HIV-1/HBV Co-Infection
Conditions
Brief summary
The primary objective of this study is to evaluate the efficacy of fixed-dose combination (FDC) of bictegravir/emtricitabine/ tenofovir alafenamide (B/F/TAF) versus dolutegravir (DTG) + emtricitabine/tenofovir disoproxil fumarate (F/TDF) in treatment-naïve and HIV-1 and hepatitis B virus (HBV) adults.
Interventions
Tablet administered orally once daily, without regard to food
DRUGB/F/TAF
50/200/25 mg B/F/TAF FDC tablet administered orally once daily, without regard to food
DRUGPlacebo to match DTG
Tablet administered orally once daily, without regard to food
DRUGPlacebo to match F/TDF
Tablet administered orally once daily, without regard to food
DRUGDTG
50 mg tablet administered orally once daily, without regard to food
DRUGF/TDF
200/300 mg tablet administered orally once daily, without regard to food
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Human immunodeficiency virus type 1 (HIV-1) co-infection: * Must be HIV antiretroviral treatment naive with plasma HIV-1 ribonucleic acid (RNA) ≥ 500 copies/mL at screening * ≤ 10 days of prior therapy with any antiretroviral agent, including lamivudine and entecavir, following a diagnosis of HIV-1 infection (except the use for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP), up to one month prior to screening) * Screening genotype report must show sensitivity to emtricitabine (FTC) and tenofovir (TFV). This report will be provided by Gilead Sciences. Alternatively, if genotype results from a local laboratory obtained ≤ 90 days prior to screening visit date show sensitivity to these drugs, this genotype will be acceptable to fulfill this inclusion criterion in the event that the genotype obtained at screening is not yet available and all other inclusion/
Exclusion criteria
have been confirmed * HBV co-infection: * Must be hepatitis B virus (HBV) treatment naive (defined as \< 12 weeks of oral antiviral treatment) * Screening HBV deoxyribonucleic acid (DNA) ≥ 2000 IU/mL * Hepatic transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) ≤ 10 x upper limit of normal (ULN) * Total bilirubin ≤ 2.5 x ULN Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm (Co-primary Endpoint) | Week 48 | The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Percentages were rounded-off. |
| Percentage of Participants With Plasma Hepatitis B Virus (HBV) DNA < 29 IU/mL at Week 48 as Defined by Missing = Failure Approach (Co-primary Endpoint) | Week 48 | This outcome measure was analyzed using a Missing = Failure approach. In this approach, all missing data were treated as HBV DNA ≥ 29 IU/mL. Percentages were rounded-off. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in CD4 Cell Count at Week 96 | Baseline, Week 96 | — |
| Change From Baseline in Percentage of CD4 Cells at Week 48 | Baseline, Week 48 | — |
| Change From Baseline in Percentage of CD4 Cells at Week 96 | Baseline, Week 96 | — |
| Percentage of Participants With Plasma HBV DNA < 29 IU/mL at Week 96 | Week 96 | This outcome measure was analyzed using a Missing = Failure approach. In this approach, all missing data were treated as HBV DNA ≥ 29 IU/mL. Percentages were rounded-off. |
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 as Defined by the US FDA-Defined Snapshot Algorithm | Week 96 | The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 96 was analyzed using the snapshot algorithm, which was defined as a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Percentages were rounded-off. |
| Percentage of Participants With ALT Normalization at Week 96 | Week 96 | ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given post baseline visit. The upper limit of the normal range (ULN) for ALT using the 2018 AASLD normal range was ≤ 25 U/L for females and ≤ 35 U/L for males. The Missing = Failure approach was used for this analysis. Percentages were rounded-off. |
| Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48 | Week 48 | HBsAg loss was defined as qualitative HBsAg changing from positive at baseline to negative at a post baseline visit. HBsAg seroconversion was defined as HBsAg loss and HBsAb changes from negative or missing at baseline to positive at a post baseline visit. The Missing = Failure approach was used for this analysis. Percentages were rounded-off. |
| Percentage of Participants With HBsAg Loss at Week 96 | Week 96 | HBsAg loss was defined as qualitative HBsAg changing from positive at baseline to negative at a post baseline visit. HBsAg seroconversion was defined as HBsAg loss and HBsAb changes from negative or missing at baseline to positive at a post baseline visit. The Missing = Failure approach was used for this analysis. Percentages were rounded-off. |
| Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48 by American Association for the Study of Liver Diseases (AASLD) Criteria | Week 48 | ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given post baseline visit. The upper limit of the normal range (ULN) for ALT using the 2018 AASLD normal range was ≤ 25 U/L for females and ≤ 35 U/L for males. The Missing = Failure approach was used for this analysis. Percentages were rounded off. |
| Change From Baseline in CD4 Cell Count at Week 48 | Baseline, Week 48 | — |
Countries
China, Dominican Republic, France, Greece, Hong Kong, Japan, Malaysia, Puerto Rico, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye), United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the North American, Asian, and European regions.
