Pharmacokinetics, SAfety/tolerability, and EFficacy of high-dose RIFampicin in tuberculosis-HIV co-infected patients on efavirenz- or dolutegravir-based antiretroviral therapy: study protocol for an open-label, phase II clinical trial (SAEFRIF)

Abstract

Background: Tuberculosis (TB) is a significant public health problem that causes substantial morbidity and mortality. Current first-line anti-TB chemotherapy, although very effective, has limitations including longtreatment duration with a possibility of non-adherence, drug interactions, and toxicities. Dose escalation of rifampicin, an important drug within the regimen, has been proposed as a potential route to higher treatment efficacy with shorter duration and some studies have suggested that dose escalation is safe; however, these have almost entirely been conducted among human immunodeficiency (HIV)-negative TB patients. TB-HIV co-infected patients on antiretroviral therapy (ART) are at increased risk of drug-drug interactions and drug-related toxicities. This study aims to determine the safety of higher doses of rifampicin and its effect on the pharmacokinetics of efavirenz (EFV) and dolutegravir (DTG) in TB-HIV coinfected patients. Methods: This study is a randomized, open-label, phase IIb clinical trial among TB-HIV infected adult outpatients attending an HIV clinic in Kampala, Uganda. Patients newly diagnosed with TB will be randomized to either standard-dose or high-dose rifampicin (35 mg/kg) alongside standard TB treatment. ART-naïve patients will be randomly assigned to first-line ART regimens (DTG or EFV). Those who are already on ART (DTG or EFV) at enrollment will be continued on the same ART regimen but with dose adjustment of DTG to twice daily dosing. Participants will be followed every 2 weeks with assessment for toxicities at each visit and measurement of drug concentrations at week 6. At the end of intensive-phase therapy (8 weeks), all participants will be initiated on continuation-phase treatment using standard-dose rifampicin and isoniazid.

High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults: A Phase II Open-Label Randomized Controlled Trial

“…We dose-adjusted dolutegravir to 50 mg twice daily, which is known to be effective with standard rifampicin [ 36 , 37 ]. An ongoing study in Uganda is examining the impact of rifampicin 35 mg/kg on dolutegravir levels [ 4 ].…”

“…The trials conducted in the 1970–80s did not pursue substantially higher doses of rifampicin (Rifampin ® ), largely due to its cost in that era [ 3 ]. Rifampicin is highly bactericidal and has important sterilizing activity, and low plasma rifamycin exposures have been linked to poor treatment outcomes and the evolution of resistance [ 4–9 ]. A growing body of evidence from animal and clinical studies in pulmonary TB suggests that high-dose rifampicin accelerates bacillary clearance, kills persister organisms, and the maximum tolerated dose in humans is ~40 mg/kg/day [ 10–14 ].…”

Potential contribution of HIV during first-line tuberculosis treatment to subsequent rifampicin-monoresistant tuberculosis and acquired tuberculosis drug resistance in South Africa: a retrospective molecular epidemiology study

“… 23 , 29 Encouragingly, there are several trials focused on increased rifampicin doses, including in people living with HIV. 30 However, these trials, assessing pharmacokinetics, safety, and efficacy, are primarily focused on the potential for treatment shortening. That they will be sufficiently powered to quantify resistance acquisition overall or to detect any differences between HIV-negative and HIV-positive individuals is highly unlikely.…”

Integrase inhibitors versus efavirenz combination antiretroviral therapies for TB/HIV coinfection: a meta-analysis of randomized controlled trials

“…We hypothesize that INIs-based ART may be more favorable than EFVbased ART, according to the evidence from studies of PLWHA without TB infection. After these ongoing studies [54] are completed and published, we will do further research to validate our hypothesis.…”