HIV/AIDS, Tuberculosis, Pulmonary
Conditions
Keywords
Biktarvy® is a fixed dose combination, TLD- fixed-drug combination single tablet, Dolutegravir 50mg, HIV/AIDS, Tuberculosis, Pulmonary
Brief summary
This study is being conducted to assess the antiretroviral activity of a fixed-drug, single tablet, combination of Bictegravir 50mg/ Emtricitabine 200mg/ Tenofovir alafenamide 25mg (Biktarvy®) dosed twice daily in HIV-1 infected, ART-naïve patients with TB co-infection receiving a rifampicin-based tuberculosis (TB) treatment regimen. This study will assess the activity of Bictegravir and dolutegravir-containing ART regimens in patients with drug-susceptible TB through 48 weeks
Detailed description
Primary objective: To characterize viral suppression rates (proportion of patients with suppressed viral load) at week 24 in the BIC arm Secondary objectives: To characterize viral suppression rates at weeks 12, 24 and 48 in the standard of care treatment (SOC) arm (currently, TDF 300mg/3TC 300mg/DTG 50mg) and at weeks 12 and 48 in the BIC/FTC/TAF arm. To compare the pharmacokinetics (PK) of BIC when given twice daily and co-administered with Rifampicin during tuberculosis treatment vs when given alone after discontinuation of Rifampicin To assess the incidence of TB associated IRIS in each arm, through week 24. To characterize the tolerability of treatment in each arm by assessing frequency of clinician-initiated treatment interruptions or switches through week 48. To assess frequency of ART drug resistance mutations in participants with detectable viral load at study visit weeks 24 and 48.
Interventions
COMBINATION_PRODUCTBiktarvy®
Biktarvy® is a fixed dose combination, single tablet containing bictegravir (BIC), emtricitabine (FTC), and tenofovir alafenamide (TAF) for oral administration. BIC is an integrase strand transfer inhibitor (INSTI). FTC, a synthetic nucleoside analog of cytidine, is an HIV nucleoside analog reverse transcriptase inhibitor (HIV NRTI). TAF, an HIV NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. Each tablet contains 50 mg of BIC (equivalent to 52.5 mg of bictegravir sodium), 200 mg of FTC, and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate) and the following inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose.
COMBINATION_PRODUCTTLD- fixed-drug combination single tablet
Standard of care Dolutegravir-based regimen
Sponsors
Johns Hopkins University
National Institute of Allergy and Infectious Diseases (NIAID)
University of Cape Town
Medical Research Council, South Africa
Centre for the AIDS Programme of Research in South Africa
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
80 participants for the Intervention Arm ART regimen which is a fixed-drug combination of a single tablet co-formulated regimen containing Bictegravir 50mg Emtricitabine 200mg and tenofovir alafenamide 25mg (BIC/FTC/TAF; Biktarvy®) that will be taken twice a day during rifampicin-containing TB treatment and 2 weeks after stopping TB treatment, thereafter the BIC/FTC/TAF single tablet co-formulation will be taken once daily. 40 participants in the Control ARM: Dolutegravir 50mg /Lamivudine 300mg/ Tenofovir 300mg (TLD- fixed-drug combination single tablet) plus Dolutegravir 50mg evening dose during TB treatment and for two weeks after completion of TB treatment, then TLD once daily thereafter- as per Standard of Care (SOC)
Eligibility
Sex/Gender
ALL
Age
18 Years to 105 Years
Healthy volunteers
No
Inclusion criteria
* Adults ≥ 18 years of age with Karnofsky score ≥ 70 * Confirmed rifampicin-susceptible tuberculosis and/or * On first-line rifampicin-based tuberculosis treatment (not \> 8 weeks at the time of enrolment) * Documented HIV-1 infection, ART-naïve OR ART non-naïve (patients to have no exposure to ART medication at least ≥ 3 months at the time of enrollment) * Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m2 * Alanine aminotransferase (ALT) ≤3 times the upper limit of normal (ULN) * Total bilirubin ≤2.5 times ULN * Creatinine ≤2 times ULN * Hemoglobin ≥ 7.0 g/dL (6.5 g/dL for females) * Platelet count ≥ 50,000/mm3 * Absolute Neutrophil Count (ANC) ≥650/mm3 * Able and willing to provide written informed consent * Female patients agree to use both a barrier and a non-barrier form of contraception during the study, starting at least 14 days prior to enrolment
Exclusion criteria
* Pregnancy or breastfeeding (or planned pregnancy within 12 months of study entry) * Prior use of antiretroviral drugs for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) \< 3 months at the time of enrolment * Hepatitis B surface antigen positive OR Hepatitis B virus (HBV) infection OR active systemic infections (other than HIV-1 infection) requiring systemic antibiotic or antifungal therapy current or within 30 days prior to baseline that could, in the opinion of the investigator, interfere with study procedures or assessment of study outcomes * Participants with a CD4+ cell count of \< 50 cells/ μl * Any verified Grade 4 laboratory abnormality, with the exception of, Grade 4 triglycerides. A single repeat test is allowed during the Screening period to verify a result * Patients on metformin (\> 500mg, 12hourly) * Patients with an uncontrolled psychiatric co-morbidity. Patients who, in the investigator's judgment, pose a significant suicidality risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk * Other condition or circumstance deemed by clinician/investigators to be detrimental to patient safety or study conduct * Unwilling to be part of the main pharmacokinetic (PK) study and have PK blood draws done (NB there is a semi-intensive PK substudy which is optional)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Viral Suppression at Week 24 | Week 24 | Viral suppression rate (HIV-1 RNA \<50 copies/mL) at week 24 in the BIC arm (using the FDA snapshot algorithm). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| BIC Drug Concentrations (Area Under the Plasma Concentration Versus Time Curve (AUC) | Week 4, 8, 12, 24,32 and 40 | To assess BIC drug levels (AUC) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion |
