ReacciónThe review of evidence for the current update exposed additional knowledge gaps to those reported in other recent updates of the guidelines. Continued research on development and on implementation remains critical for many aspects of PMTPT (136). Some information can be collected from user feedback.
Risks for progression to TB disease
Evidence of the likelihood of progression from infection to TB disease, including MDR/RR-TB, in different populations at risk will help in determining the potential benefits of TPT and in designing appropriate public health interventions. In particular, strong evidence from individually randomized controlled clinical trials is lacking, particularly for indigenous populations and people with the following: diabetes, harmful use of alcohol, tobacco smoking, underweight, fibrotic lesions in the lung on CXR, on steroid treatment, with rheumatological diseases, chronic kidney disease, cancer or COVID-19. Methods for measuring TB incidence directly and also the risk for TB disease could be explored, such as use of genotyping to distinguish between reactivation and reinfection. Evidence is also required on differential harm and the acceptability of testing and treating TBI in specific risk groups, including socially adverse effects such as stigmatization.
Defining the best algorithm for screening and ruling out TB disease
Operational and clinical studies should be conducted to exclude TB disease before TPT is given. The performance and feasibility of the algorithms proposed in these guidelines should be assessed. Data on children and pregnant women in particular are limited. Better evidence is necessary to identify the best strategies for tracing contacts, saving costs and improving feasibility (e.g. use of mobile CXR, including CAD, in people < 15 years).
For all populations and tools, more research is required to evaluate the accuracy and effectiveness of complete screening and diagnostic algorithms, including symptom screening, CXR, CRP, mWRDs and other tools used in various combinations with diagnostic evaluation to rule out TB. Research on their effectiveness should include measures of the impact on patient-important outcomes, such as mortality and treatment success. For people with HIV in settings with different TB burdens, more research is necessary to evaluate the accuracy and predictive value of measuring CRP above any cutoff higher than 5 mg/L for TB screening, when it is used either alone or in combination with other screening tests. More data are also necessary on the effectiveness, cost–effectiveness, feasibility and acceptability, frequency and optimal periodicity of routine, regular screening with the W4SS, CRP, CXR and mWRD among people with HIV. More research is also required on the potential value of screening people with HIV with mWRDs on specimens other than sputum.
Improved diagnostic tests and performance of tests of TBI in populations at risk
Diagnostic tests with better performance and predictive value for progression to TB disease are critical. In addition, the performance of tests of TBI 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 skin tests and IGRA). Targeted research to identify more accurate IGRAs is strongly encouraged.
While TBSTs are now recommended for TBI, there are gaps in the evidence, such as the specificity of the Diaskin test and C-TST in populations with a low prevalence of TBI by direct head-to-head comparisons of all three TBSTs; barriers to implementation and patient access; additional studies of accuracy in high-risk groups such as children and adolescents, people with HIV, prisoners and migrants; the epidemiological and economic impact of TBST use in the TBI diagnosis and TPT cascade; the predictive value for TB disease as compared with current tests; the cost and cost–effectiveness of TBSTs in various scenarios; and studies of the use of digital tools for reading results in order to avoid return visits.
TPT options
Research to find shorter, better-tolerated TPT 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 harmful use of alcohol and older people) are essential. There are very few data on the use of rifapentine in pregnant women. Data on use of 1HP in children and adults not infected with HIV and in people with HIV with low CD4 counts, in various settings, would also be desirable. A direct comparison of 1HP and 3HP for safety, effectiveness and cost-effectiveness would be useful, and the results of ongoing studies are expected in the near future (137,138). Pharmacokinetics studies could help to establish an optimal daily dosage of rifapentine in children and adolescents < 13 years treated with 1HP, use in pregnancy (139) and interactions between rifamycin-containing regimens and other medicines, particularly ART in adults and children. In addition, the durability of protection provided by different TPT regimens, including long-acting injectables (140,141), should be evaluated in settings endemic for TB, including the efficacy of repeated courses of TPT and, if effective, the optimal interval between treatment courses. Studies of the preferences 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 the population at risk. Programmatic data on maternal and pregnancy outcomes, possibly by trimester of exposure and including postnatal follow-up of the child, could supplement current knowledge about the safety of different TPT regimens when used in pregnancy.
