTBI testing and TB preventive therapy. In 2019, there were 463 million people living with DM (54% living in the Asia Pacific) and this is predicted to rise to 578 million by 2030 [59
Finally, there is no mention in the WHO Guidelines about what to do with HIV-uninfected persons who have fibrotic lung lesions on chest X-ray. A trial in Eastern Europe 40 years ago found a high incidence of TB in this population group with TB preventive therapy using isoniazid significantly reducing this risk [60
]. In this regard, the expanded use of chest X-ray should be further considered, and those with fibrotic lung lesions consistent with inactive TB could be assessed for LTBI testing and treatment.
4.2. Better Tests for LTBI
There is an urgent need to develop and then deploy sensitive and specific biomarkers that can distinguish infection with MTB
from immunological memory of past infection (which is essentially what TST and IGRAs do) and predict who will progress from LTBI to active TB disease. It is becoming clear that LTBI is not a single entity but rather represents a broad spectrum of asymptomatic TB infection where different degrees of inflammation, bacterial replication and host immunity determine whether disease will develop or not [61
]. An exciting development in this direction has been the use of a whole blood transcriptomic messenger RNA expression signature that in Cape Town, South Africa, predicted progression from LTBI to active TB disease with 66% sensitivity and 81% specificity [62
]. Further research is continuing in this direction [61
], but currently there are no clinically useful or affordable tests for use in the field.
4.3. Ruling Out Active TB
A “sine qua non” of TB preventive therapy is ensuring that no person with active TB starts mono- or dual therapy. Screening adults and children for suggestive symptoms of TB is recommended by WHO [33
]. Those with symptoms are investigated and if TB is not diagnosed, TB preventive therapy can be considered. While molecular technology, particularly with Xpert MTB/RIF or Xpert MTB/RIF Ultra, has greatly improved the sensitivity and specificity of diagnosing active TB [63
], diagnostic certainty cannot be guaranteed. For this reason, symptomatic persons are often not offered TB preventive therapy.
The big question is whether absence of symptoms in adults or children is sufficient for ruling out active disease or whether chest X-ray should also be performed. The systematic use of chest X-ray is not considered mandatory in resource-limited settings [33
], although WHO states that the combination of absence of any chest X-ray abnormality plus the absence of TB-related symptoms has the highest negative predictive value for ruling out TB [64
]. Mobile vans equipped with a digital chest X-ray machine are increasingly being piloted and used in resource-limited settings. A study in Zimbabwe using a mobile van and digital chest X-ray showed that nearly 10% of asymptomatic persons with chest x-rays suggestive of pulmonary TB were diagnosed and treated for TB, with 13% of them found to have bacteriologically confirmed disease [65
]. A similar study in India confirmed the value of chest X-ray in asymptomatic persons both in operational and economic terms [66
]. Currently, digital chest X-rays are read by medical officers or other trained personnel. Accuracy of TB diagnosis can be improved using artificial intelligence to read the chest X-ray [67
]: the automated technology is available and this should be considered and further researched and assessed by TB programmes where human resources are constrained.
4.4. Expanding and Refining the Use of 3HP
A growing number of countries are using 3HP although there are several issues that require further research (Table 6
). Caution is currently required before 3HP can be given safely to children < 2 years, pregnant women, injecting drug users on opioid substitution therapies (OST) and women using oral or injectable contraceptives. There is no published data on the use of 3HP in children < 2 years although a study is underway to assess safety and optimal dosing in this age group [43
]. While 3HP was given to 125 pregnant women and showed rates of abortion and birth defects similar to those in the general population [68
], this area needs further research in light of a randomised controlled trial on isoniazid preventive therapy showing a higher incidence of adverse pregnancy outcomes (stillbirth, low-birthweight, congenital anomalies) in HIV-infected women receiving isoniazid [69
]. The risk of using 3HP in injecting drug users on Opioid Substitution Therapy (OST) is that the rifamycin component may lead to an “opiate withdrawal syndrome” due to decreased serum concentrations of the drugs [43
]: this needs further study.
All rifamycin-containing regimens have potential drug–drug interactions with ARV drugs, although in general rifapentine has less interaction than rifampicin. Dolutegravir (DTG) is now recommended as a preferred drug in first-line ARV regimens in PLHIV [70
], and it has been established that 3HP can safely be used with this regimen without the need to adjust DTG doses [43
In the 3HP regimen for adults, 900 mg rifapentine (6 × 150 mg tablets) is taken with 900 mg isoniazid (3 × 300 mg tablets) along with pyridoxine: 10 tablets on one day per week [43
]. Lowering the pill burden (by offering rifapentine as a 300 mg tablet in a fixed-dose combination together with isoniazid 300 mg) would make 3HP more acceptable for people to take and would simplify procurement, distribution and storage issues at peripheral health facilities. These concerns are being taken up by generic drug manufacturers.
