HIV Infection
Conditions
Brief summary
HIV-1 infected subjects with CD4 nadir \> 200 cells/mm3, no history of virologic failure and plasma HIV RNA \<50 copies/mL for at least 48 weeks while on any United States Department of Health and Human Services (DHHS) recommended or alternative three-drug antiretroviral regimen will be randomized to dolutegravir (DTG) plus lamivudine (Arm 1) or continuation of their current regimen (Arm 2) for 48 weeks. The primary endpoint is virologic failure defined as confirmed plasma HIV-1 RNA \> 50 copies/mL before or at Week 24
Detailed description
DESIGN HIV-1 infected subjects with CD4 nadir \> 200 cells/mm3, no history of virologic failure and plasma HIV RNA \<50 copies/mL for at least 48 weeks while on any United States Department of Health and Human Services (DHHS) recommended or alternative three-drug antiretroviral regimen will be randomized to dolutegravir (DTG) plus lamivudine (Arm 1) or continuation of their current regimen (Arm 2) for 48 weeks. The primary endpoint is virologic failure defined as confirmed plasma HIV-1 RNA \> 50 copies/mL before or at Week 24 All subjects will undergo routine monitoring including plasma HIV-1 RNA, CD4/CD8 count, hematology, chemistry and fasting lipids. Resistance testing will be done in all patients who experience virologic failure. Single-copy HIV-1 assay will be done to quantify residual viremia. DURATION 48 weeks SAMPLE SIZE 90 subjects POPULATION HIV-1-infected men and women, 18 years and older, with CD4 nadir \> 200 cells/mm3, no baseline resistance, no history of virologic failure, and HIV RNA \<50 copies/mL for at least 48 weeks prior to study entry while on any DHHS recommended or alternative three-drug regimen REGIMEN Subjects will be randomized (1:1) to: Arm 1: dolutegravir 50 mg plus lamivudine 300 mg once daily OR Arm 2: Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Interventions
DRUGdolutegravir
50 mg tablet by mouth once daily for 48 weeks
DRUGlamivudine
300 mg tablet by mouth once daily for 48 weeks
DRUGContinue current antiretroviral regimen
Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Sponsors
ViiV Healthcare
Babafemi Taiwo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-1 Infection * HIV-1 RNA \<50 copies/mL on all measurements within 48 weeks prior to study entry while on any DHHS recommended or alternative three-drug antiretroviral regimen. (A history of switching for simplification and/or tolerability is allowed. At least two measurements within the previous 48 weeks are required prior to study screening.) * No history of virologic failure, defined as consecutive HIV RNA \> 50 copies/mL after 12 months of initiating ART. An isolated (non-consecutive) HIV RNA \> 50 copies/mL (but less than 400 copies/mL) is permitted after 12 months of initiating ART but not in the 48-week window prior to study entry. * Screening plasma HIV RNA \< 20 copies/mL using the COBAS AmpliPrep/COBAS TaqMan HIV-1 Test V2.0, obtained within 45 days prior to study entry * Nadir CD4 count \>200 cells/mm * Pretreatment genotype documenting no mutations in the protease or reverse transcriptase genes * No known resistance to integrase inhibitors * Laboratory values obtained within 45 days prior to study entry: ANC \>750 Hemoglobin \>10 g/dL Platelets \>50,000 Calculated creatinine clearance (CrCl) \>50 mL/min * Negative serum or urine pregnancy test * Men and women age greater or equal to 18 years. * Ability to continue current regimen (i.e, have uninterrupted access) * No evidence of chronic hepatitis B
Exclusion criteria