Collection of programmatic data on adverse events and maternal and pregnancy outcomes, including post-natal follow-up of the child, would supplement current knowledge about the safety of levofloxacin TPT when used during pregnancy and breast-feeding.
Drug resistance and TPT
Programme-based surveillance systems and clinical studies should be conducted to monitor the risk for resistance to the medicines used in TPT. Particular consideration should be given to rifamycin containing regimens because of the dearth of data. Conversely, the impact on PMTPT of high levels of resistance among prevalent TB strains to isoniazid and/or rifamycins should be studied. Programme-based surveillance and specially designed studies should be conducted to monitor the emergence of clinically relevant resistance in TB bacilli and other bacterial flora to fluoroquinolones and other medicines used on a large scale for TPT.
Adherence to and completion of treatment
Carefully designed studies, including RCTs, are required to establish the effectiveness of context-specific interventions to improve adherence and completion of treatment. The studies should include specific risk groups, depending on resources and the health-system infrastructure, and address questions on integration of TPT into differentiated models of HIV service delivery. Use of digital technology to improve adherence is an important area. Further research is required on the effectiveness of selfadministration of the 3-month regimen of weekly rifapentine plus isoniazid.
Studies on the effectiveness of context-specific interventions to enhance adherence and completion of treatment, such as self-administration with and without digital technology to ensure adherence, will be helpful. Implementation research on context-specific barriers and facilitators is necessary for TPT to MDR/RR-TB, to explore dimensions for which the evidence is often sparse, such as acceptability, feasibility, equity and resource use.
Cost–effectiveness
Research should be conducted on service delivery models for TPT in order to lower costs, improve equity and optimize the follow-up of people exposed to TB and MDR/RR-TB, whether or not they received fluoroquinolones, in terms of duration, monitoring approaches and frequency of visits. Such evidence could guide optimization of contact-tracing strategies in households and the delivery of public health interventions for common modifiable risks of affected people, such as use of tobacco, drugs and alcohol.
Preventive treatment for contacts of people with MDR/RR-TB
The strong recommendation for use of TPT for MDR/RR-TB should not be used as a justification for stopping trials or create ethical impediments to such research. RCTs with adequate power are still necessary to update the recommendation on TPT 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 people with HIV. The composition, dosage and duration of TPT regimens for MDR/RR-TB could be further optimized, and the potential role of newer agents with good sterilization properties should be investigated. Regimens that remain effective in the presence of fluoroquinolone resistance should also be studied. The effectiveness and safety of TPT for contacts of people with MDR/RR-TB should be evaluated under operational conditions. Further evidence on the risk for progression to TB disease of contacts of people with MDR/RR-TB will be important for understanding the benefits of TPT.
TPT regimens for MDR/RR-TB that are shorter than 6 months and have a good safety profile in childhood, pregnancy and in the presence of co-morbidities or a risk of drug–drug interactions will be essential. Pregnancy should not be an absolute exclusion criterion in such studies.
Studies are also necessary on the long-term efficacy of TPT regimens for MDR-TB, especially in settings with a high risk of MDR-TB re-exposure. The efficacy of fluoroquinolones and other TPT in areas with high levels of resistance in TB strains to the medications used as TPT should be monitored. Regimens that remain effective in the presence of fluoroquinolone-resistant TB strains should be identified for areas of high fluoroquinolone resistance.
Programme management
Continued epidemiological research should be conducted to determine the burden of TBI in specific geographical settings and risk groups, as a basis for nationally and locally tailored interventions, including integrated community approaches. Implementation research on context-specific barriers and facilitators is necessary for different TPT regimens to explore dimensions on which little evidence is available, such as acceptability, feasibility, equity and resource use. Research should also be conducted on service delivery models, including differentiated (community) models for TPT, to improve management, including the provision of additional interventions for tobacco smokers and harm reduction services for people who use drugs or who engage in harmful use of alcohol and for people in prison. Operational research on household implementation models to improve uptake of TPT could increase the effectiveness and efficiency of interventions. Future evidence from trials could guide optimization of contact-tracing strategies in households and elsewhere. Tools should be developed and assessed to facilitate monitoring and evaluation of PMTPT to improve future global guidance.