Pharmacokinetics and Safety of Double-dose Dolutegravir When Used With Rifapentine for HIV-associated Tuberculosis

A5406 hypothesized that dolutegravir (DTG) 50 mg taken twice daily provides adequate exposures to maintain viral suppression when dosed with rifapentine (RPT) 1200 mg for HIV-associated tuberculosis (TB).

Study Overview

• Status: Completed
• Conditions: HIV-associated Tuberculosis
• Intervention / Treatment: Drug: DTG 50 mg orally QD plus TDF/3TC; Drug: Dolutegravir (DTG) 50 mg orally BID (~12 hours apart) plus TDF/3TC; Drug: 2HPZM; Drug: 2HPM

Detailed Description

This was an open-label, single arm, phase II, multicenter pharmacokinetic (PK) study to investigate the effect of daily RPT 1200 mg on DTG exposure in participants with HIV-associated TB. Adults with HIV with newly diagnosed drug susceptible tuberculosis (DS-TB) who were not on antiretroviral therapy (ART) were recruited around the time of DS-TB diagnosis. At study entry, daily rifapentine (R) and moxifloxacin (M) plus isoniazid (H) and pyrazinamide (P) was initiated for 8 weeks followed by daily rifapentine-moxifloxacin plus isoniazid for 9 weeks for anti-tuberculosis (anti-TB) therapy. This regimen is known as the 2HPZM/2HPM regimen. DTG-based ART at 50 mg twice daily (BID) was started after 6 weeks of TB therapy. DTG 50 mg BID was continued for 2 weeks after completion of TB therapy, after which DTG was reduced to standard dose 50 mg once daily (QD).

Intensive PK sampling was performed at study week 8 (2 weeks after initiating DTG-based ART) and week 21 (2 weeks after reducing DTG to once daily) to obtain full plasma PK profiles for DTG during and after RPT co-administration.

HIV-1 viral load was measured to assess for viral suppression at study entry (pre-ART), at weeks 10 and 14 (while on RPT/DTG therapy), at week 21, week 30 (24 weeks after initiating ART and 13 weeks after completion of TB treatment), and at week 48.

Safety monitoring included hematology and liver/renal function testing at each study visit, plus clinical assessments for rifamycin hypersensitivity syndrome, and drug-induced liver injury.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Cape Town, Western Cape
    • Mowbray, Cape Town, Western Cape, South Africa, 7700
      • University of Cape Town Lung Institute (UCTLI) CRS (Site # 31792)
  • Durban
    • Wentworth, Durban, South Africa, 4052
      • Durban International CRS (Site # 11201)
  • Western Cape
    • Worcester, Western Cape, South Africa, 6850
      • South African Tuberculosis Vaccine Initiative (SATVI) CRS (Site # 31793)
• Thailand
  • Bangkok, Thailand, 10330
    • Thai Red Cross AIDS Research Centre (TRC-ARC) CRS (Site # 31802)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Weight ≥40 kg.
• Ability and willingness of participant or legal guardian/representative to provide informed consent.
• Documentation of HIV-1 status.
• CD4+ cell count ≥50 cells/mm3 obtained within 30 days prior to study entry at any network-approved non-US laboratory that is IQA certified.
• ART-naïve or not on ART for 12 consecutive weeks prior to TB diagnosis.
• Willingness and eligibility to start DTG-based ART at 6 weeks, with a window of ±1 week, after starting TB treatment, with no intention to change ART for the duration of the study.
• Documentation of pulmonary TB.
• Willingness to start 2HPZM/2HPM therapy for DS-TB.

• The following laboratory values obtained within 30 days prior to study entry:

  • Absolute neutrophil count (ANC) >750 cells/mm3
  • Hemoglobin ≥7.4 g/dL
  • Platelet count ≥50,000/mm3
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) <2.5 X the upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) <2.5 x ULN
  • Total bilirubin ≤1.5 x ULN
  • Creatinine <1.3 x ULN
• For participants who can become pregnant, negative serum or urine pregnancy test at screening within 30 days prior to entry and within 48 hours prior to entry.
• Participants who can become pregnant must agree not to participate in the conception process and if participating in sexual activity that could lead to pregnancy, must agree to use one reliable nonhormonal method of contraception.
• Documentation of Karnofsky performance score ≥50 within 30 days prior to entry.

Exclusion Criteria:

• Breastfeeding, pregnant, or plans to become pregnant.
• Known allergy/sensitivity or any hypersensitivity to components of the study drugs, or their formulations.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Requirement for ongoing use of drugs that are known to have significant drug-drug interactions with DTG or RPT.
• Known history of acute intermittent porphyria.
• Previous treatment for active TB disease within 6 months preceding initiation of study drugs.
• More than 5 days of treatment directed against active TB for the current TB episode preceding study entry.
• At the time of study entry, documentation of an M. tuberculosis isolate from the current or previous treatment episode known to be resistant to RIF or INH.
• Known history of prolonged QT syndrome.
• Known cirrhosis, a history of decompensated liver disease (ascites, hepatic encephalopathy, or esophageal varices).
• Documentation of severe opportunistic infections, in the opinion of the site investigator, within 3 months of study entry.
• Documentation of severe extra-pulmonary TB (e.g., meningitis, osteomyelitis, disseminated TB) at the time of screening.
• Acute gout at the time of screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Adults with HIV and newly diagnosed DS-TB not currently on ART; Participants received daily rifapentine-moxifloxacin plus isoniazid and pyrazinamide for 8 weeks followed by daily rifapentine-moxifloxacin plus isoniazid for 9 weeks (referred to as 2HPZM/2HPM) for anti-TB therapy at study entry. DTG-based ART at 50 mg BID was started after 6 weeks of TB therapy and continued for 2 weeks after completion of TB therapy. Two weeks after completion of TB therapy DTG was reduced to standard dose 50 mg QD.

