Trial Outcomes & Findings for Evaluating Once Daily Etravirine in Treatment-Naive Adults With HIV Infection (NCT NCT00959894)

NCT ID: NCT00959894

Last Updated: 2016-06-06

Results Overview

The primary study endpoint was the proportion of participants who achieved HIV-1 RNA \<50 copies/ml at Week 24 of study participation. The per-protocol primary analysis was conducted intention-to-treat, with missing evaluations counted as failures. Achievement of HIV-1 viral load below 50 copies/ml was defined as having HIV-1 RNA \<50 copies/ml during the Week 24 analysis window (\>18 and \<30 weeks post-entry).

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 80 participants
• Primary outcome timeframe: 24 weeks
• Results posted on: 2016-06-06

Participant Flow

80 participants were enrolled, however 1 participant was found to be ineligible on the day of entry and never started study medication (had developed acute renal failure and therefore no longer met eligibility requirements).

Participant milestones

Measure	Etravirine 400 mg Once Daily Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Overall Study STARTED	79
Overall Study COMPLETED	63
Overall Study NOT COMPLETED	16

Reasons for withdrawal

Measure	Etravirine 400 mg Once Daily Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Overall Study Lost to Follow-up	10
Overall Study Adverse Event	3
Overall Study Withdrawal by Subject	1
Overall Study Need for contraindicated medication	1
Overall Study Subject moved out of town	1

Baseline Characteristics

Evaluating Once Daily Etravirine in Treatment-Naive Adults With HIV Infection

Baseline characteristics by cohort

Measure	Etravirine 400 mg Once Daily n=79 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	79 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	29 years n=5 Participants
Sex: Female, Male Female	8 Participants n=5 Participants
Sex: Female, Male Male	71 Participants n=5 Participants
Region of Enrollment United States	79 participants n=5 Participants

PRIMARY outcome

Timeframe: 24 weeks

Population: Of 79 participants who initiated study medications, 74 had a Week 24 HIV-1 RNA measurement. The primary analysis was conducted intention-to-treat, with missing evaluations counted as failure.

The primary study endpoint was the proportion of participants who achieved HIV-1 RNA <50 copies/ml at Week 24 of study participation. The per-protocol primary analysis was conducted intention-to-treat, with missing evaluations counted as failures. Achievement of HIV-1 viral load below 50 copies/ml was defined as having HIV-1 RNA <50 copies/ml during the Week 24 analysis window (>18 and <30 weeks post-entry).

Outcome measures

Measure	Etravirine 400 mg Once Daily n=79 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
The Antiretroviral Activity of Etravirine 400 mg Given Once Daily, With Fixed-dose Truvada Once Daily, Among Treatment-naïve HIV-1 Infected Adults as Measured by the Percentage of Participants With HIV RNA < 50 Copies/mL at Week 24	0.87 proportion of participants Interval 0.78 to 0.94

SECONDARY outcome

Timeframe: 48 weeks

Population: Of 79 participants who initiated study medications, 69 had a Week 48 HIV-1 RNA measurement (4 participants had discontinued the study, 3 were lost to follow-up, and 3 missed the Week 48 visit). The analysis was conducted intention-to-treat, with missing evaluations counted as failure.

This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <50 copies/ml at Week 48 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=79 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
The Proportion of Participants With HIV RNA <50 Copies/mL at Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	0.77 proportion of participants Interval 0.66 to 0.86

SECONDARY outcome

Timeframe: 96 weeks

Population: Of 79 participants who initiated study medications, 63 had a Week 96 HIV-1 RNA measurement (6 participants had discontinued the study and 10 were lost to follow-up). The analysis was conducted intention-to-treat, with missing evaluations counted as failure.

This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <50 copies/ml at Week 96 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=79 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
The Proportion of Participants With HIV RNA <50 Copies/mL at Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	0.71 proportion of participants Interval 0.6 to 0.81

SECONDARY outcome

Timeframe: 24 weeks

Population: Of 79 participants who initiated study medications, 74 had a Week 24 HIV-1 RNA measurement (3 participants had discontinued the study, 1 was lost to follow-up, and 1 missed the Week 24 visit). The analysis was conducted intention-to-treat, with missing evaluations counted as failure.

This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <200 copies/ml at Week 24 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=79 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
The Proportion of Participants With HIV RNA <200 Copies/mL at Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	0.89 proportion of participants Interval 0.79 to 0.95

SECONDARY outcome

Timeframe: 48 weeks

Population: Of 79 participants who initiated study medications, 69 had a Week 48 HIV-1 RNA measurement (4 participants had discontinued the study, 3 were lost to follow-up, and 3 missed the Week 48 visit). The analysis was conducted intention-to-treat, with missing evaluations counted as failure.