| BIC Drug Concentrations [Peak Plasma Concentration (Cmax)] | Week 4, 8, 12, 24, 32 and 40 | To assess BIC drug levels (Cmax) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion |
| BIC Drug Concentrations [Trough/Minimum Plasma Concentration Ctrough) | Week 4, 8 12, 24, 32 and 40 | To assess BIC drug levels ( Ctrough) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion |
| Viral Suppression Rates (HIV-1 RNA <50 Copies/mL) at Weeks 12, 24 and 48 in the DTG Arm and at 12 and 48 Weeks in the BIC Arm | Week 12 and 48 | To characterize viral suppression rates at weeks 12, 24 and 48 in the standard of care treatment (SOC) arm (currently, TDF 300mg/3TC 300mg/DTG 50mg) and at weeks 12 and 48 in the BIC/FTC/TAF arm. |
| The Tolerability of Treatment in Each Arm | Through week 48 | To characterize the tolerability of treatment in each arm by assessing frequency of clinician-initiated treatment interruptions or switches through week 48 |
| Frequency of ART Drug Resistance Mutations in Participants With Detectable Viral Load at Weeks 24 and 48 | Week 24 and 48. | To assess frequency of ART drug resistance mutations in participants with detectable viral load at weeks 24 and 48 |
| The Incidence of TB Associated IRIS | Through week 24 | To assess the incidence of TB associated IRIS in each arm |
Countries
South Africa
Participant flow
Recruitment details
Potential study participants were recruited from pre-approved clinics and hospitals. A pre-screening checklist was utilized by the Recruiters to select potential study participants.
Participants by arm
| Arm | Count |
|---|---|
| BIC Arm The Intervention Arm ART regimen is a fixed-drug combination of a single tablet co-formulated regimen containing Bictegravir 50mg Emtricitabine 200mg and tenofovir alafenamide 25mg (BIC/FTC/TAF; Biktarvy®) that will be taken twice a day during rifampicin-containing TB treatment and 2 weeks after stopping TB treatment, thereafter the BIC/FTC/TAF single tablet co-formulation will be taken once daily. | 80 |
| DTG Arm Dolutegravir 50mg /Lamivudine 300mg/ Tenofovir 300mg (TLD- fixed-drug combination single tablet) plus Dolutegravir 50mg evening dose during TB treatment and for two weeks after completion of TB treatment, then TLD once daily thereafter- as per Standard of Care (SOC) | 42 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | BIC Arm | DTG Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 80 Participants | 42 Participants | 122 Participants |
| Age, median range | 35 years | 35 years | 35 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 80 Participants | 42 Participants | 122 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Africa | 80 Participants | 42 Participants | 122 Participants |
| Sex: Female, Male Female | 25 Participants | 18 Participants | 43 Participants |
| Sex: Female, Male Male | 55 Participants | 24 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 80 | 1 / 42 |
| other Total, other adverse events | 0 / 80 | 0 / 42 |
| serious Total, serious adverse events | 11 / 80 | 3 / 42 |
Outcome results
Primary
Number of Participants With Viral Suppression at Week 24
Viral suppression rate (HIV-1 RNA \<50 copies/mL) at week 24 in the BIC arm (using the FDA snapshot algorithm).
Time frame: Week 24
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BIC Arm | Number of Participants With Viral Suppression at Week 24 | Efficacy in PWH & TB through Week 24 ITT population | 75 Participants |
| BIC Arm | Number of Participants With Viral Suppression at Week 24 | Treatment failure | 0 Participants |
| DTG Arm | Number of Participants With Viral Suppression at Week 24 | Efficacy in PWH & TB through Week 24 ITT population | 40 Participants |
| DTG Arm | Number of Participants With Viral Suppression at Week 24 | Treatment failure | 0 Participants |
Secondary
BIC Drug Concentrations (Area Under the Plasma Concentration Versus Time Curve (AUC)
To assess BIC drug levels (AUC) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion
Time frame: Week 4, 8, 12, 24,32 and 40
Secondary
BIC Drug Concentrations [Peak Plasma Concentration (Cmax)]
To assess BIC drug levels (Cmax) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion
Time frame: Week 4, 8, 12, 24, 32 and 40
Secondary
BIC Drug Concentrations [Trough/Minimum Plasma Concentration Ctrough)
To assess BIC drug levels ( Ctrough) when given twice daily and co-administered with Rifampicin vs. during TB treatment vs when given alone after TB treatment completion
Time frame: Week 4, 8 12, 24, 32 and 40
Secondary
Frequency of ART Drug Resistance Mutations in Participants With Detectable Viral Load at Weeks 24 and 48
To assess frequency of ART drug resistance mutations in participants with detectable viral load at weeks 24 and 48
Time frame: Week 24 and 48.
Secondary
The Incidence of TB Associated IRIS
To assess the incidence of TB associated IRIS in each arm
Time frame: Through week 24
Secondary
The Tolerability of Treatment in Each Arm
To characterize the tolerability of treatment in each arm by assessing frequency of clinician-initiated treatment interruptions or switches through week 48
Time frame: Through week 48
Secondary
Viral Suppression Rates (HIV-1 RNA <50 Copies/mL) at Weeks 12, 24 and 48 in the DTG Arm and at 12 and 48 Weeks in the BIC Arm
To characterize viral suppression rates at weeks 12, 24 and 48 in the standard of care treatment (SOC) arm (currently, TDF 300mg/3TC 300mg/DTG 50mg) and at weeks 12 and 48 in the BIC/FTC/TAF arm.
Time frame: Week 12 and 48