Graduation Date

Fall 8-12-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Courtney V. Fletcher

Second Advisor

Susan Swindells

Third Advisor

Kimberly Scarsi

Fourth Advisor

Lani Zimmerman

Abstract

In the past decade there has been a multitude of phase 3 clinical trials targeting treatment shortening for tuberculosis (TB). The synthetic rifamycin derivative rifapentine (RPT) has been at the forefront of many of the treatment shortening approaches. RPT possesses greater potency and a longer pharmacokinetic (PK) half-life (t1/2) as compared with the long used rifamycin, rifampin (RIF). For TB preventative treatment, a 3-month, once weekly regimen of RPT and isoniazid (INH; 3HP) was shown to be as effective as 9-months of daily INH therapy in the PREVENT TB trial. Similarly, a 4-week course of daily RPT and INH (1HP) was shown to non-inferior to the daily INH therapy in people living with HIV (PLWH) in the BRIEF-TB trial. These RPT-containing regimens represent a significant shortening approach to TB preventative treatment. Furthermore, recently a 4-month course of a RPT based regimen was shown to be non-inferior to the standard 6-month RIF based treatment for active drug susceptible TB. This four month regimen was the first treatment shortening for active TB in over 40 years. However, use of rifamycins, including RPT, are complicated by their propensity to cause detrimental drug-drug interactions. This is especially important in the treatment of HIV-TB where antiretroviral therapy (ART) is often the victim of these drug-drug interactions. The work conducted in this dissertation develops novel pharmacology data to ensure the safe and effective use of modern antiretrovirals (ARVs) with RPT based TB regimens.

Comments

2022 Copyright, the authors

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