A Phase IIIb Study of the Safety, Efficacy, and Tolerability of Switching to a Fixed-dose Combination of Abacavir/Dolutegravir/ Lamivudine From Current Antiretroviral Regimen

The Food and Drug Administration (FDA) snapshot (Missing, Switch or Discontinuation = Failure) algorithm is intended to be primarily a virologic assessment of the endpoint, and as such follows a "virology first" hierarchy. Virologic Success (e.g., <50 c/mL) or virologic failure within an analysis window is typically determined by the last available HIV-1 RNA measurement in that window and in the treatment phase of interest (e.g., Week 24 snapshot outcomes of the early switch phase will not use HIV-1 RNA data from the late switch phase, even if such data is within the Week 24 analysis window). A virologic failure occurs when a participant changes to their ART regimen (e.g., addition of other ARTs to the study-specified regimens, or switches in components of the current ART regimen).

Change from Baseline in CD4+ cell counts were assessed at Baseline, Weeks 4, 8, 16 and 24. No imputation for missing data or premature discontinuation was performed and the observed values were used. Baseline value is defined as the last pre-treatment value observed. Change from Baseline was calculated as the observed value minus the Baseline value. The Week 24 data were summarized.

Virologic non-responders were defined as the participants with a viral load >=50 c/mL in the Week 24 analysis window. Virologic non-response includes participants who had HIV-1 RNA >=50 c/mL, who discontinued for lack of efficacy, who discontinued for other reasons while not suppressed, data in window but not <50 c/mL, and who changed ART regimen at Week 24. Difference is calculated as the proportion on ABC/DTG/3TC - proportion on current ART regimen.

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, based on medical or scientific judgment and all events of possible drug-induced liver injury with hyperbilirubinemia. The DAIDS table for grading the severity of adult and pediatric AEs was utilized for AE reporting. The DAIDS estimates the severity grade as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (potentially life threatening) for each parameter.

The number of participants with maximum post-Baseline emergent chemistry toxicities for each grade were summarized by parameter. A toxicity is considered emergent if it develops or increases in intensity from Baseline. For participants who were originally randomized to current ART regimen on Day 1 and then switched to ABC/DTG/3TC on Week 24, Baseline is defined as the last non-missing value from the early switch phase and maximum post-Baseline emergent during the late switch phase was determined relative to this Baseline. The DAIDS table for grading the severity of adult and pediatric AEs was utilized for AE reporting. The DAIDS defined the severity grade as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (potentially life threatening) for each parameter.

The number of participants with maximum post-Baseline emergent hematology toxicities for each grade were summarized by parameter. A toxicity is considered emergent if it develops or increases in intensity from Baseline. For participants who were originally randomized to current ART regimen on Day 1 and then switched to ABC/DTG/3TC on Week 24, Baseline is defined as the last non-missing value from the early switch phase and maximum post-Baseline emergent during the late switch phase was determined relative to this Baseline. The DAIDS table for grading the severity of adult and pediatric AEs was utilized for AE reporting. The DAIDS defined the severity grade as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe) and Grade 4 (potentially life threatening) for each parameter.

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, based on medical or scientific judgment and all events of possible drug-induced liver injury with hyperbilirubinemia.

Change from Baseline for each fasting lipid parameters included cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. Adjusted mean is the estimated mean change from Baseline in each parameter at Week 24 in each arm calculated from an analysis of covariance (ANCOVA) model which includes the following covariates: treatment, original ART third agent class, interaction of treatment and original ART 3rd agent, use of lipid modifying agent and Baseline lipid level. Difference is calculated as ABC/DTG/3TC - Current ART regimen. For fasting lipid assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast was acceptable for participants with afternoon appointments.

Change from Baseline for fasting lipid parameter total cholesterol/HDL cholesterol ratio. Adjusted mean is the estimated mean change from Baseline at Week 24 in each arm calculated from an analysis of covariance (ANCOVA) model which includes the following covariates: treatment, original ART third agent class, interaction of treatment and original ART 3rd agent, use of lipid modifying agent and Baseline lipid level. Difference is calculated as ABC/DTG/3TC - Current ART regimen. For fasting lipid assessments, an overnight fast is preferred; however, a minimum of a 6-hour fast was acceptable for participants with afternoon appointments.

The HIV treatment satisfaction questionnaire (TSQ) is a 10 item self-reported scale. Individual item scores range from 6 (very satisfied) to 0 (very dissatisfied). The treatment satisfaction total score (range 0-60) is the sum of all the 10 individual items. The general satisfaction/Clinical subscale (range 0-30) is the sum of the 5 clinical items and the lifestyle/ease subscale (range 0-30) is the sum of the remaining 5 lifestyle items. Last observation carried forward (LOCF) were used for the analysis. If a participant had a missing value at Week 24, his previous non-missing available value while on the same treatment was carried forward (ie the Week 4 or withdrawal value is used in the Week 24 summary for participants in the ABC/DTG3TC with missing Week 24 value). Data were analyzed using an ANCOVA model with factors including treatment, Baseline score and stratification factor. Treatment group difference (ABC/DTG/3TC-cART) estimate and 95% CI were presented.

