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Principal Investigator: Kristina Marie Brooks
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $114,818
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary & Abstract
Pregnant and postpartum women living with HIV (WLWH) and latent tuberculosis (TB) infection (LTBI) are at
high risk of progressing to active TB. Safe and effective treatment during the latent phase is critical to
preventing active TB, in addition to reducing TB-related maternal and infant morbidity and mortality. Isoniazid
(INH) has been used for decades to treat active and latent TB infection, and there are several international
efforts to expand the use of INH preventive therapy (IPT) to address global TB burden. A recent large-scale
clinical trial in pregnant and postpartum WLWH revealed high rates of severe hepatotoxicity with IPT (~6-7%
vs. <1% based on historical data in non-pregnant adults) during the postpartum period (IMPAACT P1078).
Available evidence suggests reactive INH metabolites are involved in the development of hepatotoxicity with
INH. However, there are currently no data on the pharmacokinetics of INH metabolites in pregnant or
postpartum women. Additionally, there are immunologic and metabolic changes that occur during and after
pregnancy, which may further predispose this population to a higher risk of developing hepatotoxicity during
the postpartum period. Mechanistic insights are needed to inform the safe use of IPT in this population.
This proposal will leverage existing samples collected under the P1078 study to comprehensively examine PK,
immunologic, and metabolic changes in pregnant and postpartum WLWH on IPT using a case-control design.
The following aims are proposed: (1) to quantify INH metabolite PK in pregnant and postpartum WLWH
receiving IPT, (2) to identify biomarkers of hepatotoxicity in pregnant and postpartum WLWH receiving IPT,
and (3) to model relationships between INH metabolite exposures, toxicity biomarkers, and the development of
hepatotoxicity. In Aim 1, INH metabolites will be measured from intensive and sparse PK samples to quantify
INH metabolite PK in pregnant and postpartum women. In Aim 2, an enriched case-control design will be
applied to evaluate baseline and on-treatment biomarkers of hepatotoxicity using metabolomics and cytokine
arrays. Aim 3 will integrate data generated from Aims 1 and 2 to examine relationships between INH
metabolite exposures, metabolic and immunology biomarkers, and the development of hepatotoxicity. This
work will be complemented by a mentoring team comprised of experts in pharmacology, metabolomics,
immunology, and statistics, in addition to collaborators from the P1078 study. Dr. Brooks will also pursue
focused training and coursework in biostatistics, PK modeling, metabolomics, and hands-on experience in the
laboratory setting.
Dr. Brooks's career goal is to become an expert in the clinical pharmacology of TB medications and
mechanisms of immune-mediated adverse drug reactions. The proposed work in Dr. Brooks's K08 application
will provide her with a strong foundation to develop into an independent investigator in this field. Furthermore,
this work will address critical knowledge gaps in a vulnerable population to help support the safe uptake and
expansion of TB preventive therapies on a global scale.
Terms: <21+ years old><AIDS Virus><Acetyltransferase><Acids><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adult><Adult Human><Area><Biological Markers><Biometrics><Biometry><Biostatistics><Cellular Immune Function><Characteristics><Chronologic Fetal Maturity><Clinical><Clinical Pharmacology><Clinical Trials><Clinical Trials Network><Data><Development><Drug Kinetics><Drugs><Early Diagnosis><Early treatment><Ensure><Enzyme Gene><Enzymes><Fetal Age><Foundations><Gestation><Gestational Age><Goals><HIV><HIV/Mtb><HIV/TB><HIV/mycobacterium tuberculosis><HIV/tuberculosis><Health><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hepatotoxic effect><Hepatotoxicity><Human><Human Immunodeficiency Viruses><IMPAACT><Immune><Immune Markers><Immunes><Immunochemical Immunologic><Immunologic><Immunologic Markers><Immunological><Immunologically><Immunologics><Immunology><Individual><Inducer Cells><Inducer T-Lymphocytes><Inflammatory><Inflammatory Response><International><International Maternal Pediatric Adolescent AIDS Clinical Trials><International Maternal Pediatric Adolescent HIV/AIDS Clinical Trials><Investigators><Isonicotinic Acid Hydrazide><Kidney><Kidney Urinary System><Knowledge><LAV-HTLV-III><Laboratories><Late pregnancy><Link><Literature><Liver Toxicity><Logistic Regressions><Lymphadenopathy-Associated Virus><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M. tuberculosis/HIV><M.tb infection><M.tuberculosis infection><MTB infection><Maternal Mortality><Measures><Mediating><Medication><Mentors><Metabolic><Modeling><Modern Man><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><NIH><National Institutes of Health><Outcome><Parents><Patients><Pharmaceutical Preparations><Pharmacogenetics><Pharmacokinetics><Pharmacology><Phase><Physiologic><Physiological><Population><Post-partum Women><Postpartum Period><Postpartum Women><Predictive Value><Pregnancy><Pregnant Women><Prevalence><Preventative therapy><Preventive therapy><Recommendation><Regimen><Research><Research Personnel><Research Priority><Researchers><Safety><Sampling><Site><Special Population><TB infection><TB therapy><TB treatment><Testing><Toxic effect><Toxic effect on liver cells><Toxicities><Training><Tuberculosis><United States National Institutes of Health><Virus-HIV><Vulnerable Populations><Woman><Women's cohort><Work><World Health Organization><adulthood><adverse drug reaction><after pregnancy><bio-markers><biologic marker><biomarker><biomarker identification><career><case control><case-controlled><cell type><cohort><cohort in women><cohort on women><cytokine><data integration><design><designing><developmental><disseminated TB><disseminated tuberculosis><drug induced hepatotoxicity><drug induced liver disease><drug induced liver injury><drug/agent><early detection><early therapy><effective therapy><effective treatment><expectant mother><expecting mother><experience><female cohort><glomerular filtration><hepatic toxicity><hepatoxicity><high risk><identification of biomarkers><identification of new biomarkers><immune function><immune-based biomarkers><immunological biomarkers><immunological markers><infant morbidity/mortality><infection due to Mycobacterium tuberculosis><insight><interest><intervention arm><isoniazid><marker identification><maternal death><maternal morbidity><metabolic phenotype><metabolism measurement><metabolomics><metabonomics><metabotype><mortality><parent><post pregnancy><post-partum><pregnant mothers><prevent><preventing><renal><response><statistics><treat M. tuberculosis><treat Mtb><treat Mycobacterium tuberculosis><treat tb><treat tuberculosis><treatment arm><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy><uptake><vulnerable group><vulnerable individual><vulnerable people>