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Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis
Background: HIV-associated tuberculosis (HIV-TB) comprises 9% of global tuberculosis cases but contributes a disproportionate 17% of tuberculosis deaths. Tuberculosis is the leading cause of death, hospitalization and in-hospital death in HIV-positive patients world-wide with case fatality rates in...
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| Format: | Thesis |
| Language: | English |
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Department of Medicine
2023
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| _version_ | 1867614186590175232 |
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| access_status_str | Open Access |
| author | Schutz,Charlotte |
| author2 | Meintjes, Graeme |
| author_browse | Meintjes, Graeme Schutz,Charlotte |
| author_facet | Meintjes, Graeme Schutz,Charlotte |
| author_sort | Schutz,Charlotte |
| collection | Thesis |
| description | Background: HIV-associated tuberculosis (HIV-TB) comprises 9% of global tuberculosis cases but contributes a disproportionate 17% of tuberculosis deaths. Tuberculosis is the leading cause of death, hospitalization and in-hospital death in HIV-positive patients world-wide with case fatality rates in hospitalized patients ranging between 13% and 32%. Underlying causes of mortality remain poorly characterized and better characterization of causes could inform development of novel management strategies to improve survival. This study aimed to assess determinants of mortality in hospitalized HIV-TB patients. I assessed the association of clinical, microbiologic and treatment factors, host soluble inflammatory mediators, markers of tuberculosis dissemination, antituberculosis drug concentrations and markers of microbial translocation with 12-week mortality in hospitalized HIV-TB patients. Methods: We conducted a prospective observational cohort study and enrolled adult HIV-positive patients hospitalized with a new diagnosis of HIV-TB in Khayelitsha Hospital in Cape Town between 2014-2016. Detailed tuberculosis diagnostic testing was performed (including urine Xpert testing) and we collected clinical samples for analysis at baseline. We performed intensive pharmacokinetic studies in a subset of patients on the third day of antituberculosis therapy. Patients were followed up for 12 weeks to ascertain vital status. Results: We enrolled 682 participants and included 576 patients with tuberculosis in the cohort analyses. Twelve-week mortality was 124/576 (21.5%) with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Determinants of mortality included tuberculosis dissemination, rifampicin resistance and having features of sepsis syndrome. Using principal components analysis, we characterised an innate immune profile which was associated with mortality and with biomarkers of disseminated tuberculosis. A large proportion of patients had sub-optimal concentrations of rifampicin and isoniazid. Patients who presented with elevated lactate concentrations had higher rifampicin concentration and exposure. Opportunistic infections other than tuberculosis and microbial translocation did not have a significant association with mortality. Conclusions: There was high early mortality in hospitalized HIV-TB patients. An innate immune profile was associated with tuberculosis dissemination and mortality. Rifampicin and isoniazid concentrations and exposure were sub-optimal. These findings provide novel pathophysiologic insight and provide rationale to test high dose rifampicin and immune modulatory therapy for safety and efficacy to improve survival in this patient population. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/37439 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:48:02.707Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | Department of Medicine |
| publisherStr | Department of Medicine |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/37439 Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis Schutz,Charlotte Meintjes, Graeme Wilkinson, Robert J Shey, Muki Medicine Background: HIV-associated tuberculosis (HIV-TB) comprises 9% of global tuberculosis cases but contributes a disproportionate 17% of tuberculosis deaths. Tuberculosis is the leading cause of death, hospitalization and in-hospital death in HIV-positive patients world-wide with case fatality rates in hospitalized patients ranging between 13% and 32%. Underlying causes of mortality remain poorly characterized and better characterization of causes could inform development of novel management strategies to improve survival. This study aimed to assess determinants of mortality in hospitalized HIV-TB patients. I assessed the association of clinical, microbiologic and treatment factors, host soluble inflammatory mediators, markers of tuberculosis dissemination, antituberculosis drug concentrations and markers of microbial translocation with 12-week mortality in hospitalized HIV-TB patients. Methods: We conducted a prospective observational cohort study and enrolled adult HIV-positive patients hospitalized with a new diagnosis of HIV-TB in Khayelitsha Hospital in Cape Town between 2014-2016. Detailed tuberculosis diagnostic testing was performed (including urine Xpert testing) and we collected clinical samples for analysis at baseline. We performed intensive pharmacokinetic studies in a subset of patients on the third day of antituberculosis therapy. Patients were followed up for 12 weeks to ascertain vital status. Results: We enrolled 682 participants and included 576 patients with tuberculosis in the cohort analyses. Twelve-week mortality was 124/576 (21.5%) with 46/124 (37.1%) deaths occurring within 7 days of enrolment. Determinants of mortality included tuberculosis dissemination, rifampicin resistance and having features of sepsis syndrome. Using principal components analysis, we characterised an innate immune profile which was associated with mortality and with biomarkers of disseminated tuberculosis. A large proportion of patients had sub-optimal concentrations of rifampicin and isoniazid. Patients who presented with elevated lactate concentrations had higher rifampicin concentration and exposure. Opportunistic infections other than tuberculosis and microbial translocation did not have a significant association with mortality. Conclusions: There was high early mortality in hospitalized HIV-TB patients. An innate immune profile was associated with tuberculosis dissemination and mortality. Rifampicin and isoniazid concentrations and exposure were sub-optimal. These findings provide novel pathophysiologic insight and provide rationale to test high dose rifampicin and immune modulatory therapy for safety and efficacy to improve survival in this patient population. 2023-03-14T11:07:59Z 2023-03-14T11:07:59Z 2021 2022-11-23T09:11:02Z Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/37439 eng application/pdf Department of Medicine Faculty of Health Sciences |
| spellingShingle | Medicine Schutz,Charlotte Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis |
| thesis_degree_str | Doctoral |
| title | Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis |
| title_full | Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis |
| title_fullStr | Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis |
| title_full_unstemmed | Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis |
| title_short | Diagnosis, treatment and determinants of mortality in patients hospitalized with HIV-associated tuberculosis |
| title_sort | diagnosis treatment and determinants of mortality in patients hospitalized with hiv associated tuberculosis |
| topic | Medicine |
| url | http://hdl.handle.net/11427/37439 |
| work_keys_str_mv | AT schutzcharlotte diagnosistreatmentanddeterminantsofmortalityinpatientshospitalizedwithhivassociatedtuberculosis |