This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA <200 copies/ml at Week 48 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=79 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
The Proportion of Participants With HIV RNA <200 Copies/mL at Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	0.82 proportion of participants Interval 0.72 to 0.9

SECONDARY outcome

Timeframe: 96 weeks

Population: Of 79 participants who initiated study medications, 63 had a Week 96 HIV-1 RNA measurement (6 participants had discontinued the study and 10 were lost to follow-up). The analysis was conducted intention-to-treat, with missing evaluations counted as failure.

This secondary outcome assessed the proportion of participants who achieved HIV-1 RNA 200 copies/ml at Week 96 of study treatment. The per-protocol analysis was conducted intention-to-treat, with missing evaluations counted as failures.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=79 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
The Proportion of Participants With HIV RNA <200 Copies/mL at Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	0.77 proportion of participants Interval 0.66 to 0.86

SECONDARY outcome

Timeframe: Baseline to 24 weeks

Population: Of 79 participants who initiated study medications, 73 had a Week 24 CD4+ cell count measurement (4 discontinued study participation prior to Week 24,1 missed the Week 24 visit, and 1 did not have a Week 24 CD4+ cell count measurement).

The per-protocol analysis of change in CD4+ cell count from baseline to Week 24 was calculated using the measurement closest to schedule and within the analysis window, and quantified with an estimated median and distribution-free 95% confidence interval (CI).

Outcome measures

Measure	Etravirine 400 mg Once Daily n=73 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in CD4+ Cell Count From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	156 cells/uL Interval 113.0 to 200.0

SECONDARY outcome

Timeframe: Baseline to 48 weeks

Population: Of 79 participants who initiated study medications, 69 had a Week 48 CD4+ cell count measurement (4 discontinued study participation prior to Week 48 visit, 3 were lost to follow-up, and 3 missed the Week 48 visit).

The per-protocol intention-to-treat analysis of change in CD4+ cell count from baseline to Week 48 was calculated using the measurement closest to schedule and within the analysis window, and quantified with an estimated median and distribution-free 95% CI.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=69 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in CD4+ Cell Count From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	163 cells/uL Interval 136.0 to 203.0

SECONDARY outcome

Timeframe: Baseline to 96 weeks

Population: Of 79 participants who initiated study medications, 63 had a Week 48 CD4+ cell count measurement (6 discontinued study participation prior to Week 96 and 10 were lost to follow-up).

The per-protocol intention-to-treat analysis of change in CD4+ cell count from baseline to Week 96 was calculated using the measurement closest to schedule and within the analysis window, and quantified with an estimated median and distribution-free 95% CI.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=63 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in CD4+ Cell Count From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	224 cells/uL Interval 188.0 to 266.0

SECONDARY outcome

Timeframe: 96 weeks

Population: Of participants with confirmed virologic failure, 8 had HIV-1 RNA levels ≥ 500 copies/mL and 6 of these had viral genotype results available (1 had previously discontinued study medication at Week 2, and 1 was missing).

Per-protocol, genotype testing was conducted at confirmation of virologic failure if the confirmatory HIV-1 RNA was above the laboratory-specified threshold of 500 copies/mL. HIV-1 genotype was determined using the TRUGENE® HIV-1 assay (Siemens Healthcare Diagnostics, Tarrytown, NY)

Outcome measures

Measure	Etravirine 400 mg Once Daily n=6 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Resistance Mutations in the Subset of Patients With Confirmed Virologic Failure Who Have HIV RNA >500 Copies/mL and Genotype Resistance Results Y181C	1 participants
Resistance Mutations in the Subset of Patients With Confirmed Virologic Failure Who Have HIV RNA >500 Copies/mL and Genotype Resistance Results E138K	1 participants
Resistance Mutations in the Subset of Patients With Confirmed Virologic Failure Who Have HIV RNA >500 Copies/mL and Genotype Resistance Results E138K, Y181C, M230L, M184I, K219E, V75I	1 participants
Resistance Mutations in the Subset of Patients With Confirmed Virologic Failure Who Have HIV RNA >500 Copies/mL and Genotype Resistance Results No resistance-associated mutations detected	3 participants

SECONDARY outcome

Timeframe: 96 weeks

Population: The analysis population for this outcome is all participants who received at least one dose of etravirine, regardless of whether or not they were still receiving etravirine at the time of the safety/tolerability event.

The safety/tolerability endpoint was defined as the first grade 3 or higher sign, symptom or laboratory abnormality that was at least one grade higher than baseline among participants ever exposed to etravirine (regardless of treatment status), or permanent discontinuation of etravirine due to any toxicity (regardless of grade). Modification of tenofovir/emtricitabine was not a safety/tolerability event.

