Dolutegravir Compared to Darunavir/Ritonavir , Each in Combination With Dual Nucleoside Reverse Transcriptase Inhibitors (NRTIs) in ART-naive Subjects

Assessment was done using Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm.This algorithm treated all participants without HIV-1 RNA data at Week 48 as nonresponders, as well as participants who switched their concomitant ART prior to Week 48 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment in the snapshot window (Week 48 +/- 6 weeks). Modified Intent-To-Treat Exposed (mITT-E) Population:all randomized participants who received at least one dose of investigational product

The time to viral suppression (i.e. first viral load value <50 copies/mL) through Week 48 was derived and summarized using Kaplan-Meier plots. Participants who withdrew for any reason without having suppressed prior to the analysis were censored. Confidence intervals were estimated using the Brookmeyer-Crowley method.

The percentage of participants with Plasma HIV-1 RNA <400 c/mL at Week 48 was assessed MSDF, as codified by the FDA "snapshot" algorithm. This algorithm treated all participants without HIV-1 RNA data at Week 48 as nonresponders, as well as participants who switched their concomitant ART prior to Week 48 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment in the snapshot window (Week 48 +/- 6 weeks).

Change from Baseline in plasma HIV-1 RNA (log10 c/mL) was assessed at Weeks 4, 8, 12, 16, 24, 36 and 48 . Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different visits, so the overall number of participants analyzed reflects everyone in the mITT-E Population.

Change from Baseline in CD4+ cell counts was assessed at Weeks 4, 8, 12, 16, 36 and 48. Change from Baseline in CD8+ cell counts was assessed at Weeks 4, 12, 24 and 48. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different visits and parameters, so the overall number of participants analyzed reflects everyone in the mITT-E Population.

The number of participants with HIV-1 disease progression (AIDS or death) was assessed per the Centers for Disease Control and Prevention (CDC) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. The CDC classifies HIV infection as Category A (participants with asymptomatic HIV infection, acute HIV infection with accompanying illness, or persistent generalized lymphadenopathy), Category B (participants with symptomatic non-AIDS condition, i.e., conditions that are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection), and Category C (includes AIDS indicator conditions as defined by diagnostic or presumptive measures).

Fasting LDL cholesterol change from Baseline was analyzed. Values represented are for adjusted means. Estimates are calculated from a repeated measures model including the following covariates: treatment, visit, Baseline plasma HIV-1 RNA, background dual NRTI therapy, Baseline LDL cholesterol, treatment*visit interaction and Baseline LDL cholesterol*visit interaction. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants with data available at the specified time points were analyzed.

Hematology and clinical chemistry data were summarized according to the division of AIDS (DAIDS) table for grading the Severity of adverse events, version 1.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for which an increase in fasting LDL cholesterol to Grade 2 or higher occurred. Only those participants with data available at the specified time points were analyzed.

Hematology and clinical chemistry data were summarized according to the division of AIDS (DAIDS) table for grading the Severity of adverse events, version 1.0. Grade 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to Grade 3 or Grade 4 occurred.

An assessment was made of every change across all amino acids within the integrase (IN), reverse transcriptase (RT), and Protease (PRO) encoding region at Baseline and at time of suspected PDVF. PDVF is defined as the confirmed plasma HIV-1 RNA >200 c/mL >=Week 24. PDVF Genotypic Population included all participants in the mITT-E population with available on-treatment genotypic resistance data, at time of PDVF. Only those participants with data available at the specified time points were analyzed.

SDM is a 20-item self-reported measure that addresses the presence and perceived distress linked to symptoms commonly associated with HIV or its treatment. Each item is rated from 0 to 4 where 0 (complete absence of symptom) and 4 (very bothersome symptom). Overall score calculated as the sum of the scores for each of the 20 items of the questionnaire and ranged from 0 (best health) and 80 (worst health). Values represented are for adjusted mean. Estimates are calculated from an ANCOVA model adjusting for age, sex, race, baseline viral load, background dual NRTI therapy and baseline symptom bother score. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. A positive change from Baseline indicates a decline in a participant's quality of life over that period.

The EQ-5D is a 5-question quality of life instrument that provides a utility score and visual analogue scale score that describes the participants' health status. The primary reason for including the EQ-5D is to elicit utility values for potential cost-effectiveness analysis for submission to health technology assessment agencies. The EQ-5D total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome. Values represented are for adjusted mean. Estimates are calculated from an ANCOVA model adjusting for age, sex, race, baseline viral load, background dual NRTI therapy and Baseline EQ-5D utility score. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

The European Quality of Life -5 Dimensions (EQ-5D) is a 5-question quality of life instrument that provides a utility score and visual analogue scale score that describes the participants' health status. The primary reason for including the EQ-5D is to elicit utility values for potential cost-effectiveness analysis for submission to health technology assessment agencies. Thermometer score is based on a visual analogue scale (VAS) ranging from 100 (best imaginable health state) to 0 (worst imaginable health state).Values represented are for adjusted mean. Estimates are calculated from an ANCOVA model adjusting for age, sex, race, Baseline viral load, background dual NRTI therapy and Baseline EQ-5D thermometer score. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

Participant treatment satisfaction was measured using the self-reported scale (HIVTSQ), which consists of 10 items (1-satisfaction, 2-HIV control, 3-adverse effects, 4-level of demand, 5-convenience, 6-flexibility, 7-knowledge, 8-life habits, 9-recommendability, and 10-willingness to continue). Items are scored from 0 (very dissatisfied) to 6 (very satisfied), other than item 4, which has an inverted score from 6 (very demanding) to 0 (very undemanding). The treatment satisfaction score (range: 0-60) was the sum of the individual items. HIVTSQ mITT-E Population=Only participants from USA, France, Germany, Italy, Spain for whom valid translations were available from the mITT-E Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different visits, so the overall number of participants analyzed reflects everyone in the HIVTSQ mITT-E population.

Participant treatment satisfaction was measured using the self-reported scale (HIVTSQ), which consists of 10 items (1-satisfaction, 2-HIV control, 3-adverse effects, 4-level of demand, 5-convenience, 6-flexibility, 7-knowledge, 8-life habits, 9-recommendability, and 10-willingness to continue). Items are scored from 0 (very dissatisfied) to 6 (very satisfied), other than item 4, which has an inverted score from 6 (very demanding) to 0 (very undemanding). The lifestyle/ease score is the sum of items 4, 5, 6, 7 and 8 (range: 0-30). Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different visits, so the overall number of participants analyzed reflects everyone in the HIVTSQ mITT-E population.

Participant treatment satisfaction was measured using the self-reported scale (HIVTSQ), which consists of 10 items (1-satisfaction, 2-HIV control, 3-adverse effects, 4-level of demand, 5-convenience, 6-flexibility, 7-knowledge, 8-life habits, 9-recommendability, and 10-willingness to continue). Items are scored from 0 (very dissatisfied) to 6 (very satisfied), other than item 4, which has an inverted score from 6 (very demanding) to 0 (very undemanding). The convenience score is the score for item 5 (range: 0-6). Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different visits, so the overall number of participants analyzed reflects everyone in the HIVTSQ mITT-E population.