Drug: DTG 50 mg orally QD plus TDF/3TC; DTG 50 mg orally QD plus TDF/3TC from two weeks after completion of TB treatment to end of study (week 48).; Drug: Dolutegravir (DTG) 50 mg orally BID (~12 hours apart) plus TDF/3TC; Dolutegravir (DTG) 50 mg orally BID (~12 hours apart) plus TDF/3TC, from study week 6 until 2 weeks after completion of TB treatment: Morning dose DTG 50 mg QD plus TDF/3TC from study-supplied ART regimen. Evening dose: DTG 50 mg orally QD from study-supplied source.; Drug: 2HPZM; Daily regimen of rifapentine 1200mg, moxifloxacin 400mg, isoniazid 300mg, and pyrazinamide at standard doses adjusted for body weight from study entry through study week 8.; Drug: 2HPM; Daily regimen of rifapentine 1200mg, moxifloxacin 400mg, and isoniazid 300mg from study week 8 through study week 17.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Model-simulated 5th Percentile and Corresponding 95% Confidence Interval of DTG Cmin at 50 mg BID When Co-administered With Daily RPT 1200 mg Plus HZM	Model-simulated 5th percentile and corresponding 95% confidence interval of dolutegravir (DTG) minimum concentrations (Cmin) at 50 mg BID (twice daily) when co-administered with daily rifapentine (RPT) 1200 mg plus HZM (isoniazid, pyrazinamide, and ethambutol). Pharmacokinetic parameters were estimated using nonlinear mixed-effects modelling (FOCE-I). The final model was used to simulate 10000 individuals, incorporating parameter uncertainty. Covariates included fat-free mass on disposition parameters, rifapentine on clearance and bioavailability, and baseline unconjugated bilirubin on clearance. Measurements were taken at steady state, which was assumed to be achieved after at least 5 half-lives.	Measured at week 8 and week 21. Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DTG Minimum Concentration (Cmin)	Primary pharmacokinetic (PK) parameters were estimated using nonlinear mixed-effects modelling. Secondary model-predicted parameters were derived post-hoc via simulations in R using the mrgsolve package.	Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.
DTG Maximum Concentration (Cmax)	Primary pharmacokinetic parameters were estimated using nonlinear mixed-effects modelling. Secondary model-predicted parameters were derived post-hoc via simulations in R using the mrgsolve package.	Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.
DTG Area Under the Concentration-time Curve (AUC0-24)	Primary pharmacokinetic parameters were estimated using nonlinear mixed-effects modelling. Secondary model-predicted parameters were derived post-hoc via simulations in R using the mrgsolve package.	Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.
DTG Clearance	Primary pharmacokinetic parameters were estimated using nonlinear mixed-effects modelling. Secondary model-predicted parameters were derived post-hoc via simulations in R using the mrgsolve package.	Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.
DTG Terminal Half Life	Primary pharmacokinetic parameters were estimated using nonlinear mixed-effects modelling. Secondary model-predicted parameters were derived post-hoc via simulations in R using the mrgsolve package.	Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.
Percent of Participants Who Experienced Grade 3 or Higher Adverse Events (AE)	The time frame specifically encompasses the time period the participants were on both ART and TB treatment which was scheduled to occur between study weeks 6 and 17. Adverse events were graded on a scale from 1-5: 1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death.	Week 6 through week 17
Percent of Participants Who Experienced Rifamycin Hypersensitivity	The time frame specifically encompasses the time period the participants were on both ART and TB treatment which was scheduled to occur between study weeks 6 and 17.	Week 6 through week 17
Percent of Participants Who Experienced Drug-induced Liver Injury	Drug-induced liver injury was defined as alanine animotransferase (ALT) ≥3xULN (upper limit of normal) with symptoms/jaundice or ALT ≥5xULN. The time frame specifically encompasses the time period the participants were on both ART and TB treatment which was scheduled to occur between study weeks 6 and 17.	Week 6 through week 17
Percent of Participants Who Prematurely Discontinued Study Treatment	The time frame specifically encompasses the time period the participants were on both ART and TB treatment which was scheduled to occur between study weeks 6 and 17. Study treatment discontinuation included discontinuing either ART, TB treatment, or both.	Week 6 through week 17
Percent of Participants With Viral Suppression	Viral suppression is defined as HIV-1 RNA below 50 copies/mL.	Weeks 10, 14, 21, and 30

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: ViiV Healthcare; Mylan Inc.

Publications and helpful links

Helpful Links

• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2024
• Primary Completion (Actual): May 7, 2025
• Study Completion (Actual): November 12, 2025

Study Registration Dates

• First Submitted: November 18, 2022
• First Submitted That Met QC Criteria: November 18, 2022
• First Posted (Actual): November 30, 2022

Study Record Updates

• Last Update Posted (Actual): July 20, 2026
• Last Update Submitted That Met QC Criteria: July 16, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors; Antiviral Agents; Reverse Transcriptase Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; dolutegravir
• Other Study ID Numbers: A5406

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie results in the publication, after deidentification.
• IPD Sharing Time Frame: Beginning 3 months following publication and available throughout period of funding of the ACTG (Advancing Clinical Therapeutics Globally) by NIH.
• IPD Sharing Access Criteria: With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the ACTG.; For what types of analyses? To achieve aims in the proposal approved by the ACTG.; By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/submit-a-proposal/. Researchers of approved proposals will need to sign an ACTG Data Use Agreement before receiving the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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