Systematic monitoring is needed for common and important side effects. The most serious side effect of any isoniazid-containing regimen is drug-induced hepatitis [36
], which if unrecognised can lead to acute liver failure and death. 3HP is associated with less hepatoxicity than 9-months IPT [71
]. Nevertheless, programmes need to think about systematically excluding those at high risk of drug-induced hepatitis (for example, with pre-existing liver disease or chronic hepatitis C infection) and monitor this aspect closely. Given the absence of laboratory monitoring in most resource-constrained countries, those taking 3HP and health workers must be educated about the symptoms and signs of hepatitis and the need to stop the drug and immediately report to a health facility if these occur.
3HP is said to be more cost-effective when given by clinic-based direct observation (DOT) [72
]. However, in the USA, self-administered 3HP with monthly monitoring with or without weekly text messaging was non-inferior to 3HP by DOT in terms of safety and treatment completion [73
]. Video observed therapy (VOT) has also emerged recently as a method to mimic in-person visits, especially in the smartphone era with internet data connections. VOT was associated with higher treatment completion in persons taking 3HP compared with DOT in New York [74
], and in South India VOT was preferred over DOT in terms of support during care and treatment of TB [75
]. This is an important research topic in low- and middle-income countries where local information on demographics and smartphone ownership is crucial to understand who might and might not benefit from this digital technology.
TB preventive therapy reduces but does not completely prevent TB, and all individuals must be monitored for the development of active TB during treatment, and, if possible, after treatment as well. This requires education of those initiated on preventive therapy as well as their attending health care workers, with clear instructions to attend health facilities for screening and investigation if suggestive TB symptoms arise. For PLHIV living in high TB exposure environments, there is a need to determine whether repeat courses of 3HP are required to maintain TB preventive effects.
4.5. Recording and Reporting
Keeping track of who is eligible, who initiates, who completes TB preventive therapy and who is free of TB 12 months after completing therapy is essential for (i) monitoring each individual’s journey, (ii) assessing the TB preventive therapy cascade, (iii) charting the progress made against indicators (such as rates of coverage, completion or failure) at subnational, national and international level and (iv) drug forecasting so that procurement and distribution match demand. Drug shortages and interrupted supplies were the most common reasons for discontinuing IPT in children in an Ethiopian community-based LTBI treatment study [76
In PLHIV, National HIV/AIDS Programmes take responsibility for recording and reporting on who is screened for TB, diagnosed with TB and given TB preventive therapy. These data, collated annually for countries and at global level, are usually presented in the Global TB Reports [4
For household contacts of index TB patients and for all other high-risk groups, the National TB Programme generally takes responsibility. Done properly, this is an enormous task requiring adequate human, financial and technical resources. To fully comprehend how all the steps of preventive therapy work at the programme level, a sufficient amount of detail must initially be collected. Table 7
outlines the key indicators for which data should be collected in household contacts of index patients with TB. This should identify bottlenecks or problem areas where operational research or further work might be required to close gaps in the TB preventive therapy cascade and better streamline activities. If the index patient is HIV-positive or has DM, further testing of household contacts with respect to these parameters would be indicated.
4.6. Consideration of Other TB Prevention Activities
TB preventive therapy is an important part of a larger effort to prevent TB. The development and widespread use of an effective vaccine would have an enormous impact. BCG vaccine protects children from severe disease such as disseminated TB and meningitis, but it does not afford long term protection against pulmonary disease. However, a novel candidate vaccine, M72/AS01E
, provided 50% protection over three years against progression to pulmonary TB in adults with LTBI enrolled in Kenya, South Africa and Zambia [77
]. While more work on this vaccine is needed in different populations and age-groups as well as people with no evidence of LTBI, this is an exciting and promising development.
Intervening on socioeconomic and other determinants of TB can yield valuable preventive dividends. For example, ART is an excellent TB prevention tool in PLHIV [78
], and in South Korea the use of metformin in elderly people with DM significantly reduced their risk of TB [79
]. On a much larger scale, poverty reduction at the country level predictably reduces TB incidence [80
], and targeted socioeconomic poverty reduction interventions such as cash transfers can also reduce TB risk [81
]. Good infection control policies and practices in health care facilities and congregate settings such as refugee camps and prisons can reduce MTB
transmission and lower TB incidence.