HIV-1-infection, Tuberculosis
Conditions
Keywords
Rifampicin, RIF/INH, Tenofovir alafenamide fumarate (TAF), Pharmacokinetics, Intracellular tenofovir-diphosphate
Brief summary
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)
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.
Interventions
DRUGPhase 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)
DRUGPhase 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)
DRUGPhase 3: Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz
TDF/FTC/EFV 300/200/600 mg once daily. RIF/INH 600mg \<70kg, 750mg \>70kg
Sponsors
University of Cape Town
Professor Francois Venter
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| IC TFV-DP concentrations during coadministration of TAF or TDF with RIF/INH in TB/HIV-1 coinfected participants | 56 days | Intracellular and plasma TFV-DP concentrations measured during coadministration of TAF or TDF with RIF/INH |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maintenance of irological suppression (HIV-1 RNA < 50 copies/mL) | At screening, day 28, completion of TB and EOS visits | Assessment of maintenance of virological suppression (HIV-1 RNA \< 50 copies/mL) while on TAF/RIF |
| Comparison plasma concentrations of TAF with TDF | 56 days | Assessment to compare the plasma concentrations of tenofovir of TAF with TDF during coadministration of RIF/INH in TB/HIV-1 coinfected participants |
| Comparison of IC TFV-DP concentrations of TDF | 56 days | 4\. To compare the IC TFV-DP concentrations of TDF with and without coadministration with RIF/INH in TB/HIV-1 coinfected participants |
Countries
South Africa
Outcome results
None listed