The Kaplan-Meier method was used to estimate the proportion of participants ever exposed to etravirine who remained event-free through Week 96, with a 95% CI using Greenwood's variance estimate and a log-log transformation. Time was handled as continuous (weeks from treatment start to event or censoring).

Outcome measures

Measure	Etravirine 400 mg Once Daily n=79 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Tolerability of Etravirine in HIV-1 Infected Adults Initiating Antiretroviral Therapy At least one safety/tolerability event	23 participants
Tolerability of Etravirine in HIV-1 Infected Adults Initiating Antiretroviral Therapy Signs or Symptoms	13 participants
Tolerability of Etravirine in HIV-1 Infected Adults Initiating Antiretroviral Therapy Laboratory Abnormalities	10 participants

SECONDARY outcome

Timeframe: 96 weeks

Population: The analysis population for this outcome is all participants who received at least one dose of etravirine, regardless of whether or not they were still receiving etravirine at the time of the safety/tolerability event.

The Kaplan-Meier method was used to estimate the proportion of participants ever exposed to etravirine who remained event-free through Week 96, with a 95% CI using Greenwood's variance estimate and a log-log transformation. Time was handled as continuous (weeks from treatment start to event or censoring).

Outcome measures

Measure	Etravirine 400 mg Once Daily n=79 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Probability of Remaining Free of a Safety/Tolerability Event at 96 Weeks	0.69 proportion of participants Interval 0.57 to 0.78

SECONDARY outcome

Timeframe: Baseline to 24 weeks

Population: This per-protocol sub-study analysis of metabolic outcomes was conducted in the as-treated population in the metabolic sub-study.

Metabolic data analyses were conducted as-treated. Changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting blood glucose from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=36 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Total cholesterol	-7 mg/dL Interval -17.0 to 4.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine HDL-cholesterol	1 mg/dL Interval -4.0 to 9.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine LDL-cholesterol	-9 mg/dL Interval -14.0 to -1.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Triglycerides	-16 mg/dL Interval -33.0 to 18.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Fasting glucose	1 mg/dL Interval -6.0 to 9.0

SECONDARY outcome

Timeframe: Baseline to 24 weeks

Population: This per-protocol sub-study analysis of metabolic outcomes was conducted in the as-treated population in the metabolic sub-study.

Metabolic data analyses were conducted as-treated. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5. Changes from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=27 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in Glucose Metabolism (Insulin Resistance), in a Subgroup of up to 40 Participants, From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	-0.08 µU/ml*mmol/L Interval -0.72 to 0.27

SECONDARY outcome

Timeframe: Baseline to 48 weeks

Population: This per-protocol sub-study analysis of metabolic outcomes was conducted in the as-treated population in the metabolic sub-study.

Metabolic data analyses were conducted as-treated. Changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting blood glucose from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=32 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Total cholesterol	6 mg/dL Interval -14.0 to 21.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine HDL-cholesterol	5 mg/dL Interval -2.0 to 12.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine LDL-cholesterol	-1 mg/dL Interval -10.0 to 14.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Triglycerides	-10 mg/dL Interval -26.0 to 21.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Fasting glucose	2 mg/dL Interval -5.0 to 6.0

SECONDARY outcome

Timeframe: Baseline to 48 weeks

Population: This per-protocol sub-study analysis of metabolic outcomes was conducted in the as-treated population in the metabolic sub-study.

Metabolic data analyses were conducted as-treated. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5. Changes from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=23 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in Glucose Metabolism (Insulin Resistance), in a Subgroup of up to 40 Participants, From Baseline to Week 48 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	0.71 µU/ml*mmol/L Interval -0.01 to 2.21

SECONDARY outcome

Timeframe: Baseline to 96 weeks

Population: This per-protocol sub-study analysis of metabolic outcomes was conducted in the as-treated population in the metabolic sub-study.

Metabolic data analyses were conducted as-treated. Changes in total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting blood glucose from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=22 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Total cholesterol	6 mg/dL Interval -14.0 to 21.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine HDL-cholesterol	4 mg/dL Interval -3.0 to 15.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine LDL-cholesterol	-5 mg/dL Interval -26.0 to 7.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Triglycerides	3 mg/dL Interval -18.0 to 16.0
Change in the Lipid Profile and Glucose Metabolism, in a Subgroup of up to 40 Participants, From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Fasting glucose	2 mg/dL Interval -6.0 to 6.0

SECONDARY outcome

Timeframe: Baseline to 96 weeks

Population: This per-protocol sub-study analysis of metabolic outcomes was conducted in the as-treated population in the metabolic sub-study.