Pre-assignment details
381 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Blinded Phase: B/F/TAF Participants who were HIV-1 and HBV coinfected and treatment-naïve received Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (50/200/25 mg) fixed-dose combination (FDC) tablet orally, once daily without regard to food for 96 weeks. Participants also received placebo to match (PTM) dolutegravir (DTG) tablet and PTM FDC emtricitabine/ tenofovir desoproxil fumarate (F/TDF) tablet orally once daily without regard to food for 96 weeks. | 121 |
| Blinded Phase: DTG + F/TDF Participants who were HIV-1 and HBV coinfected and treatment-naïve received DTG (50 mg) tablet + F/TDF (200/300 mg) FDC tablet, orally, once daily without regard to food for 96 weeks. Participants also received PTM FDC B/F/TAF tablet, orally, once daily without regard to food for 96 weeks. | 122 |
| Total | 243 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Blinded Phase | Adverse Event | 1 | 0 | 0 | 0 |
| Blinded Phase | Death | 2 | 0 | 0 | 0 |
| Blinded Phase | Investigator's Discretion | 2 | 1 | 0 | 0 |
| Blinded Phase | Lost to Follow-up | 3 | 3 | 0 | 0 |
| Blinded Phase | Non-compliance With Study Drug | 0 | 2 | 0 | 0 |
| Blinded Phase | Randomized But Never Treated | 1 | 0 | 0 | 0 |
| Blinded Phase | Withdrew Consent | 2 | 3 | 0 | 0 |
| Open-label Extension Phase | Death | 0 | 0 | 1 | 0 |
| Open-label Extension Phase | Lost to Follow-up | 0 | 0 | 3 | 1 |
Baseline characteristics
| Characteristic | Blinded Phase: B/F/TAF | Total | Blinded Phase: DTG + F/TDF |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 120 Participants | 241 Participants | 121 Participants |
| Age, Continuous | 33 years STANDARD_DEVIATION 9.2 | 33 years STANDARD_DEVIATION 9.3 | 33 years STANDARD_DEVIATION 9.4 |
| CD4 Cell Count | 282 cells/µL STANDARD_DEVIATION 193.1 | 274 cells/µL STANDARD_DEVIATION 193.5 | 266 cells/µL STANDARD_DEVIATION 194.3 |
| CD4 Percentage | 16.0 percentage of CD4 cells STANDARD_DEVIATION 8.62 | 15.4 percentage of CD4 cells STANDARD_DEVIATION 8.44 | 14.8 percentage of CD4 cells STANDARD_DEVIATION 8.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 17 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 114 Participants | 226 Participants | 112 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 108 Participants | 214 Participants | 106 Participants |
| Race/Ethnicity, Customized Race Black | 2 Participants | 8 Participants | 6 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 10 Participants | 19 Participants | 9 Participants |
| Region of Enrollment China | 27 Participants | 56 Participants | 29 Participants |
| Region of Enrollment Dominican Republic | 4 Participants | 10 Participants | 6 Participants |
| Region of Enrollment Hong Kong | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Japan | 2 Participants | 7 Participants | 5 Participants |
| Region of Enrollment Malaysia | 15 Participants | 37 Participants | 22 Participants |
| Region of Enrollment Puerto Rico | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment South Korea | 2 Participants | 2 Participants | 0 Participants |
| Region of Enrollment Spain | 4 Participants | 7 Participants | 3 Participants |
| Region of Enrollment Taiwan | 5 Participants | 12 Participants | 7 Participants |
| Region of Enrollment Thailand | 55 Participants | 94 Participants | 39 Participants |
| Region of Enrollment Turkey | 4 Participants | 9 Participants | 5 Participants |
| Region of Enrollment United States | 1 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Female | 9 Participants | 11 Participants | 2 Participants |
| Sex: Female, Male Male | 112 Participants | 232 Participants | 120 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 122 | 1 / 122 | 1 / 95 | 0 / 89 |
| other Total, other adverse events | 102 / 121 | 98 / 122 | 42 / 95 | 40 / 89 |
| serious Total, serious adverse events | 17 / 121 | 16 / 122 | 4 / 95 | 2 / 89 |
Outcome results
Primary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm (Co-primary Endpoint)
The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Percentages were rounded-off.