* Serious illness or AIDS-related complication within 21 days of screening requiring systemic treatment and/or hospitalization * Treatment within 30 days prior to study entry with immune modulators * Vaccination within 7 days * Active HCV treatment or anticipated need for treatment within study period. (HCV infection alone is not exclusionary) * Unstable liver disease or severe hepatic impairment * Known allergy or hypersensitivity to DTG or lamivudine. * Active drug or alcohol use or dependence that could interfere with adherence to study requirements * ALT (alanine aminotransferase) \>5 x ULN (upper limit of normal) OR ALT \>3 x ULN and total bilirubin \>1.5 x ULN (with 35% direct bilirubin)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Treatment Failure | 24 weeks | Proportion of participants with treatment failure (defined as virologic failure (HIV RNA \>50 copies/mL), loss to follow-up, or treatment discontinuation) between those who switch to DTG + lamivudine and those who continue their current ART regimen |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Virologic Success | 48 weeks | Proportion of participants with virologic success (\<50 copies/mL) based on FDA snapshot definition |
| Change in CD4 Count From Baseline to Week 48 | Baseline and 48 weeks | Change in CD4 count between arms will be presented in the attached statistical analysis table |
| Change in Total Cholesterol From Baseline to Week 48 | Baseline and 48 weeks | Change in Total Cholesterol between arms will be presented in the attached statistical analysis table |
| Change in Creatinine Clearance From Baseline to Week 48 | Baseline and Week 48 | Change in Creatinine Clearance between arms will be presented in the attached statistical analysis table |
| Drug Resistance Associated Mutations | 48 weeks | Drug resistance mutations measured by HIV genotyping in patients with confirmed virologic failure |
| Change in LDL Cholesterol From Baseline to Week 48 | Baseline and Week 48 | Change in Low-density lipoprotein (LDL) cholesterol between arms will be presented in the attached statistical analysis table |
Other
| Measure | Time frame | Description |
|---|---|---|
| Residual Viremia by HIV-1 Single-copy Assay | 48 weeks | Difference in HIV-1 detection by the HIV-1 single copy assay between arms will be presented in statistical analysis |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dolutegravir Plus Lamivudine dolutegravir 50 mg plus lamivudine 300 mg once daily
dolutegravir: 50 mg tablet by mouth once daily for 48 weeks
lamivudine: 300 mg tablet by mouth once daily for 48 weeks | 44 |
| Continue Current ART Regimen Continue current DHHS recommended or alternative three-drug antiretroviral regimen
Continue current antiretroviral regimen: Continue current DHHS recommended or alternative three-drug antiretroviral regimen | 45 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
Baseline characteristics
| Characteristic | Dolutegravir Plus Lamivudine | Total | Continue Current ART Regimen |
|---|---|---|---|
| Age, Continuous | 46 years | 47 years | 50 years |
| CD4 Cell Count | 694 cells/mm3 | 680 cells/mm3 | 646 cells/mm3 |
| Current ART Regimen Integrase Inhibitor | 18 Participants | 33 Participants | 15 Participants |
| Current ART Regimen Nonnucleoside reverse transcriptase inhibitor | 12 Participants | 27 Participants | 15 Participants |
| Current ART Regimen Protease Inhibitor | 14 Participants | 29 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 13 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 75 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 34 Participants | 15 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 | 23 Participants | 52 Participants | 29 Participants |
| Sex: Female, Male Female | 5 Participants | 11 Participants | 6 Participants |
| Sex: Female, Male Male | 39 Participants | 78 Participants | 39 Participants |
| Time on Antiretroviral Therapy | 5.28 years | 5.7 years | 6.03 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 45 |
| other Total, other adverse events | 0 / 44 | 3 / 45 |
| serious Total, serious adverse events | 1 / 44 | 2 / 45 |
Outcome results
Primary
Proportion of Participants With Treatment Failure
Proportion of participants with treatment failure (defined as virologic failure (HIV RNA \>50 copies/mL), loss to follow-up, or treatment discontinuation) between those who switch to DTG + lamivudine and those who continue their current ART regimen
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dolutegravir Plus Lamivudine | Proportion of Participants With Treatment Failure | 0.0682 proportion of participants |