Metabolic data analyses were conducted as-treated. Insulin resistance was estimated by the homeostasis model assessment of insulin resistance (HOMA-IR), and was calculated as [fasting insulin (µU/mL) × fasting glucose (mmol/L)]/22.5. Changes from baseline to follow-up were calculated using the value closest to schedule and within the analysis window, and were quantified with the median and inter-quartile range.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=18 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in Glucose Metabolism (Insulin Resistance), in a Subgroup of up to 40 Participants, From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	0.23 µU/ml*mmol/L Interval -0.67 to 1.15

SECONDARY outcome

Timeframe: Baseline to 24 weeks

Population: This per-protocol sub-study analysis was conducted in the as-treated population of participants in the metabolic sub-study.

Changes from baseline to follow-up in limb fat, trunk fat, total body fat, and lean mass were calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=37 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in Limb and Trunk Fat Distribution as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Total body fat	0.43 percentage of body fat Interval -0.63 to 1.1
Change in Limb and Trunk Fat Distribution as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Limb fat	0.48 percentage of body fat Interval -0.64 to 0.99
Change in Limb and Trunk Fat Distribution as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Trunk fat	0.32 percentage of body fat Interval -0.41 to 1.66

SECONDARY outcome

Timeframe: Baseline to 96 weeks

Population: This per-protocol sub-study analysis was conducted in the as-treated population of participants in the metabolic sub-study.

Changes from baseline to follow-up in limb fat, trunk fat, total body fat, and lean mass were calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=25 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in Limb and Trunk Fat Distribution as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Total body fat	1.44 percentage of body fat Interval -0.4 to 3.86
Change in Limb and Trunk Fat Distribution as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Limb fat	0.82 percentage of body fat Interval -1.55 to 4.12
Change in Limb and Trunk Fat Distribution as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine Trunk fat	1.93 percentage of body fat Interval 0.31 to 4.67

SECONDARY outcome

Timeframe: Baseline to 24 weeks

Population: This per-protocol sub-study analysis was conducted in the as-treated population of participants in the metabolic sub-study.

Change from baseline to follow-up in fat mass ratio was calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Fat mass ratio was calculated as the ratio of trunk fat percentage and lower limb fat percentage (% trunk fat mass / % lower limb fat mass). Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=37 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in Fat Mass Ratio as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 24 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	0.02 ratio of trunk fat % : lower limb fat % Interval -0.01 to 0.09

SECONDARY outcome

Timeframe: 4 weeks

Population: Of 79 participants who initiated study medications, 14 provided paired plasma and genital secretion samples. The goal was to enroll a total of 20 participants (10 men and 10 women) into the genital secretion sub-group, however no women enrolled into this subgroup. Data are presented for semen and plasma etravirine concentrations for 14 men.

This secondary outcome measure assessed the ratio of semen:plasma concentration of etravirine in paired semen and plasma samples collected from 14 male participants at Week 4 of treatment with etravirine and fixed dose tenofovir/emtricitabine.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=14 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Pharmacokinetics of Etravirine in Genital Secretions of up to 10 Men and up to 10 Women at Week 4 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	0.192 ratio of semen:plasma drug concentration Interval 0.138 to 0.309

SECONDARY outcome

Timeframe: Baseline to 96 weeks

Population: This per-protocol sub-study analysis was conducted in the as-treated population of participants in the metabolic sub-study.

Change from baseline to follow-up in fat mass ratio was calculated. Whole body Dual X-ray Absorptiometry (DEXA) scans (Hologic Discovery W, Hologic Inc., Bedford, MA) were conducted at baseline, Week 24, and Week 96 to assess body fat distribution. Fat mass ratio was calculated as the ratio of trunk fat percentage and lower limb fat percentage (% trunk fat mass / % lower limb fat mass). Calculations of change from baseline to follow-up used the value closest to schedule and within the analysis window, and were quantified with the estimated median and distribution-free 95% CI.

Outcome measures

Measure	Etravirine 400 mg Once Daily n=25 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Change in Fat Mass Ratio as Measured by DEXA Scan, in the Same Subgroup of up to 40 Participants (as in Aim 8), From Baseline to Week 96 of Treatment With Etravirine and Fixed-dose Tenofovir/Emtricitabine	0.06 ratio of trunk fat % : lower limb fat % Interval 0.02 to 0.09

SECONDARY outcome

Timeframe: At or after 4 weeks

Population: 57 participants who provided samples at multiple time points relative to etravirine dosing.

