5. Research gaps

Research gaps related to HIV-associated TB were identified during the respective GDG meetings and are listed below. Further research gaps, some of which may have already been addressed, can be found in Priority research questions for TB/HIV in HIV-prevalent and resource-limited settings (134).

5.1 Find and treat TB

5.1.1 Screening for TB among people living with HIV

Research gaps relating to TB screening among people living with HIV are listed below. A more comprehensive list of research priorities on TB screening can be found in the consolidated guidelines on TB screening (12).

Well-designed clinical trials are needed on the accuracy, effectiveness (including the impact on patient-important outcomes such as mortality), feasibility and cost implications of using the W4SS, CRP, CXR and mWRD to screen for TB across all HIV subpopulations in settings with low, medium and high burdens of HIV and TB with and without high ART coverage.
Sub-populations of people living with HIV for whom further investigation is required would include, but not be limited to, inpatients, acute care service attendees, people with ART treatment failure, people newly diagnosed with HIV and enrolling in ART clinics, people living with HIV who are clinically stable and established on ART, pregnant women, and children and adolescents living with HIV
Evaluation is needed of the accuracy and effectiveness of complete screening and diagnostic algorithms, including symptom screening, CXR, CRP and mWRDs used in various combinations with diagnostic evaluation. Research into their effectiveness should include measures of the impacts on patient-important outcomes, such as mortality and treatment success.
More data are needed 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 living with HIV.
Evaluation is needed of the accuracy and predictive value of measuring CRP above any cut-off higher than 5 mg/L for TB screening in settings with different TB prevalences, when it is used either alone or in combination with other screening tests.
Studies that explore the optimal placement of mWRDs for screening in antenatal care settings versus within ART clinics are also needed.
Assessments of the potential for screening of people living with HIV with mWRDs using specimens other than sputum are needed. Further evidence is also required about the performance of CAD software stratified according to the characteristics of the individual being evaluated (e.g. by smear status, HIV status, age cohort, history of TB, smoking status, sex) to allow for better setting-specific and patient-specific calibration of CAD software.

5.1.2 Diagnosis of TB among people living with HIV

Research gaps relating to the initial tests for TB diagnosis that may be more pertinent for TB diagnosis among people living with HIV are listed below. The more comprehensive lists of research priorities relating to TB diagnosis are highlighted within the WHO consolidated guidelines on tuberculosis. Module 3: diagnosis – rapid diagnostics for tuberculosis detection, 2021 update (14).

Xpert MTB/RIF and Xpert Ultra

Identification of an improved reference standard that accurately defines TB disease in children and paucibacillary specimens is needed because the sensitivity of all available diagnostics is suboptimal.
Comparisons of different tests should be made, including Xpert MTB/RIF and Xpert Ultra, to determine which tests (or strategies) yield superior diagnostic accuracy. The preferred study design is one in which all participants receive all available diagnostic tests or are randomly assigned to receive a particular test. Studies should include children and people living with HIV. Future research should acknowledge the concern associated with culture as a reference standard and consider ways to address this limitation.
Development of rapid point-of-care diagnostic tests for extrapulmonary TB is also needed. Research groups should focus on developing diagnostic tests and strategies that use readily available clinical specimens such as urine rather than specimens that require invasive procedures for collection.

Truenatᵀᴹ MTB, MTB Plus and MTB-RIF Dx assays

Evaluations should be conducted to assess the diagnostic accuracy of TruenatTM (MTB, MTB Plus and MTB-RIF) in specific populations such as people living with HIV, former TB patients for pulmonary TB and extrapulmonary TB in adults and children.

Loop-mediated isothermal amplification (TB-LAMP)

Evaluations are needed of diagnostic algorithms in different epidemiological and geographical settings and populations (including people living with HIV).
More rigorous studies should be conducted with higher quality reference standards (including multiple specimen types and extrapulmonary specimens) to improve confidence in specificity estimates.

Moderate complexity automated nucleic acid amplification test (NAATs)

Studies are needed of the diagnostic accuracy in specific populations (e.g. children, people living with HIV, and people with signs and symptoms of extrapulmonary TB) and in non-sputum samples.
The impact of diagnostic technologies on clinical decision-making and outcomes that are important to affected individuals (e.g. cure, mortality, time to diagnosis and time to start treatment) should be assessed in all populations.
Studies are needed on the use, integration and optimization of diagnostic technologies in the overall landscape of testing and care, as well as diagnostic pathways and algorithms.
The effect of moderate complexity automated NAATs in fostering collaboration and integration between disease programmes should also be evaluated.

LF-LAM assay

Development of simple, more accurate tests based on LAM detection is needed, with the potential to be used for HIV-negative populations.
Studies should be conducted on the use of LF-LAM in people living with HIV without signs and symptoms of TB.
Evaluation of the use of LF-LAM in children and adolescents with HIV should be undertaken.
Studies should be conducted to assess the combination of parallel use of LF-LAM and rapid qualitative CD4 cell count systems.
Undertaking implementation research into the acceptance, scale-up and impact of LF-LAM in routine clinical settings is also needed.
Qualitative research should be carried out on user perspectives of LF-LAM for feasibility, accessibility and equity issues.
Implementation research on LF-LAM integrated into HIV care packages should also be undertaken.
Evaluations are required to assess the performance of LF-LAM as the HIV epidemic evolves and a higher proportion of people living with HIV who are hospitalized may be on treatment with viral load suppression.
Studies of the cost-effectiveness of LF-LAM are needed.
Evaluation of other rapid LAM-based tests such as FujiLAM is also required.

