The Effect of Rifampicin on the Pharmacokinetics of Intracellular Tenofovir-diphosphate and Tenofovir When Coadministered With Tenofovir Alafenamide Fumarate During the Maintenance Phase of Tuberculosis Treatment in TB/HIV-1 Coinfected Participants (EpiTAF)

This is a pharmacokinetic study investigating the effect of rifampicin on the pharmacokinetics of intracellular tenofovir-diphosphate and plasma tenofovir when coadministered with tenofovir alafenamide fumarate during the maintenance phase of tuberculosis treatment in TB/HIV-1 coinfected participants (EpiTAF)

Study Overview

• Status: Completed
• Conditions: Tuberculosis; HIV-1-infection
• Intervention / Treatment: Drug: Phase 1: Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz coadministered with Rifampicin/Isoniazid; Drug: Phase 2: Tenofovir alafenamide/Lamivudine/Efavirenz coadministered with Rifampicin/Isoniazid; Drug: Phase 3: Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz

Detailed Description

This is an open-label, sequential, single centre pharmacokinetic (PK) study investigating the effect of rifampicin on the pharmacokinetics of intracellular tenofovir-diphosphate and plasma tenofovir when coadministered with tenofovir alafenamide fumarate during the maintenance phase of tuberculosis treatment in TB/HIV-1 coinfected participants (EpiTAF).

An open-label, sequential, pharmacokinetic (PK) drug-drug interaction study will be conducted in medically stable virologically suppressed HIV-1 infected adults coinfected with TB, who are in the maintenance phase of their TB treatment. After intensive PK evaluation of IC TFV-DP and pTFV, participants will be switched from their standard-of-care tenofovir disoproxil fumarate (TDF)/FTC/EFV regimen, to TAF + 3TC + EFV at the start of the study treatment period. After 28 days each participant will have intensive PK evaluation of IC TFV-DP and pTFV on TAF + 3TC + EFV with rifampicin (RIF). After the second intensive PK assessment is completed, participants will be switched back to TDF/FTC/EFV, with a final intensive PK evaluation of IC TFV-DP and pTFV 8 days after completion of TB treatment, at the final study visit. Eighteen volunteers will be enrolled for a target of 13 participants completing the study.

The study includes screening and enrolment visits, 1 visit on day 28 and an end of study visit 28 days after the end of TB treatment.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2196
      • Charlotte Maxeke Johannesburg Academic Hospital
    • Johannesburg, Gauteng, South Africa
      • Wits RHI Yeoville Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult (≥ 18 years old) male or female
2. HIV-1 infected on TDF/FTC/EFV with HIV RNA < 50 copies/mL in the last three months
3. On TB treatment in the maintenance phase (RIF/INH) with at least one month of TB treatment needed for completion
4. Women of childbearing potential must not be pregnant or breastfeeding, with a negative pregnancy test at screening
5. Women must be postmenopausal, surgically sterile or practicing an effective birth control method (established before and maintained throughout the trial). Women who are not sexually active must agree to use an effective birth control method if they become heterosexually active during the trial
6. Understand the purpose of and procedures required for the study and having confirmed they are willing to participate in the study by signing the informed consent document.

Exclusion Criteria:

1. Weight < 40 kg
2. Estimated creatinine clearance < 50 mL/min
3. Any active clinically significant or life-threatening disease (e.g. acute infections, pancreatitis, hepatitis, cardiac dysfunction), medical or psychiatric condition, or findings during screening, that in the investigator's opinion would compromise the safety of the participant or the study outcome, or their ability to comply with the study procedures
4. Chronic medical requirement for any drugs that are known to affect the PK of the study drugs
5. Active drug/alcohol abuser
6. History of allergy or hypersensivity to any of the study drugs
7. Currently enrolled in an investigational drug study or has participated in an investigational drug study within the 4 weeks before screening
8. Unable to comply with study protocol and study protocol restrictions

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Tenofovir Alafenamide; TAF 25 mg once-daily administered with RIF/INH 600*/300mg

Drug: Phase 1: Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz coadministered with Rifampicin/Isoniazid; TDF/FTC/EFV 300/200/600 mg once daily plus RIF/INH 600*/300 mg daily from screening until enrolment (days -15 to 0); Other Names: Atripla; Rifinah; Drug: Phase 2: Tenofovir alafenamide/Lamivudine/Efavirenz coadministered with Rifampicin/Isoniazid; TAF 25 mg + 3TC 300 mg + EFV 600 mg once daily plus RIF/INH 600/*300 mg daily (days 1 to ≤ 56); Other Names: Stocrin; HepBest; Drug: Phase 3: Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz; TDF/FTC/EFV 300/200/600 mg once daily. RIF/INH 600mg <70kg, 750mg >70kg; Other Names: Atripla; Rifinah

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IC TFV-DP concentrations during coadministration of TAF or TDF with RIF/INH in TB/HIV-1 coinfected participants	Intracellular and plasma TFV-DP concentrations measured during coadministration of TAF or TDF with RIF/INH	56 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maintenance of irological suppression (HIV-1 RNA < 50 copies/mL)	Assessment of maintenance of virological suppression (HIV-1 RNA < 50 copies/mL) while on TAF/RIF	At screening, day 28, completion of TB and EOS visits
Comparison plasma concentrations of TAF with TDF	Assessment to compare the plasma concentrations of tenofovir of TAF with TDF during coadministration of RIF/INH in TB/HIV-1 coinfected participants	56 days
Comparison of IC TFV-DP concentrations of TDF	4. To compare the IC TFV-DP concentrations of TDF with and without coadministration with RIF/INH in TB/HIV-1 coinfected participants	56 days

Collaborators and Investigators

• Sponsor: Professor Francois Venter
• Collaborators: University of Cape Town

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 5, 2019
• Primary Completion (ACTUAL): October 30, 2020
• Study Completion (ACTUAL): October 30, 2020

Study Registration Dates

• First Submitted: June 5, 2020
• First Submitted That Met QC Criteria: June 5, 2020
• First Posted (ACTUAL): June 9, 2020

Study Record Updates

• Last Update Posted (ACTUAL): June 7, 2022
• Last Update Submitted That Met QC Criteria: June 6, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Rifampicin, RIF/INH; Tenofovir alafenamide fumarate (TAF); Intracellular tenofovir-diphosphate
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Fatty Acid Synthesis Inhibitors; Tenofovir; Emtricitabine; Lamivudine; Rifampin; Efavirenz; Isoniazid; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: WRHI061

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No