Renal markers included creatinine and summarized based on an observed case (OC) data set at Week 24. Adjusted mean is the estimated mean change from Baseline in each biomarker at Week 24 in each arm calculated from an ANCOVA analysis of covariance model including the following covariates: treatment, original ART third agent class, interaction of treatment and original ART third agent class, and Baseline biomarker level. Differences are calculated as ABC/DTG/3TC - Current ART regimen.

Renal markers included GFR from creatinine adjusted using chronic kidney disease epidemiology collaboration (CKD-EPI) equation and summarized based on an OC data set at Week 24. Adjusted mean is the estimated mean change from Baseline in each biomarker at Week 24 in each arm calculated from an ANCOVA analysis of covariance model including the following covariates: treatment, original ART third agent class, interaction of treatment and original ART third agent class, and Baseline biomarker level. Differences are calculated as ABC/DTG/3TC - Current ART regimen.

Renal markers included GFR from creatinine adjusted using modification of diet in renal disease (MDRD) enzymatic equation and summarized based on an OC data set at Week 24. Adjusted mean is the estimated mean change from Baseline in each biomarker at Week 24 in each arm calculated from an ANCOVA analysis of covariance model including the following covariates: treatment, original ART third agent class, interaction of treatment and original ART third agent class, and Baseline biomarker level. Differences are calculated as ABC/DTG/3TC - Current ART regimen.

Renal markers included urea and summarized based on an OC data set at Week 24. Adjusted mean is the estimated mean change from Baseline in each biomarker at Week 24 in each arm calculated from an ANCOVA analysis of covariance model including the following covariates: treatment, original ART third agent class, interaction of treatment and original ART third agent class, and Baseline biomarker level. Differences are calculated as ABC/DTG/3TC - Current ART regimen.

Renal markers included urine albumin/creatinine ratioand summarized based on an OC data set at Week 24. Adjusted mean is the estimated mean change from Baseline in each biomarker at Week 24 in each arm calculated from an ANCOVA analysis of covariance model including the following covariates: treatment, original ART third agent class, interaction of treatment and original ART third agent class, and Baseline biomarker level. Differences are calculated as ABC/DTG/3TC - Current ART regimen.

Outcome Measure Description: Bone biomarkers analytes include bone specific alkaline phosphatase, osteocalcin, procollagen 1 n-terminal propeptide, type I collagen c-telopeptides and were analyzed based on log transformed data. Estimates were from an ANCOVA model adjusting for ART third agent class, interaction of treatment and original ART third agent class, age, sex (male or female), body mass index (BMI) (<25 kilogram per meter [kg/m] or >=25 kg/m), smoking status (never smoked or former smoker or current smoker), Baseline vitamin D (no vitamin D use at Baseline or vitamin D use at Baseline), and Baseline biomarker level.

Cardiovascular biomarkers were analyzed based on log transformed data. Estimates were from an ANCOVA model adjusting for ART third agent class, interaction of treatment and original ART third agent class, sex, race (white, black or African American, Other), and Baseline biomarker level.

Cardiovascular biomarkers were analyzed based on log transformed data. Estimates were from an ANCOVA model adjusting for ART third agent class, interaction of treatment and original ART third agent class, sex, race (white, black or African American, Other), and Baseline biomarker level.

Cardiovascular biomarkers were analyzed based on log transformed data. Estimates were from an ANCOVA model adjusting for ART third agent class, interaction of treatment and original ART third agent class, sex, race (white, black or African American, Other), and Baseline biomarker level.

Cardiovascular biomarkers were analyzed based on log transformed data. Estimates were from an ANCOVA model adjusting for ART third agent class, interaction of treatment and original ART third agent class, sex, race (white, black or african american, other), and Baseline biomarker level.

Cardiovascular biomarkers were analyzed based on log transformed data. Estimates were from an ANCOVA model adjusting for ART third agent class, interaction of treatment and original ART third agent class, sex, race (white, black or african american, other), and Baseline biomarker level.

Cardiovascular biomarkers were analyzed based on log transformed data. Estimates were from an ANCOVA model adjusting for ART third agent class, interaction of treatment and original ART third agent class, sex, race (white, black or african american, other), and Baseline biomarker level.

Cardiovascular biomarkers were analyzed based on log transformed data. Estimates were from an ANCOVA model adjusting for ART third agent class, interaction of treatment and original ART third agent class, sex, race (white, black or african american, other), and Baseline biomarker level.

Genotypic and phenotypic testing was conducted for participants who met the confirmed virologic withdrawal criteria, i.e., confirmed HIV-1 RNA >=400 c/mL any time after Day 1. The sample from the "suspected virologic withdrawal criterion" visit was tested for HIV-1 PRO and RT genotype and phenotype and HIV-1 integrase genotype and phenotype (i.e., the first of the two consecutive results >=400 c/mL). At the time of the data cut-off for this Week 24 analysis, no participants met the confirmed virologic withdrawal criteria over 24 weeks; therefore, the virologic analyses were not assessed.