The burden of HIV-associated tuberculosis in Botswana

Lucy Mupfumi is a Zimbabwean Medical Scientist, and Research Associate at the Botswana Harvard AIDS Institute Partnership (BHP) in Gaborone, and a Fellow of Developing Excellence, Leadership, and Training in Science in Africa (DELTAS Africa) at the Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE). SANTHE is one of the 11 DELTAS Africa programmes, which fund collaborative consortia led by Africa-based scientists to amplify Africa-led development of world-class research and scientific leaders on the continent, while strengthening African institutions. DELTAS Africa is implemented through the Alliance for Accelerating Excellence in Science in Africa (AESA), a funding, agenda-setting, programme management initiative of the African Academy of Sciences (AAS), the African Union Development Agency (AUDA-NEPAD), founding and funding global partners, and through a resolution of the summit of African Union Heads of Governments. DELTAS Africa is supported by Wellcome and the United Kingdom Foreign, Commonwealth and Development Office (FCDO, formerly DFID).

Summary
The risk of developing tuberculosis (TB) is estimated to be between 16-27 times greater in people living with HIV than among those without HIV infection. In Botswana, researchers reported a high burden of TB in the antiretroviral program, particularly within the first year of ART, consistent with previous studies in other African settings. This finding highlights the challenges of TB diagnosis in patients with HIV, as well as the need for a combination of interventions in order to reduce the burden of TB. 

Background

TB is the leading cause of death in people living with HIV (PLWH) and the leading cause of death by an infectious disease.  While anti-retroviral therapy (ART) reduces the risk of TB by about 64% (Lawn and Wood 2012), the risk of getting TB remains high in PLWH compared to HIV-uninfected patients. This suggests that although TB is an opportunistic infection in PLWH with advanced immunodeficiency, ART does not completely restore the immune response to TB, resulting in persistent risk of TB while on ART.

This persistent risk of TB is highest within the first year of ART, and even higher in patients with low CD4 counts at the time of ART initiation. This suggests that multiple interventions are needed for PLWH, such as early diagnosis, active case finding, and therapy for prevention of TB, in order to reduce the burden of TB.

Description of study

For her PhD research, Lucy Mupfumi sought to understand the burden of TB and the factors associated with the disease among PLWH in Botswana. Whilst there is universal access to ART, Botswana is currently among the 30 countries with the highest TB/HIV burden.

Approximately 53% of people diagnosed with TB in Botswana are co-infected with HIV. Therefore, a secondary aim of the study was to identify biomarkers (blood-based biological markers) of TB treatment response in PLWH. The current methods require patients to cough up sputum, but this is not always possible, particularly for patients with advanced immunodeficiency. Mupfumi’s aim is therefore to learn if blood samples can be used to determine a relationship between changes in the immune response and TB treatment outcomes.

Effective interventions to reduce the TB treatment period

1. People who have had TB in the past are at risk of developing it again, a condition known as recurrent TB. This risk is about five times higher in those who have HIV compared to those without HIV. It is therefore important to identify people who are at increased risk of TB. Recent studies have shown that it is possible to use the information on how genes are turned on/off in specific cells in blood samples to identify patients who may be at risk of developing TB (Zak, Penn-Nicholson et al. 2016, Darboe, Mbandi et al. 2019). 
2. In addition, investigators in Tanzania recently developed an assay that has potential for both TB diagnosis and treatment monitoring (Portevin, Moukambi et al. 2014). This T-cell activation marker assay (TAM-TB) measures a surface antigen, CD27, that is expressed on CD4+ T-cells that produce a marker of inflammation, interferon-gamma (IFN-ᵧ), in response to stimulation by M.tuberculosis (M.tb) antigens.
3. The recently-published Nix-TB trial (Conradie, Diacon et al. 2020) shows that more than 90% of patients treated with an all-oral DR-TB regimen consisting of three drugs (Bedaquiline, Pretonamid and Linezolid-BPaL) had favourable outcomes after six months of treatment. These are encouraging results because they have the potential to improve treatment at both the individual and health facility level. Using blood-based biomarkers can allow identification of patients at risk of relapse or those who can benefit from shortened treatment regimens, thus making tailored TB treatment regimens possible for TB patients.

Anticipated impact

1. Mupfumi and colleagues reported a high burden of TB in the Botswana antiretroviral program, particularly within the first year of ART, consistent with previous studies in other African settings. This finding highlights the challenges of TB diagnosis in patients with HIV, as well as the need for a combination of interventions in order to reduce the burden of TB.
2. They also showed that the use of the surface markers HLA-DR and CD38, expressed on T-cells that are responding to Mtb stimulation, distinguished patients with latent TB from those with active TB. These changes in the expression of the two markers with treatment mirrored declines in bacterial load reflected by negative culture results from sputum samples collected at two months.

Conclusion

The study of blood-based biomarkers enables investigators to understand the pathogenesis (chain of events leading to disease) of TB. It is important to translate the current complex methods that require antigen stimulation and expensive flow cytometers into scalable and cost-effective formats. Further studies to refine the diagnostic performance of these assays need to be conducted in patients with other forms of pulmonary disease that is not due to TB.

Literature referred to (Additional resources)

• Darboe, F., S. K. Mbandi, K. Naidoo, N. Yende-Zuma, L. Lewis, E. G. Thompson, F. J. Duffy, M. Fisher, E. Filander, M. van Rooyen, N. Bilek, S. Mabwe, L. R. McKinnon, N. Chegou, A. Loxton, G. Walzl, G. Tromp, N. Padayatchi, D. Govender, M. Hatherill, S. A. Karim, D. E. Zak, A. Penn-Nicholson, T. J. Scriba and S. C. I. Team (2019). "Detection of Tuberculosis Recurrence, Diagnosis and Treatment Response by a Blood Transcriptomic Risk Signature in HIV-Infected Persons on Antiretroviral Therapy." Frontiers in microbiology 10: 1441-1441.
• Portevin, D., F. Moukambi, P. Clowes, A. Bauer, M. Chachage, N. E. Ntinginya, E. Mfinanga, K. Said, F. Haraka, A. Rachow, E. Saathoff, M. Mpina, L. Jugheli, F. Lwilla, B. J. Marais, M. Hoelscher, C. Daubenberger, K. Reither and C. Geldmacher (2014). "Assessment of the novel T-cell activation marker–tuberculosis assay for diagnosis of active tuberculosis in children: a prospective proof-of-concept study." The Lancet Infectious Diseases 14(10): 931-938.
• Zak, D. E., A. Penn-Nicholson, T. J. Scriba, E. Thompson, S. Suliman, L. M. Amon, H. Mahomed, M. Erasmus, W. Whatney, G. D. Hussey, D. Abrahams, F. Kafaar, T. Hawkridge, S. Verver, E. J. Hughes, M. Ota, J. Sutherland, R. Howe, H. M. Dockrell, W. H. Boom, B. Thiel, T. H. M. Ottenhoff, H. Mayanja-Kizza, A. C. Crampin, K. Downing, M. Hatherill, J. Valvo, S. Shankar, S. K. Parida, S. H. E. Kaufmann, G. Walzl, A. Aderem, W. A. Hanekom, Acs and G. C. c. s. groups (2016). "A blood RNA signature for tuberculosis disease risk: a prospective cohort study." Lancet 387(10035): 2312-2322.