5.1.3 TB treatment for people living with HIV

Research gaps relating to the TB treatment that may be more relevant for TB diagnosis among people living with HIV are listed below. The more comprehensive lists of research priorities relating to TB diagnosis are highlighted within the respective WHO consolidated guidelines on drug-susceptible (17) and drug resistant TB (16).

Drug susceptible TB

More evidence is needed on the use of the 4-month regimen of isoniazid, rifapentine, moxifloxacin and pyrazinamide for drug susceptible pulmonary TB among people living with HIV on nonefavirenz-based ART regimens, and with a CD4 cell count less than 100 cells/mm³, and people with diabetes mellitus and people with a body weight of less than 40 kg.
Operational research is needed to define how best to provide high-quality integrated TB and HIV interventions at facility and community levels in order to inform global and national policy and strategy development.
The optimal steroid dose for TB meningitis (including different drug formulations) should be studied.
The optimal steroid duration for TB meningitis should also be assessed and whether this duration differs between different grades of meningitis.
Studies should be conducted on the different effects of steroids on people living with or without HIV, or who are being treated (or not) with ART.
Additional work is needed on fixed dose formulations for drug-susceptible TB to further decrease the pill burden, especially among people with comorbidities.

Drug-resistant TB

The efficacy, safety and tolerability of the bedaquiline, pretomanid, linezolid and moxifloxacin regimen (BPaLM/BPaL) should be studied for subpopulations for whom current data are limited or missing; that is, children aged below 14 years, people with extrapulmonary TB, people living with HIV with CD4 counts below 100 cells/mm³, and pregnant and lactating women.
Inclusion and separate reporting of outcomes for longer regimens for multidrug- or rifampicinresistant TB (MDR/RR-TB) are needed in key subgroups in RCTs, especially children, pregnant and breastfeeding women, and people living with HIV on treatment.
Better understanding is needed of the role of delamanid in MDR-TB regimens, including in children (pharmacokinetics and pharmacodynamics), people living with HIV and pregnant women; mechanisms of development of drug resistance; and optimization of the treatment duration in both adults and children.
High-quality studies should be conducted on treatment prolongation among people living with HIV with regimens for rifampicin-susceptible and isoniazid-resistant TB (Hr-TB).

5.2 TB prevention

Research gaps relating to TPT that are more pertinent for people living with HIV are listed below. The more comprehensive lists of research priorities relating to TB diagnosis are highlighted within the WHO consolidated guidelines on tuberculosis. Module 1: prevention – tuberculosis preventive treatment (22).

Diagnostic tests with improved performance and predictive value for progression to TB disease are needed.
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).
Research to find shorter, better-tolerated TPT regimens than those currently recommended remains a priority.
Trial data on 1HP in people living with HIV with low CD4 counts is needed, under different settings.
Research on the direct comparison of 1HP vs. 3HP for safety, effectiveness, and cost-effectiveness will be useful.
Pharmacokinetics studies should be conducted to establish interactions between rifamycin-containing regimens and other medicines, particularly ART, in both adults and children.
Studies should be undertaken to assess the durability of protection of different preventive treatment regimens including long-acting injectables, in settings in which TB is endemic, and should include the efficacy of repeated courses of preventive treatment. Studies of the preferences of different stakeholders for different regimen characteristics would be helpful.
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 people living with HIV. 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 TB disease will be important to understand the benefits of preventive treatment.
Prospective randomized studies should be undertaken 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.
Carefully designed studies including RCTs should be conducted to generate evidence on the effectiveness of context-specific interventions to enhance adherence and completion of TPT. These studies should address questions about how to integrate TPT into differentiated models of HIV service delivery.

5.3 Find and treat HIV

A more comprehensive list of research gaps is outlined within the consolidated guidelines for HIV (21) and the guidelines on diagnosing and managing histoplasmosis in people living with HIV (20) but a selection of research gaps more relevant for reducing the burden of HIV in people with presumptive or diagnosed TB are listed below.

Studies are needed to assess how initiating ART among people with TB symptoms (excluding those with signs and symptoms of meningitis) affects mortality, TB and HIV outcomes, adverse events, IRIS, retention in care and ART adherence.
The role of prophylactic corticosteroids to reduce the incidence of IRIS among people with TB and HIV in public health settings should also be studied, as well as the timing of this prophylaxis.
Safety and tolerability of earlier ART initiation should also be evaluated among children, pregnant and breastfeeding women living with HIV and TB, and for people living with HIV who have drug-resistant TB.
Studies are also needed of the long-term safety and tolerability of newer ARV drugs used in first-, second- or third-line regimens in the context of TB and HIV coinfection.
More data are needed on the use of corticosteroids for people living with HIV who have low CD4 cell counts, to prevent IRIS.
Improved long-term information on suppression of viral loads among people using formulations containing efavirenz 400 mg is needed, especially among pregnant women and individuals requiring TB co-treatment, particularly including rifampicin.
The pharmacokinetics and safety of alternative dosing of tenofovir alafenamide (TAF) when used during TB co-treatment need to be better understood.
Finally, additional research is needed to determine the outcomes of treating TB and histoplasmosis coinfection.

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