Population pharmacokinetics were calculated using sparse sampling. Plasma concentrations of etravirine measured in samples from participants who provided blood samples at multiple study visits, with variation in sampling times relative to dosing of etravirine used to cover the spectrum of the dosing schedule. Model simulations and fitting were performed with NONMEM ® 7.3. (ICON, plc) and model exploration was performed with Berkeley Madonna (Berkeley, CA, USA)

Outcome measures

Measure	Etravirine 400 mg Once Daily n=57 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Population Pharmacokinetics of Etravirine 400 mg Once Daily, in Combination With Fixed-dose Emtricitabine-tenofovir Among Treatment-naïve HIV-1 Infected Adults Etravirine trough plasma concentration	217.47 ng/mL Interval 154.29 to 295.31
Population Pharmacokinetics of Etravirine 400 mg Once Daily, in Combination With Fixed-dose Emtricitabine-tenofovir Among Treatment-naïve HIV-1 Infected Adults Etravirine peak plasma concentration	480.99 ng/mL Interval 416.77 to 559.49

SECONDARY outcome

Timeframe: At or after 4 weeks

Population: 57 participants who provided samples at multiple time points relative to etravirine dosing.

Population pharmacokinetics were calculated using sparse sampling. Plasma concentrations of etravirine measured in samples from participants who provided blood samples at multiple study visits, with variation in sampling times relative to dosing of etravirine used to cover the spectrum of the dosing schedule. Model simulations and fitting were performed with NONMEM ® 7.3. (ICON, plc) and model exploration was performed with Berkeley Madonna (Berkeley, CA, USA)

Outcome measures

Measure	Etravirine 400 mg Once Daily n=57 Participants Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Population Pharmacokinetics of Etravirine 400 mg Once Daily, in Combination With Fixed-dose Emtricitabine-tenofovir Among Treatment-naïve HIV-1 Infected Adults: Etravirine AUC-24 Hours at Steady State	8024.40 ng*hr/mL Interval 6410.2 to 9968.28

Adverse Events

Etravirine 400 mg Once Daily

Serious events: 12 serious events

Other events: 17 other events

Deaths: 0 deaths

Serious adverse events

Measure	Etravirine 400 mg Once Daily n=79 participants at risk Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Gastrointestinal disorders Vomiting	1.3% 1/79 • Number of events 2 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Gastrointestinal disorders Viral gastroenteritis	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Gastrointestinal disorders Colitis	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Renal and urinary disorders Renal impairment	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Nervous system disorders Meningitis	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Infections and infestations Cellulitis	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Surgical and medical procedures Osteoplasty of the mandible	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Surgical and medical procedures Hip arthroplasty	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Surgical and medical procedures Prostatectomy	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Infections and infestations Disseminated atypical mycobacterium infection	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) malignant melanoma of skin	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Psychiatric disorders Depressive disorder	1.3% 1/79 • Number of events 1 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.

Other adverse events

Measure	Etravirine 400 mg Once Daily n=79 participants at risk Etravirine 400 mg once daily with fixed dose tenofovir/emtricitabine (Truvada) one tablet once daily Etravirine (Intelence): Etravirine 400 mg (four 100 mg or two 200 mg tablets) taken orally once a day with one pill of Truvada (200 mg of emtricitabine and 300 mg of tenofovir) taken orally once a day
Skin and subcutaneous tissue disorders Rash	6.3% 5/79 • Number of events 5 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Hepatobiliary disorders Elevated level of transaminase	11.4% 9/79 • Number of events 13 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Hepatobiliary disorders Hyperbilirubinemia	7.6% 6/79 • Number of events 20 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Blood and lymphatic system disorders Neutropenia	5.1% 4/79 • Number of events 8 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
General disorders Fatigue	5.1% 4/79 • Number of events 4 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Gastrointestinal disorders vomiting	5.1% 4/79 • Number of events 4 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
General disorders Headache	5.1% 4/79 • Number of events 4 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Endocrine disorders Hyperglycemia	5.1% 4/79 • Number of events 7 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.
Metabolism and nutrition disorders Hyperlipidemia	7.6% 6/79 • Number of events 9 • Up to 96 weeks for each participant Participants were assessed for adverse events routinely every 4 weeks in first 3 months and every 12 weeks thereafter, by standardized interview \& clinical/lab exam. Labs, rash \& central nervous system symptoms Grade 2 or above, other symptoms above Grade 2, and any symptom that led to change in study treatment were recorded in the database.

Additional Information

Michelle Floris-Moore, M.D., M.S.

UNC School of Medicine

Phone: 919-966-2537

Email: mfloris@med.unc.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place