| Continue Current ART Regimen | Proportion of Participants With Treatment Failure | 0.0667 proportion of participants |
Comparison: A sample size of 41 participants per arm provided 80% power to show noninferiority of DTG/3TC to cART based on a 12% noninferiority margin, assuming an estimated treatment failure rate of 5% per arm by week 24 and 5% 1-sided type I error rate.90% CI: [-0.098, 0.102]
Secondary
Change in CD4 Count From Baseline to Week 48
Change in CD4 count between arms will be presented in the attached statistical analysis table
Time frame: Baseline and 48 weeks
Population: Population with CD4 count data available at baseline and week 48
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dolutegravir Plus Lamivudine | Change in CD4 Count From Baseline to Week 48 | 39 cells/mm^3 |
| Continue Current ART Regimen | Change in CD4 Count From Baseline to Week 48 | 28 cells/mm^3 |
p-value: 0.866Wilcoxon (Mann-Whitney)
Secondary
Change in Creatinine Clearance From Baseline to Week 48
Change in Creatinine Clearance between arms will be presented in the attached statistical analysis table
Time frame: Baseline and Week 48
Population: Population with creatinine clearance data available at baseline and week 48
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dolutegravir Plus Lamivudine | Change in Creatinine Clearance From Baseline to Week 48 | -4 ml/min |
| Continue Current ART Regimen | Change in Creatinine Clearance From Baseline to Week 48 | 0 ml/min |
p-value: 0.074Wilcoxon (Mann-Whitney)
Secondary
Change in LDL Cholesterol From Baseline to Week 48
Change in Low-density lipoprotein (LDL) cholesterol between arms will be presented in the attached statistical analysis table
Time frame: Baseline and Week 48
Population: Population with LDL cholesterol data available at baseline and week 48
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dolutegravir Plus Lamivudine | Change in LDL Cholesterol From Baseline to Week 48 | 2 mg/dL |
| Continue Current ART Regimen | Change in LDL Cholesterol From Baseline to Week 48 | -3 mg/dL |
p-value: 0.42Wilcoxon (Mann-Whitney)
Secondary
Change in Total Cholesterol From Baseline to Week 48
Change in Total Cholesterol between arms will be presented in the attached statistical analysis table
Time frame: Baseline and 48 weeks
Population: Population with total cholesterol data available at baseline and week 48
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dolutegravir Plus Lamivudine | Change in Total Cholesterol From Baseline to Week 48 | 0 mg/dL |
| Continue Current ART Regimen | Change in Total Cholesterol From Baseline to Week 48 | -1 mg/dL |
p-value: 0.613Wilcoxon (Mann-Whitney)
Secondary
Drug Resistance Associated Mutations
Drug resistance mutations measured by HIV genotyping in patients with confirmed virologic failure
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dolutegravir Plus Lamivudine | Drug Resistance Associated Mutations | 0 Participants |
| Continue Current ART Regimen | Drug Resistance Associated Mutations | 0 Participants |
Secondary
Proportion of Participants With Virologic Success
Proportion of participants with virologic success (\<50 copies/mL) based on FDA snapshot definition
Time frame: 48 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dolutegravir Plus Lamivudine | Proportion of Participants With Virologic Success | 0.9091 proportion of participants |
| Continue Current ART Regimen | Proportion of Participants With Virologic Success | 0.8889 proportion of participants |
95% CI: [-0.126, 0.165]
Other Pre-specified
Residual Viremia by HIV-1 Single-copy Assay
Difference in HIV-1 detection by the HIV-1 single copy assay between arms will be presented in statistical analysis
Time frame: 48 weeks
Population: Participants with HIV-1 single copy assays performed at baseline and week 48 timepoints
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dolutegravir Plus Lamivudine | Residual Viremia by HIV-1 Single-copy Assay | 4.7 copies/mL | Standard Deviation 7 |
| Continue Current ART Regimen | Residual Viremia by HIV-1 Single-copy Assay | 4.2 copies/mL | Standard Deviation 6 |
p-value: 0.7695% CI: [-3, 4.1]Regression, Linear