Time frame: Week 48
Population: The Full Analysis Set included all participants who were randomized into the study, received at least 1 dose of study drug, and had at least 1 postbaseline HIV-1 RNA or HBV DNA result while on study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinded Phase: B/F/TAF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm (Co-primary Endpoint) | 95.0 percentage of participants |
| Blinded Phase: DTG + F/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Defined by the US FDA-Defined Snapshot Algorithm (Co-primary Endpoint) | 91.0 percentage of participants |
95.001% CI: [-2.5, 10.8]
p-value: 0.2113Cochran-Mantel-Haenszel
Primary
Percentage of Participants With Plasma Hepatitis B Virus (HBV) DNA < 29 IU/mL at Week 48 as Defined by Missing = Failure Approach (Co-primary Endpoint)
This outcome measure was analyzed using a Missing = Failure approach. In this approach, all missing data were treated as HBV DNA ≥ 29 IU/mL. Percentages were rounded-off.
Time frame: Week 48
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinded Phase: B/F/TAF | Percentage of Participants With Plasma Hepatitis B Virus (HBV) DNA < 29 IU/mL at Week 48 as Defined by Missing = Failure Approach (Co-primary Endpoint) | 63.0 percentage of participants |
| Blinded Phase: DTG + F/TDF | Percentage of Participants With Plasma Hepatitis B Virus (HBV) DNA < 29 IU/mL at Week 48 as Defined by Missing = Failure Approach (Co-primary Endpoint) | 43.4 percentage of participants |
95.001% CI: [5.9, 27.3]
p-value: 0.0023Cochran-Mantel-Haenszel
Secondary
Change From Baseline in CD4 Cell Count at Week 48
Time frame: Baseline, Week 48
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinded Phase: B/F/TAF | Change From Baseline in CD4 Cell Count at Week 48 | 200 cells/µL | Standard Deviation 139.3 |
| Blinded Phase: DTG + F/TDF | Change From Baseline in CD4 Cell Count at Week 48 | 175 cells/µL | Standard Deviation 124.7 |
p-value: 0.170195% CI: [-10, 58]ANOVA
Secondary
Change From Baseline in CD4 Cell Count at Week 96
Time frame: Baseline, Week 96
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinded Phase: B/F/TAF | Change From Baseline in CD4 Cell Count at Week 96 | 261 cells/uL | Standard Deviation 161.6 |
| Blinded Phase: DTG + F/TDF | Change From Baseline in CD4 Cell Count at Week 96 | 229 cells/uL | Standard Deviation 174 |
p-value: 0.185395% CI: [-14, 74]ANOVA
Secondary
Change From Baseline in Percentage of CD4 Cells at Week 48
Time frame: Baseline, Week 48
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinded Phase: B/F/TAF | Change From Baseline in Percentage of CD4 Cells at Week 48 | 8.43 percentage of CD4 cells | Standard Deviation 4.1 |
| Blinded Phase: DTG + F/TDF | Change From Baseline in Percentage of CD4 Cells at Week 48 | 7.75 percentage of CD4 cells | Standard Deviation 4.3 |
p-value: 0.283995% CI: [-0.49, 1.67]ANOVA
Secondary
Change From Baseline in Percentage of CD4 Cells at Week 96
Time frame: Baseline, Week 96
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinded Phase: B/F/TAF | Change From Baseline in Percentage of CD4 Cells at Week 96 | 10.69 percentage of CD4 cells | Standard Deviation 5.047 |
| Blinded Phase: DTG + F/TDF | Change From Baseline in Percentage of CD4 Cells at Week 96 | 10.42 percentage of CD4 cells | Standard Deviation 5.096 |
p-value: 0.845695% CI: [-1.2, 1.46]ANOVA
Secondary
Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48 by American Association for the Study of Liver Diseases (AASLD) Criteria
ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given post baseline visit. The upper limit of the normal range (ULN) for ALT using the 2018 AASLD normal range was ≤ 25 U/L for females and ≤ 35 U/L for males. The Missing = Failure approach was used for this analysis. Percentages were rounded off.
