604. Effect of rifabutin in dolutegravir dosing: a case series
Authors: Mendoza Maria A , Alshaer Mohammad H , Roldan Giovanni , Castro Jose G , Peloquin Charles A , Boulanger Catherine 
Published: December 2022

Abstract

Background
Tuberculosis (TB) is the leading cause of death in human immunodeficiency virus (HIV) infected people worldwide. Patients with HIV who have latent TB are 20-30 times more likely to develop active TB. Integrated antiretroviral therapy (ART) early in the treatment for tuberculosis is recommended due to improved morbidity and mortality, however, there can be serious drug interactions.
Rifamycins are potent inducers of the CYP3A4 isoform, which can cause sub-therapeutic concentrations of anti-retroviral drugs, among these, rifabutin (RBN) is a less potent inducer of CYP3A4. Pharmacokinetic (PK) studies done on healthy adults showed that rifampin decreased dolutegravir (DTG) concentrations by more than 50 % whereas RBN decreased it by 30%. RBN has been preferred given that its favorable pharmacokinetic and toxicity profile. Currently there are no studies examining the use of RBN and DTG in co-infected persons. This is a case series of 4 co-infected patients receiving both agents who underwent PK analysis.

Methods
Retrospective analysis of patients in the respiratory care unit (RCU) at Jackson Memorial Hospital in Miami. We included adult patients, admitted to the RCU, with a concomitant diagnosis of HIV and active TB disease who received DTG and RBN, and for which DTG and RBN plasma concentrations were measured for therapeutic drug monitoring (TDM). A non-compartmental analysis was performed and the area under the concentration-time curve (AUC) was calculated for DTG and RBN.

Results
We report 4 patients (Figure 1) that met criteria and underwent PK analysis. All patients with TB who were treated with RBN had low concentrations of DTG, requiring higher doses of DTG (Table 1 & 2). After adjustments based on PK analysis, there was evidence of a favorable response to treatment in 2 patients, with a less than robust in the 2 others. Adequate suppression of viral load could not be determined for 3 of the patients because of the short observation time. Figure 1:Timelines of patients describing admission and HIV and tuberculosis treatment providedDTG, dolutegravir. RFB, rifabutin. VL, viral load. AFB, Acid fast bacilli. LAD, lymphadenopathy. TAF, Tenofovir alafenamide. FTC, Emtricitabine. TDF, Tenofovir Disoproxil Fumarate. INH, Isoniazid. PYZ, Pyrazinamide. BID, twice a day. QD, daily. IRIS, Immune reconstitution inflammatory syndrome. GU, genitourinary. TB, tuberculosis.Table 1:Patients’ pharmacokinetics of DTGAUCX-Y, area under the concentration-time curve from time X to Y hours; AUC0-tau, area under the concentration-time curve from time zero to the end of the dosing interval; DTG, dolutegravir; TDM, therapeutic drug monitoring. a) AUC0-6 was calculated.Table 2:Patients’ pharmacokinetics of RBNAUCX-Y, area under the concentration-time curve from time X to Y hours; AUC0-tau, area under the concentration-time curve from time zero to the end of the dosing interval; RBN, Rifabutin; TDM, therapeutic drug monitoring. a) All RBN doses given every 24 hours, b) RBN value was trace and AUC was not calculated.

Conclusion
All patients with HIV and TB who were treated with RBN had low concentrations of DTG. This case series demonstrates that for optimal concomitant use of rifabutin and dolutegravir it is highly recommended to use TDM. Prospective clinical studies are needed to further determine the PK interactions between RBN and DTG and virologic response to treatment.

Disclosures
All Authors: No reported disclosures.