3. Research gaps

The evidence reviewed ahead of the current update exposed additional knowledge gaps to the ones reported in other recent updates of the guidelines. Continued research on development and on implementation science remain critical for many aspects of the PMTPT. Some of this information may be collected as part of user feedback put in place by the implementing programme.

Risks for progression to active TB

Evidence on the likelihood of progression from infection to active TB in different at-risk populations will help determine the potential benefits of TB preventive treatment and for the design of appropriate public health interventions. In particular, strong evidence from clinical trials is lacking particularly for indigenous populations and people under the following circumstances: diabetes, harmful use of alcohol, tobacco smoking, underweight, silica exposure, on steroid treatment, rheumatological diseases, and cancer. Both direct measurement of the incidence of active TB and methods for measuring the risk for active TB disease could be explored, such as use of genotyping to investigate reactivation. Evidence is also required on differential harm and the acceptability of LTBI testing and TB preventive treatment in specific risk groups, including socially adverse effects such as stigmatization.

Defining the best algorithm for ruling out active TB

Operational and clinical studies should be conducted to exclude active TB before preventive treatment is given. The performance and feasibility of the algorithms proposed in these guidelines should be assessed. Data on children and pregnant women are particularly limited. Better evidence is needed to identify the best strategies to trace contacts and to save cost and improve feasibility (e.g. use of mobile chest radiography).

Improved diagnostic tests and performance of LTBI tests in at-risk populations

Diagnostic tests with improved performance and predictive value for progression to active TB are critically needed. In addition, the performance of LTBI tests should be evaluated in various risk groups, to assess reinfection, and to understand how best to use available tools in each population (e.g. combination or sequential use of TST and IGRA).

Treatment options for LTBI

Research to find shorter, better-tolerated TB preventive treatment regimens than those currently recommended remains a priority. Studies of efficacy and adverse events in certain risk groups (e.g. people who use drugs, people who engage in the harmful use of alcohol and older persons) are essential. There remain very limited data on the use of rifapentine in children < 2 years and in pregnant women. Trial data on 1HP in children and adults not infected with HIV and in PLHIV with low CD4 counts, under different settings, would also be desirable. A direct comparison of 1HP vs. 3HP for safety, effectiveness, and cost-effectiveness will be useful. Pharmacokinetics studies could help establish an optimal daily dosage of rifapentine in children under 13 years, and interactions between rifamycin containing regimens and other medicines, particularly ART in both adults and children. In addition, the durability of protection of different preventive treatment regimens, including long-acting injectables, need to be evaluated in settings in which TB is endemic, including the efficacy of repeated courses of preventive treatment. Studies of the preference of different stakeholders for different regimen characteristics would be helpful.

Monitoring of adverse events

Prospective randomized studies are required to determine the incremental benefits of routine monitoring of liver enzyme levels over education and clinical observation alone for preventing severe clinical adverse events, with stratification of the evidence by at-risk population. Programmatic data on maternal and pregnancy outcomes, inclusive of post-natal follow-up of the child, could supplement current knowledge about the safety of different LTBI regimens when used in pregnancy.

Drug resistance and TB preventive treatment

Programme-based surveillance systems and clinical studies are needed to monitor the risk for resistance to the medicines used in TB preventive treatment. Particular consideration should be given to rifamycin-containing regimens because of the dearth of data. Conversely the impact on preventive treatment efforts of high levels of resistance to isoniazid and/or rifamycins among prevalent TB strains would be useful to study.

Adherence to and completion of treatment

Carefully designed studies, including RCTs, are required to generate evidence on the effectiveness of context-specific interventions to enhance adherence and completion of treatment. The studies should include specific risk groups, depending on the available resources and the health system infrastructure and address questions about how to integrate TB preventive treatment into differentiated models of HIV service delivery. Use of digital technologies to improve adherence is an important area. Further research is required on the effectiveness of self-administration of the 3-month regimen of weekly rifapentine plus isoniazid.

Cost–effectiveness

Although a number of studies of the cost-effectiveness of TB preventive treatment are available, their wide heterogeneity obviates a comprehensive appraisal of the cost-effectiveness of LTBI management stratified by population group, and type of regimen or intervention. Cost-effectiveness analysis using parameters from different resource settings could allow better planning for the extension of a PMTPT strategy at national or local level.

Preventive treatment for contacts of people with MDR-TB

The WHO recommendation on MDR-TB preventive treatment should not signal a lesser need for continued studies or create ethical impediments. RCTs with adequate power are urgently needed to update the recommendation on preventive treatment for contacts of people with MDR/RR-TB. Trials should be performed with both adult and paediatric populations and with at-risk populations such as PLHIV. The composition, dosage and duration of preventive treatment regimens for MDR-TB should be optimized, and the potential role of newer agents with good sterilization properties should be investigated. The effectiveness and safety of preventive treatment for contacts of people with MDR-TB should be evaluated under operational conditions. Further evidence on the risk of contacts of people with MDR-TB for progression to active TB will be important to understand the benefits of preventive treatment.

Programme management

Continued epidemiological research should be conducted to determine the burden of LTBI in various geographical settings and risk groups and as a basis for nationally and locally tailored interventions, including integrated community-based approaches. Implementation research on context-specific barriers and facilitators is needed for different LTBI regimens, to explore dimensions for which evidence is often sparse, such as acceptability, feasibility, equity and resource use. Research is also needed on service delivery models to improve management including the provision of additional interventions for smokers, harm reduction services for people who use drugs or who engage in the harmful use of alcohol and in prison. Household implementation models could increase the effectiveness and efficiency of delivery of interventions. Future trial evidence could guide better how to optimise contact tracing strategies in households and elsewhere. Tools should be developed and assessed to facilitate monitoring and evaluation of PMTPT efforts as an accessory to improving future global guidance.

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