Time frame: Week 48
Population: Participants in the Full Analysis Set with Baseline ALT \> ULN were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinded Phase: B/F/TAF | Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48 by American Association for the Study of Liver Diseases (AASLD) Criteria | 73.3 percentage of participants |
| Blinded Phase: DTG + F/TDF | Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48 by American Association for the Study of Liver Diseases (AASLD) Criteria | 55.3 percentage of participants |
p-value: 0.065595% CI: [-1.5, 35.7]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With ALT Normalization at Week 96
ALT normalization was defined as an ALT value that changed from above the normal range at baseline to within the normal range at the given post baseline visit. The upper limit of the normal range (ULN) for ALT using the 2018 AASLD normal range was ≤ 25 U/L for females and ≤ 35 U/L for males. The Missing = Failure approach was used for this analysis. Percentages were rounded-off.
Time frame: Week 96
Population: Participants in the Full Analysis Set with Baseline ALT \> ULN were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinded Phase: B/F/TAF | Percentage of Participants With ALT Normalization at Week 96 | 71.7 percentage of participants |
| Blinded Phase: DTG + F/TDF | Percentage of Participants With ALT Normalization at Week 96 | 57.4 percentage of participants |
p-value: 0.125395% CI: [-4.3, 32.6]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With HBsAg Loss at Week 96
HBsAg loss was defined as qualitative HBsAg changing from positive at baseline to negative at a post baseline visit. HBsAg seroconversion was defined as HBsAg loss and HBsAb changes from negative or missing at baseline to positive at a post baseline visit. The Missing = Failure approach was used for this analysis. Percentages were rounded-off.
Time frame: Week 96
Population: Participants in the Serologically Evaluable Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinded Phase: B/F/TAF | Percentage of Participants With HBsAg Loss at Week 96 | 22.7 percentage of participants |
| Blinded Phase: DTG + F/TDF | Percentage of Participants With HBsAg Loss at Week 96 | 14.0 percentage of participants |
p-value: 0.065595% CI: [-0.7, 19.2]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48
HBsAg loss was defined as qualitative HBsAg changing from positive at baseline to negative at a post baseline visit. HBsAg seroconversion was defined as HBsAg loss and HBsAb changes from negative or missing at baseline to positive at a post baseline visit. The Missing = Failure approach was used for this analysis. Percentages were rounded-off.
Time frame: Week 48
Population: The Serologically Evaluable Full Analysis Set for HBsAg loss/seroconversion included all participants who were in the Full Analysis Set and with HBsAg positive and HBsAb negative or missing at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinded Phase: B/F/TAF | Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48 | 12.6 percentage of participants |
| Blinded Phase: DTG + F/TDF | Percentage of Participants With Hepatitis B Surface Antigen (HBsAg) Loss at Week 48 | 5.8 percentage of participants |
p-value: 0.059195% CI: [-0.8, 15]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 as Defined by the US FDA-Defined Snapshot Algorithm
The percentage of participants achieving HIV-1 RNA \< 50 copies/mL at Week 96 was analyzed using the snapshot algorithm, which was defined as a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. Percentages were rounded-off.
Time frame: Week 96
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinded Phase: B/F/TAF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 as Defined by the US FDA-Defined Snapshot Algorithm | 87.4 percentage of participants |
| Blinded Phase: DTG + F/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 as Defined by the US FDA-Defined Snapshot Algorithm | 87.7 percentage of participants |
p-value: 0.942795% CI: [-8.9, 8.3]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With Plasma HBV DNA < 29 IU/mL at Week 96
This outcome measure was analyzed using a Missing = Failure approach. In this approach, all missing data were treated as HBV DNA ≥ 29 IU/mL. Percentages were rounded-off.
Time frame: Week 96
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinded Phase: B/F/TAF | Percentage of Participants With Plasma HBV DNA < 29 IU/mL at Week 96 | 74.8 percentage of participants |
| Blinded Phase: DTG + F/TDF | Percentage of Participants With Plasma HBV DNA < 29 IU/mL at Week 96 | 70.5 percentage of participants |
Comparison: The difference in percentages of participants with HBV DNA \< 29 IU/mL between treatment groups and its 95% CI were calculated based on the MH proportions adjusted by baseline HBeAg status (positive vs negative) and baseline HBV DNA category (\< 8 log10 IU/mL vs ≥ 8 log10 IU/mL).p-value: 0.636795% CI: [-8.3, 13.4]Cochran-Mantel-Haenszel